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Exploring the Biological Contributions to Human Health Does Sex Matter? Committee on Understanding the Biology of Sex and Gender Differences Theresa M. Wizemann and Mary-Lou Pardue, Editors Board on Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, DC 20418 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 U.S. Department of Health and Human Services (Office on Women's Health, National Institutes of Health Office of Research on Women's Health, National Institute of Environmental Health Sciences, National Institute on Drug Abuse, National Institute of Mental Health, U.S. Food and Drug Administration, Centers for Disease Control and Prevention), the National Science Foundation, the Environ- mental Protection Agency, the National Aeronautics and Space Administration, the Society for Women's Health Research, the Research Foundation for Health and Environmental Effects, Ortho-McNeil/Johnson & Johnson, and the Unilever United States Foundation. The views presented in this report are those of the Committee on Understanding the Biology of Sex and Gender Differences and are not necessarily those of the funding organizations. Library of Congress Cataloging-in-Publication Data Institute of Medicine (U.S.~. Committee on Understanding the Biology of Sex and Gender Differences. Exploring the biological contributions to human health: does sex matter? / Committee on Understanding the Biology of Sex and Gender Differences; Theresa M. Wizemann and Mary-Lou Pardue, editors. p. ; cm. Includes bibliographical references and index. ISBN 0-309-07281-6 (hardcover) 1. Sex differences. 2. Sex factors in disease. [DNLM: 1. Sex Factors. 2. Genetics, Biochemical. 3. Health. 4. Research Design standards. 5. Sex Characteristics. QZ 53 I59e 2001] I. Wizemann, Theresa M. II. Pardue, Mary Lou. III. Title. QP81.5 .156 2001 616'.001'57846 dc21 2001002537 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's home page at www.nap.edu. The full text of this report is available at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2001 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Cover photograph: Human X and Y Chromosomes (magnified 35,000 times). Source: Biophoto Associates, Photo Researchers, Inc.

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"I(nowing is not enough; we invest apply. Willing is not enough; we invest do." Goethe ............. .......... -.-- .-.- ....... .... . .. . . ....... I NSTITUTE OF MEDICI N E Shaping the Future for Health

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National Acaclemy of Sciences National Acaclemy of Engineering Institute of Meclicine National Research Council 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. William 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. Kenneth I. Shine 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 services to the government, the public, and the scientific and engineering commu- nities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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COMMITTEE ON UNDERSTANDING THE BIOLOGY OF SEX AND GENDER DIFFERENCES MARY-LOU PARDUE (Chair), Boris Magasanik Professor, Department of Biology, Massachusetts Institute of Technology, Cambridge DANIEL L. AZARNOFF, President, D. L. Azarnoff Associates, and Senior Vice President, Clinical/Regulatory Affairs, Cellegy Pharmaceuticals, South San Francisco SHERI BERENBAUM, Professor, Department of Physiology, Southern Illinois University School of Medicine, Carbondale KAREN I. BERKLEY, McKenzie Professor, Program in Neuroscience, Florida State University, Tallahassee ANNE FAUSTO-STERLING, Professor of Biology and Women's Studies, Senior Fellow, Francis Wayland Collegium, Brown University, Providence DANIEL D. FEDERMAN, Senior Dean for Alumni Relations and Clinical Teaching, Carl W. Walter Professor of Medicine and Medical Education, Harvard Medical School, Boston BARBARA ANN GILCHREST, Professor and Chairman, Department of Dermatology, Boston University, Boston MELVIN M. GRUMBACH, Edward B. Shaw Professor of Pediatrics, University of California San Francisco School of Medicine, San Francisco SHIRIKI KUMANYIKA, Associate Dean, Health Promotion and Disease Prevention, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia JUDITH H. LaROSA, Professor, Department of Preventive Medicine and Community Health, State University of New York Downstate Medical Center at Brooklyn, Brooklyn MICHAEL D. LOCKSHIN, Director, Barbara Volcker Center for Women and Rheumatic Disease, Hospital for Special Surgery, and Professor of Medicine, Weill College of Medicine of Cornell University, New York JILL PANETTA, Senior Research Scientist, Research Manager, Lilly Center for Women's Health, Eli Lilly & Company, Indianapolis CARMEN SAPIENZA, Professor of Pathology, Temple University School of Medicine, Philadelphia SALLY E. SHAYWITZ, Professor of Pediatrics, Yale University School of Medicine, New Haven JOHN G. VANDENBERGH, Professor, Department of Zoology, North Carolina State University, Raleigh v

