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Executive Summary The explosion in the growth of new biological information over the past decade has made it increasingly apparent that many normal physi- ological functions and, in many cases, pathological functions are in- fluenced either directly or indirectly by sex-based differences in biology (also referred to throughout this report as sex differences). In recent years, considerable attention has been given to the differ- ences and similarities between females and males (1) at the societal level by researchers evaluating how individual behaviors, lifestyles, and sur- roundings affect one's biological development and health and (2) at the level of the whole organism by clinicians and applied researchers investi- gating the component organs and systems of humans. However, scien- tists have paid much less attention to the direct and intentional study of these differences at the basic cellular and molecular levels. Where data are available, they have often been a by-product of other areas of research. Historically, the research community assumed that beyond the reproduc- tive system such differences do not exist or are not relevant. Scientific evidence of the importance of sex1 differences throughout the life span abounds. Investigators are now positioned to take this work 1The committee defines sex as the classification of living things, generally as male or female according to their reproductive organs and functions assigned by the chromosomal complement, and gender as a person's self-representation as male or female, or how that person is responded to by social institutions on the basis of the individual's gender presen- tation. Gender is shaped by environment and experience.
2 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH to the next level, at which the mechanisms and origins of such differences can be explored. This will allow scientists and clinicians to understand the implications of these differences for human health. The critical questions to be answered are · How can information on sex differences be translated into preven- tive, diagnostic, and therapeutic practice? · How can the new knowledge about and understanding of biologi- cal sex differences and similarities most effectively be used to positively affect patient outcomes and improve health and health care? SCOPE OF THE REPORT In November 1999, the Institute of Medicine (IOM) formed the Com- mittee on Understanding the Biology of Sex and Gender Differences in response to combined requests from a consortium of public and private sponsors. The committee members brought expertise from a broad array of disciplines in basic and applied biomedical research. In general, the sponsors asked the committee to evaluate and consider the current un- derstanding of sex differences and determinants at the biological level. Specifically, they asked that the following issues be addressed: · the knowledge base on and research priorities for animal and cel- lular models that could be used to determine when sex and gender differ- ences exist and when they are relevant to biological functioning at the cellular, developmental, organ, organismal, and behavioral levels; · current and potential barriers to the conduct of valid and produc- tive research on sex and gender differences and their determinants, in- cluding ethical, financial, sociological, and scientific factors; and · strategies that can be used to overcome such barriers and promote the acceptance of this research by the scientific community and the gen- eral public. The committee was not charged with the task of preparing a defini- tive text on all known differences and similarities between the sexes but, rather, was charged with considering factors and traits that characterize and differentiate males and females across the life span and that underlie sex differences in health (including genetic, biochemical, physiological, physical, and behavioral elements). Thus, the focus of this report is on sex-based differences, versus similarities, as they are more likely to suc- cessfully demonstrate the need for further research and lead to greater understanding of the significance of sex in human biology and health. Moreover, despite the influence of pregnancy, parity, and parenthood on the manifestation of some diseases and health outcomes, this report does
EXECUTIVE SUMMARY 3 not directly address these issues, as they are deserving of separate and more in-depth attention. On the basis of its review, the committee arrived at a series of findings and conclusions and developed recommendations that are designed to facilitate scientific endeavors in this area, take advantage of new opportu- nities in basic and applied research, and fill identified research gaps. OVERARCHING CONCLUSIONS Three common, recurring messages emerged as the committee ad- dressed its primary task (reviewing and evaluating the current state of knowledge about sex differences in health and illness and scientific evi- dence related to sex differences in health and illness) and as it met with scientific experts across diverse disciplines. · Sex matters. Sex, that is, being male or female, is an important basic human variable that should be considered when designing and ana- lyzing studies in all areas and at all levels of biomedical and health- related research. Differences in health and illness are influenced by indi- vidual 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, the routes of entry and the processing of a foreign 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 hormones. · The study of sex differences is evolving into a mature science. There is now sufficient knowledge of the biological basis of sex differ- ences to validate the scientific study of sex differences and to allow the generation of hypotheses. The next step is to move from the descriptive to the experimental and to establish the conditions that must be in place to facilitate and encourage the scientific study of the mechanisms and ori- gins of sex differences. Naturally occurring variations in sexual differen- tiation and development can provide unique opportunities to obtain a better understanding of basic differences and similarities between and within the sexes. · 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, including ethical, financial, sociological, and scientific factors. After considering the data and examples presented throughout this report, the committee expects that the public, scientific, and policy com-