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HUNTINGTON F. WILLARD, President and Director, Research Institute of University Hospitals of Cleveland; Director, Center for Human Genetics, University Hospitals of Cleveland; and Professor, Department of Genetics, Case Western Reserve University, Cleveland Board on Health Sciences Policy Liaison MARY WOOLLEY, President, Research!America, Washington, D.C. IOM Project Staff THERESA M. WIZEMANN, Study Director THELMA COX, Project Assistant SARAH PITLUCK, Research Associate (through rune 2000) IOM Staff ANDREW POPE, Director, Board on Health Sciences Policy ALDEN CHANG, Administrative Assistant DALIA GILBERT, Senior Project Assistant CARLOS GABRIEL, Financial Associate MICHAEL EDINGTON, Managing Editor (through February 2001) Copy Editor MICHAEL K. HAYES Consultant KATHI MANNA Al

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with pro- cedures approved by the National Research Council's (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: LESLIE Z. BENET, Professor, Department of Biopharmaceutical Sciences, University of California, San Francisco DAVID P. CREWS, Ashbel Smith Professor of Zoology and Psychology, University of Texas at Austin ALICE EAGLY, Professor, Department of Psychology, Northwestern University, Evanston, IL SHERINE E. GABRIEL, Director, Center for Patient Oriented Research, Mayo Clinic, Rochester, MN JANET S. HYDE, Chair, Department of Psychology, University of Wisconsin at Madison ELEANOR E. MACCOBY, Professor Emeritus, Department of Psychology, Stanford University, Stanford v''

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V111 REVIEWERS BRUCE S. MCEWEN, Alfred E. Mirsky Professor, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York RUTH B. MERKATZ, Director/Team Leader Pfizer Women's Health, Pfizer Inc., New York, Associate Clinical Professor, Albert Einstein College of Medicine, New York HARRY OSTRER, Associate Professor and Director of Human Genetics Program, Department of Pediatrics, New York University School of Medicine, New York ORA H. PESCOVITZ, Section Director of Pediatrics, Edwin Letzter Professor of Pediatrics, Indiana University, Indianapolis DAVID S. PISETSKY, Professor of Medicine and Professor of Immunology, Duke University Medical Center, Durham, NC CHRISTINE E. SEIDMAN, Professor, Department of Genetics, Harvard Medical School, Boston CAROLINE C. WHITACRE, Professor and Chair, Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus 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 ELIZABETH BARRETT-CONNOR, Professor and Chief, Division of Epidemiology, University of California, San Diego, appointed by the Institute of Medi- cine, and BARBARA CALEEN HANSEN, Professor of Physiology and Director, Obesity and Diabetes Research Center, University of Maryland School of Medicine at Baltimore, appointed by the NRC's Report Review Committee, who were responsible for making certain that an indepen- dent examination of this report was carried out in accordance with insti- tutional procedures and that all review comments were carefully consid- ered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Preface Does sex matter? Almost anyone would answer "yes" to this simple question. However, subsumed within this question are two much more difficult questions: When does sex matter? and How does sex matter? These two questions define the task undertaken by the Committee on Understanding the Biology of Sex and Gender Differences. This commit- tee was charged with evaluating the current scientific understanding of the answers to these questions with respect to their influence on human health. Specifically, the committee was charged with considering biology at the cellular, developmental, organ, organismal, and behavioral levels. The goal, as in all studies of biology, is to understand the organism in terms of all of the interactions that occur between levels within the organism as well as the mutual interactions between the organism and its environ- ment. This was a broad charge, which required a committee made up of individuals drawn from a wide range of subfields of biology and medi- cine. We have learned much from each other and from a number of in- vited speakers specializing in fields in which the committee did not have expertise. We also made an extensive survey of the relevant literature. The most obvious and best-studied differences between the sexes are in the reproductive systems. Much less work has been done on sex differ- ences in nonreproductive areas of biology, and this is where the commit- tee has focused its efforts. Differences are much less expected in nonre- productive areas of biology, but differences do occur, and some of these differences have important consequences. Understanding these differ- IX