4 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH munities alike will agree that the understanding of sex differences in health and illness merits serious scientific inquiry in all aspects of bio- medical and health-related research. Some of the answers have been stumbled upon fortuitously. Until the question of sex, however, is rou- tinely asked and the results positive or negative are routinely reported, many opportunities to obtain a better understanding of the pathogenesis of disease and to advance human health will surely be missed. FINDINGS AND RECOMMENDATIONS Every Cell Has a Sex The biological differences between the sexes have long been recog- nized at the biochemical and cellular levels. Rapid advances in molecular biology have revealed the genetic and molecular bases of a number of sex- based differences in health and human disease, some of which are attrib- uted to sexual genotype XX in the female and XY in the male. Genes on the sex chromosomes can be expressed differently between males and females because of the presence of either single or double copies of the gene and because of several other phenomena: of different meiotic effects, X-chromosome inactivation, and genetic imprinting. The inheritance of either a male or a female genotype is further influenced by the source (maternal or paternal) of the X chromosome. The relative roles of the sex chromosome genes and their expressions explain X-chromosome-linked diseases and are likely to illuminate the reasons for the heterogeneous expression of some diseases within and between the sexes. These findings argue that there are multiple, ubiquitous differences in the basic cellular biochemistries of males and females that can affect an individual's health. Many of these differences do not necessarily arise as a result of differences in the hormonal regime to which males and females are exposed but are a direct result of the genetic differences between the two sexes. Thus, the committee makes the following recommendation: RECOMMENDATION 1: Promote research on sex at the cellular level. The committee recommends that research be conducted to · determine the functions and effects of X-chromosome- and Y- chromosome-linked genes in somatic cells as well as germ-line cells; · determine how genetic sex differences influence other levels of biological organization (cell, organ, organ system, organism), including susceptibility to disease; and · develop systems that can identify and distinguish between the effects of genes and the effects of hormones.
EXECUTIVE SUMMARY 5 Sex Begins in the Womb Sex differences of importance to health and human disease occur throughout the life span, although their specific expression varies at dif- ferent stages of life. Some differences originate in events occurring in the intrauterine environment, where developmental processes differentially organize tissues for later activation in the male or female. In the prenatal period, sex determination and differentiation occur in a series of sequen- tial processes governed by genetic and environmental factors. During the prepubertal period, behavioral and hormonal changes manifest the sec- ondary sexual characteristics that reinforce the sexual identity of the indi- vidual through adolescence and into adulthood. Hormonal events occur- ring in puberty lay a framework for biological differences that persist through life and contribute to the variable onset and progression of dis- ease in males and females. It is important to study sex differences at all stages of the life cycle, relying on animal models of disease and including sex as a variable in basic and clinical research designs. RECOMMENDATION 2: Study sex differences from womb to tomb. The committee recommends that researchers and those who fund research focus on the following areas: · inclusion of sex as a variable in basic research designs, · expansion of studies to reveal the mechanisms of intrauterine effects, and · encouragement of studies at different stages of the life span to determine how sex differences influence health, illness, and longevity. Sex is an important marker of individual variability. Some of this sex- related variability results from events that occur in the intrauterine envi- ronment but that do not materialize until later in life. Current research varies in its level of attention to these matters. The committee acknowledges that inclusion of people, animals, or cells and tissues of both sexes in all studies is not always feasible or appropriate. Rather, the committee is urging researchers to regard sex, that is, being male or female, as an important basic human variable that should be considered when designing, analyzing, and reporting findings from studies in all areas and at all levels of biomedical research. Statistical methods can be used to evaluate the effect of sex without necessarily doubling the sample size of every study. In addition, it is particularly important that researchers revisit and revise approaches to studying whole-animal physiology in light of what has been learned in the past decade about major sex differences.
6 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH RECOMMENDATION 3: Mine cross-species information. · Researchers should choose models that mirror human sex differ- ences and that are appropriate for the human conditions being ad- dressed. Given the interspecies variation, the mechanisms of sex differ- ences in nonhuman primates may be the best mimics for some mechanisms of sex differences in humans. Continued development of appropriate animal models, including those involving nonhuman pri- mates, should be encouraged and supported under existing regulations and guidelines (see the Guide for the Care and Use of Laboratory Ani- mals [National Research Council, 19961~. · Researchers should be alert to unexpected phenotypic sex differ- ences resulting from the production of genetically modified animals. Sex Affects Behavior and Perception Basic genetic and physiological differences, in combination with envi- ronmental factors, result in behavioral and cognitive differences between males and females. Sex differences in the brain, sex-typed behavior and gender identity, and sex differences in cognitive ability should be studied at all points in the life span. Hormones play a role in behavioral and cognitive sexual dimorphism but are not solely responsible. In addition, sex differences in the perception of pain have important clinical implica- tions. Research is needed on the natural variations between and within the sexes in behavior, cognition, and perception, with expanded investi- gation of sex differences in brain organization and function. To better understand the influences and roles of factors that may lead to sex differ- ences, the committee makes the following recommendations: RECOMMENDATION 4: Investigate natural variations. · Examine genetic variability, disorders of sex differentiation, re- productive status, and environmental influences to better understand human health. Naturally occurring variations provide useful models that can be used to study the influences and origins of a range of factors that influence sex differences. RECOMMENDATION 5: Expand research on sex differences in brain organization and function. New technologies make it possible to study sex-differential environ- mental and behavioral influences on brain organization and function and to recognize modulators of brain organization and function. Innovative
EXECUTIVE SUMMARY ways to expand the availability of and reduce the cost of new technolo- gies need to be explored. Sex Affects Health Males and females have different patterns of illness and different life spans, raising questions about the relative roles of biology and environ- ment in these disparities. Dissimilar exposures, susceptibilities, and re- sponses to initiating agents and differences in energy storage and me- tabolism result in variable responses to pharmacological agents and the initiation and manifestation of diseases such as obesity, autoimmune dis- orders, and coronary heart disease, to name a few. Understanding the bases of these sex-based differences is important to developing new ap- proaches to prevention, diagnosis, and treatment. RECOMMENDATION 6: Monitor sex differences and similarities for all human diseases that affect both sexes. Investigators should · consider sex as a biological variable in all biomedical and health- related research; and · design studies that will -control for exposure, susceptibility, metabolism, physiology (cycles), and immune response variables; -consider how ethical concerns (e.g., risk of fetal injury) con- strain study designs and affect outcomes; and -detect sex differences across the life span. The Future of Research on Biological Sex Differences: Challenges and Opportunities Being male or female is an important fundamental variable that should be considered when designing and analyzing basic and clinical research. Historically, the terms sex and gender have been loosely, and sometimes inappropriately, used in the reporting of research results, a situation that should be remedied through further clarification. Conduct- ing studies that account for sex differences might require innovative de- signs, methods, and model systems, all of which might require additional resources. Studies relying on biological materials would benefit from a determination and disclosure of the sex of origin of the material, and clinical researchers should attempt to identify the endocrine status of research subjects. Longitudinal studies should be designed to allow analy- sis of data by sex. Once studies are conducted, data regarding sex differ- ences, or the lack thereof, should be readily available in the scientific
8 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH literature. Interdisciplinary efforts are needed to conduct research on sex differences. RECOMMENDATION 7: Clarify use of the terms sex and gender. Researchers should specify in publications their use of the terms sex and gender. To clarify usage and bring some consistency to the lit- erature, the committee recommends the following: · In the study of human subjects, the term sex should be used as a classification, generally as male or female, according to the reproduc- tive organs and functions that derive from the chromosomal comple- ment. · In the study of human subjects, the term gender should be used to refer to a person's self-representation as male or female, or how that person is responded to by social institutions on the basis of the indi- vidual's gender presentation. · In most studies of nonhuman animals the term sex should be used. RECOMMENDATION 8: Support and conduct additional research on sex differences. Because differences between the sexes are pervasive across all subdis- ciplines of biology, all research sponsors should encourage research ini- tiatives on sex differences. Research sponsors and peer-review commit- tees should recognize that research on sex differences may require additional resources. RECOMMENDATION 9: Make sex-specific data more readily avail- able. Journal editors should encourage researchers to include in their re- ports descriptions of the sex ratios of the research population and to specify the extent to which analyses of the data by sex were included in the study. If there is no effect (absence of a sex difference), that should be stated in the results. When designing or updating databases of scientific journal articles and other information, informatics developers should de- vise ways of reliably accessing sex-specific data. RECOMMENDATION 10: Determine and disclose the sex of origin of biological research materials. The origin and sex chromosome constitutions of cells or tissue cul- tures used for cell biological, molecular biological, or biochemical experi- ments should be stated when they are known. Attempts should be made