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x PREFACE ences makes it possible to design health care more effectively for indi- viduals, both males and females. An additional and more general reason for studying differences be- tween the sexes is that these differences, like other forms of biological variation, can offer important insights into underlying biological mecha- nisms. An often-quoted piece of advice to those studying biology is to "cherish your exceptions." These exceptions traditionally include organ- isms with mutations and organisms from different species that accom- plish the same goal in slightly modified ways. Only relatively recently has it been recognized that sexual variations are as important as these excep- tions in providing similarities and contrasts that can reveal important details about the processes involved. This is an especially opportune time to take stock of what is known about differences and similarities in the basic biology of the sexes, be- cause in the last few years biological research has acquired an arsenal of powerful tools that can be used to answer new questions. Reviews like the one presented in this report juxtapose knowledge from different sub- fields, create new connections between subfields, and inevitably, raise new questions. The arsenal of new tools enables us to answer questions that only a short time ago seemed impossible to answer. The picture that emerges from the study described in this report shows that there are numerous sex differences in nonreproductive tis- sues. Some of these differences can be explained by what we now know. Some are unexplained and point to important questions for future study. Some are large and have known effects on the health of individuals; these differences have immediate consequences in terms of health care. Some of the differences are small, with no known effects on health, but they may provide clues that can be used to solve new biological questions. This report provides a broad view of the research and issues that the commit- tee considered. It is, of necessity, a summary with a small number of examples chosen to illustrate the points that we make and to convey the interesting science that is being done in these areas. Sex does matter. It matters in ways that we did not expect. Undoubt- edly, it also matters in ways that we have not begun to imagine. Mary-Lou Pardue, Ph.D. Chair

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Acknowledgments The committee is indebted to the experts in many scientific disci- plines who presented informative talks to the committee and participated in lively discussions (see Appendix A). In addition, the committee is grate- ful to the members of the scientific community who made themselves available by phone and e-mail for consultation and technical advice. The committee also wishes to thank the Institute of Medicine staff who contributed to the report. Theresa Wizemann has done a superb job as study director. Thelma Cox has taken very good care of the committee, in spite of severe weather conditions at two of the meetings that pre- sented challenges to her management skills. Sarah Pitluck provided able assistance in the early part of the study and Dalia Gilbert assisted in the later stages. Kathi Hanna, Michael Hayes, and Michael Edington pro- vided helpful style guidance and technical editing. Valerie Setlow helped guide the early development stages of the project. The committee thanks Andrew Pope, Director of the Board on Health Sciences Policy for his continuing interest in this work and guidance throughout the process. Many thanks go to Bruce Alberts, President of the National Academy of Sciences and Chair of the National Research Council, and Ken Shine, President of the Institute of Medicine, for advice and guidance in focusing the task. Thanks also go to the staff of the National Research Council Board on Biology for helpful suggestions and nominations of committee members and reviewers. This report was made possible by the generous support of 14 spon- sors: U.S. Department of Health and Human Services (Office on Women's Health, National Institutes of Health Office of Research on Women's Xl

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X11 ACKNOWLEDGMENTS Health, National Institute of Environmental Health Sciences, National Institute on Drug Abuse, National Institute of Mental Health, U.S. Food and Drug Administration, Centers for Disease Control and Prevention), the National Science Foundation, the Environmental Protection Agency, the National Aeronautics and Space Administration, the Society for Women's Health Research, the Research Foundation for Health and Envi- ronmental Effects, Ortho-McNeil/Iohnson & Johnson, and the Unilever United States Foundation. Special thanks go to Phyllis Greenberger of the Society for Women's Health Research, Vivian Pinn of the National Insti- tutes of Health Office of Research on Women's Health, and Susan Wood, formerly of the Office on Women's Health of the U.S. Department of Health and Human Services for their persistence and vision in develop- ing the proposal for this study.