EXECUTIVE SUMMARY 9 to discern the sex of origin when it is unknown. Journal editors should encourage inclusion of such information in Materials and Methods sec- tions as standard practice. RECOMMENDATION 11: Longitudinal studies should be conducted and should be constructed so that their results can be analyzed by sex. The health status of males and females can vary considerably, both within and between the sexes, across the life span from intrauterine development to old age. Most longitudinal studies have been designed with specific disease end points, thereby precluding consideration of many other relevant developmental issues and other diseases, disorders, and conditions. RECOMMENDATION 12: Identify the endocrine status of research subjects (an important variable that should be considered, when pos- sible, in analyses). Data on cycles (menstrual, circadian, etc.) are often lacking. Most studies do not define which part of the cycle participants were in at the time of study, note participants only by age and not whether they are pre- or postmenopausal, or are based on only one cycle. RECOMMENDATION 13: Encourage and support interdisciplinary re- search on sex differences. Interdisciplinary research is generally accepted as valuable and im- portant. Opportunities for interdisciplinary collaboration to enhance the understanding of sex differences, however, have not been fully realized. The committee recommends the continued development of interdiscipli- nary research programs and strategies for more effective communication and cooperation to achieve the following goals: · synergy between and among basic scientists, epidemiologists, so- cial scientists, and clinical researchers; · enhanced collaboration across medical specialties; and · better translational or bench-to-bedside research and interlevel integration of data (cellular, to animal, to human). RECOMMENDATION 14: Reduce the potential for discrimination based on identified sex differences. The committee noted that, historically, studies on race, ethnicity, age, nationality, religion, and sex have sometimes led to discriminatory prac- tices. The committee believes, therefore, that these historical practices should be taken into consideration so that they will not be repeated. The
10 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH past should not limit the future of research but should serve as a guide to its use. Ethical research on the biology of sex differences is essential to the advancement of human health and should not be constrained. SUMMARY Despite the progress made in focusing on women's health research and including women in clinical trials, such research will have limited value unless the underlying implications that is, the actual differences between males and females that make such research so critical are sys- tematically studied and elucidated. Such research can enhance the basis for interpreting the results of separate studies with males and females, helping to clarify findings of no essential sex differences and suggesting mechanisms to be pursued when sex differences are found.
EXECUTIVE SUMMARY 11
12 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TOHUMANHEALTH: DOES SEX MATTER? hormonal effects as well as the environmental, behavioral, and societal influences that shape that individual. The question presented above might therefore be better phrased as follows: How can information on sex differences be translated into preventative, diagnostic, ant! therapeutic practice? How can the new knowledge about and understanding of biological sex differences and similarities most effectively be used to positively affect patient outcomes and improve health and health care? Answers to these questions will help reshape the biomedical and health-related research con- ducted in the fixture. SCOPE OF THE REPORT In November 1 999, the Institute of Medicine (IOM) formed the Committee on Understanding the Biology of Sex arid Gender Differences in response to combined requests from a consortium of public and private sponsors.3 In general, the sponsors asked that the IOM committee evaluate and consider the current understanding of sex differences and determinants at the biological level. Specifically, the sponsors asked the committee to address the following issues: . the knowledge base on and research priorities for animal aIld cellular models that could be used to detennine when sex and gender differences exist and when they are relevant to biological functioning at the cellular, developmental, organ, organismal, and behavioral levels; . current and potential barriers to the conduct of valid and productive research on sex and gender differences and their determinants, including ethical, financial, sociological, and scientific factors; and . strategies that can be used to overcome such barriers and promote the acceptance of this re- search by the scientific community and the general public. The comminee's charge was not to prepare a definitive text on all known differences be- tween the sexes but, rather, to consider factors and traits that characterize and differentiate males and females across the life span and that underlie sex differences in health (including behavioral, biochemical, genetic, physical, and physiological elements). The committee members brought expertise from a broad array of disciplines in basic and ap- plied biomedical research, including behavioral science, cellular biology, clinical research, de- velopmental psychology, developmental and reproductive biology, epidemiology, genetics, health sciences policy, immunology, molecular biology, neuroscience, pathology, pharmacology, physiology' women~s health' arid zoology. 3U.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, Na- tional Institute on Drug Abuse, National Institute of Mental Health, U.S. Food and Drug Administration, Centers for Disease Control and Prevention); National Science Foundation, Environmental Protection Agency, National Aeronautics and Space Administration, Society for Women's Health Research, Re- search Foundation for Health and Environmental Effects, Ortho-McNeil/Johnson & Johnson; Unilever United States Foundation.