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Contents ABSTRACT EXECUTIVE SUMMARY 1 INTRODUCTION Scope of the Report, 14 Sex Differences Beyond the Reproductive System, 19 Evolving Research Policy, 21 Organization of Report, 26 2 EVERY CELL HAS A SEX Sex and the Human Genome, 29 Basic Molecular Genetics: What Is the Potential for Differences Between the Sexes?, 32 Effects of Parental Imprinting on the Expression of Genetic Information, 40 Unexpected or Nonobvious Sex Differences, 41 Genetics as a Tool, 42 Findings and Recommendations, 44 3 SEX BEGINS IN THE WOMB Biology of Sex, 46 Early Development, 50 Puberty, 62 Adulthood, 72 Findings and Recommendations, 77 . . . x''' ax 1 13 28 45

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xIv 4 SEX AFFECTS BEHAVIOR AND PERCEPTION Sex Differences in Behavior and Cognitive Abilities, 79 Effects of Hormones on Behavior and Cognition, 89 Sex Differences in Perception of Pain, 105 Animal Models of Cerebrovascular and Cardiovascular Diseases, 112 Findings and Recommendations, 115 5 SEX AFFECTS HEALTH Sex Differences in Response to Therapeutic Agents: Diagnostic and Therapeutic Interventions, 118 Metabolism, Lifestyle, and Physical Performance, 130 Sex Differences in Autoimmune Conditions, 142 A Spectrum of Sex Differences Across a Disease: Coronary Heart Disease, 158 Findings and Recommendations, 170 CONTENTS 79 117 6 THE FUTURE OF RESEARCH ON BIOLOGICAL SEX DIFFERENCES: CHALLENGES AND OPPORTUNITIES 173 Terminology, 174 Research Tools and Resources, 176 Interdisciplinary and Collaborative Research, 181 Non-Health-Related Implications of Research on Sex Differences in Health, 183 REFERENCES APPENDIXES A Data Sources and Acknowledgments B Physiological and Pharmacological Differences Between the Sexes C Glossary D Committee and Staff Biographies INDEX TABLES, FIGURES, AND BOXES Tables 3-1 Some Genes Involved in Human Sex Determination, 53 3-2 Selected Examples of Variations in Sexual Differentiation, 63 185 229 233 239 243 255

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CONTENTS 3-3 Life Expectancy at Birth, Age 65, and Age 75 Years, United States, All Races, 1998, 75 xv Sex Prevalence of Some Common Painful Syndromes and Potential Contributing Causes, 106 A Growing List of Therapies for Pain, 110 Sex-Specific Responses to an Experimental Traumatic or Ischemic Cerebral Insult, 113 5-1 Factors Affecting Absorption of Chemicals, 120 5-2 Differences in Drug Concentrations Between the Mother and Fetus and Between Males and Females, 124 5-3 Receptor, Enzyme, and Structural Differences Between Males and Females, 128 5-4 Obesity Prevalence Data for Selected U.S. Adults, by Sex, 135 5-5 Sex Differences in Immunocytes as Determined in Representative Recent Studies, 145 5-6 Sex Differences in Immunization, 146 5-7 Sex Differences in Viral Infections in Humans, 148 5-8 Sex Differences in Mycobacterial, Fungal, and Parasitic Diseases, 149 5-9 Female/Male Ratios Associated with Common Autoimmune Diseases, 150 5-10 Autoimmune Diseases in Which Environmental Triggers Are Prominent, 151 5-11 Peak Ages of Various Autoimmune Diseases, 154 5-12 Animal Models of Human Autoimmune Diseases, 156 5-13 Estimated Risk of Symptoms of Coronary Heart Disease and Death from Myocardial Infarction in Heterozygotes at Different Ages, 160 5-14 Smoking Prevalence by Race and Sex, 1998, 163 5-15 Complications of Acute Myocardial Infarctions, by Sex, 167 5-16 Male: Female Odds Ratios for Use of Diagnostic Procedures for Coronary Heart Disease, 169 Figures 2-1 Schematic representations of two general models used to explain sex differences in gene expressions, 30 Comparison of gene content and gene organization on the X and Y chromosomes, 33 Schematic representation of X-chromosome inactivation in female somatic cells, 36

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X'7t1 Van i CONTENTS 3-1 From genotype to phenotype: a diagrammatic representation of hu- man sex determination and differentiation, 52 Hypothetical diagrammatic representation of the cascade of sex chromosomal and autosomal genes involved in testis determination and the hormones involved in male sex differentiation (representa- tion 1), 56 Hypothetical diagrammatic representation of the cascade of sex chromosomal and autosomal genes involved in testis determination (A) and the hormones involved in male sex differentiation (B) (rep- resentation 2), 57 3-4 Comparison of the pattern of change of serum testosterone (T) levels and hCG and serum pituitary LH (LER-960) and FSH (LER-869) levels in the human male fetus during gestation with morphological changes in the fetal testis, 59 3-5 Adolescent growth spurts in girls and boys (growth velocity curves), 69 3-6 Life expectancy at birth for males and females in several U.S. ethnic groups (data are from 1989 to 1994), 76 Life expectancy at birth for males and females, selected years be- tween 1900 and 1998, United States, all races, 76 Frequency distribution of scores on a hypothetical cognitive test plotted separately by sex, 85 Behavioral development in rodents, 96 Composite images of the distribution of activations upon perfor- mance of rhyme-case tasks (phonological processing) for 19 males and 19 females, 103 5-1 Schematic representation of absorption, distribution, metabolism, and excretion of drugs, 119 5-2 The major affecters of body fat, 132 5-3 Death rates for diseases of the heart by age and sex, 1995-1997, 161 5-4 Age-adjusted high serum cholesterol levels (>240 mg/dl) among individuals ages 20 to 74 years by sex and race, 1988-1994, 163 5-5 Non-age-adjusted high serum cholesterol levels (>240 mg/dl) by sex and age, 164 5-6 5-7 Mortality from coronary heart disease and diabetes in men and women ages 25 to 64, 166 External agents, 171

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CONTENTS . . XVII Boxes 1 Summary of Barriers to Progress in Research on Sex Differences, 10 2 Summary of Recommendations, 11 Definitions, 17 Examples of Sex Differences Beyond the Reproductive System, 22 2-1 Genetic Factors That May Differentially Affect the Basic Biochemis- try of Male and Female Cells, 31 Sex Differences in the Relationship of Onset of Pubertal Growth Spurt to Sexual Maturation in Girls and Boys, 67 Sex Differences in the Timing of the Onset of Estrogen Synthesis in Girls and Boys, 68 5-1 Definitions, 118 5-2 Levels and Types of Models for Study of Infection and Inflammation, 143

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Abstract One of the most compelling reasons for looking at what is known about the biology of sex differences is that there are striking differences in human disease that are not explained at this time. Being male or female is an important basic human variable that affects health and illness throughout the life span. Differences in health and illness are influenced by individual genetic and physiological constitutions, as well as by an individual's interaction with environmental and experiential factors. The incidence and severity of diseases vary between the sexes and may be related to differences in exposures, routes of entry and the process- ing of aforeign agent, and cellular responses. Although in many cases these sex differences can be traced to the direct or indirect effects of hormones associated with reproduction, differences cannot be solely attributed to hor- mones. Therefore, sex should be considered when designing and analyzing studies in all areas and at all levels of biomedical and health-related re- search. The study of sex differences is evolving into a mature science. There is now sufficient knowledge of the biological basis of sex differences to validate the scientific study of sex differences and to allow the generation of hypoth- eses with regard to health. The next step is to move from the descriptive to the experimental phase and establish the conditions that must be in place to facilitate and encourage the scientific study of the mechanisms and origins of sex differences. Naturally occurring variations in sex differentiation can provide unique opportunities to obtain a better understanding of basic differences and similarities between and within the sexes.

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xx ABSTRACT Barriers to the advancement of knowledge about sex differences in health and illness exist and must be eliminated. Scientists conducting research on sex differences are confronted with an array of barriers to progress, includ- ing ethical,financial, sociological, and scientific factors. The committee provides scientific evidence in support of the conclusions presented above and makes recommendations to advance the understand- ing of sex differences and their effects on health and illness.