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Introduction There has been an explosion in the growth of new biological informa- tion over the past decade, in large part because of the development of highly advanced techniques that can be used to study the cellular and molecular mechanisms of normal and abnormal human biology. As a result, it has become increasingly apparent that many normal physiologi- cal functions and, in many cases, pathological functions are influenced either directly or indirectly by sex-based differences in biology (also re- ferred to throughout this report as sex differences). Scientific evidence of the importance of sex2 differences throughout the life span abounds. Investigators are now positioned to take this work to the next level, at which the mechanisms and origins of such differences Biology is defined as the study of life and living organisms (Dorland's Illustrated Medical Dictionary, 1994; Stedman's Medical Dictionary, 1995~. Given that no living organism carries out its life alone and that there is no such thing as a null environment (void of any influ- ence), the committee defines biology, for the purposes of this report, to include the genetic, molecular, biochemical, hormonal, cellular, physiological, behavioral, and psychosocial as- pects of life. 2The 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. See additional discussion later in this chapter. 13

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4 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH can be explored. This will allow scientists and clinicians to understand the implications of these differences for human health. Although many specific questions beg to be asked, the critical under- lying question to be answered is this: How and when do the basic biological differences between males andfemales matter to the overall health of boys and girls or men and women? This is a complex question, the answer to which is not easily derived. There is no such thing as a pure biological effect, just as there is no such thing as a null environment (one void of any influence). The "biology" of a given individual therefore includes genetic, physiological, and 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, and 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 conducted in the future. 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.3 In general, the sponsors asked that the IOM committee evalu- ate and consider the current understanding of sex differences and deter- minants at the biological level. Specifically, the sponsors asked the committee to address the follow- . . ng Issues: the knowledge base on and research priorities for animal and cel- 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 Environ- mental Health Sciences, National 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, Research Foundation for Health and Environmental Effects, Ortho-McNeil/Johnson & Johnson; Unilever United States Foundation.

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INTRODUCTION 15 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's charge was not to prepare a definitive text on all known differences between 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 applied biomedical research, including behav- ioral science, cellular biology, clinical research, developmental psychol- ogy, developmental and reproductive biology, epidemiology, genetics, health sciences policy, immunology, molecular biology, neuroscience, pathology, pharmacology, physiology, women's health, and zoology. Focusing the Analysis on Biology Across the Life Span After critical review of the task and a discussion with the study spon- sors at the first meeting, the committee acknowledged the potentially broad scope that a comprehensive analysis of sex and gender differences in health would have. This is evidenced by the expansive National Insti- tutes of Health (NIH) report Agenda for Research on Women's Healthfor the 21st Century (National Institutes of Health, Office of Research on Women's Health, l999a-f), a six-volume report that synthesizes the proceedings of four scientific workshops that were held in 1996 and 1997 and that in- cluded presentations and testimony from more than 1,500 scientific ex- perts, policy makers, and public participants. The resulting document is a survey of ongoing research on women's health, and five overarching themes recur throughout: (1) "Women's health is expanding into the larger concept of gender-specific medicine," (2) "Research on women's health must include the full biological life cycle of the woman," (3) "Multidisciplinary research is essential," (4) "The importance of social and behavioral science to research on women's health is unquestionable," and (5) "The collection of first-hand information from women [is needed] to correct male models of normal function and of pathophysiology of disease" (National Institutes of Health, Office of Research on Women's Health, 1999a, p. 13-14~.

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16 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH With its inventory of current research, the NIH report served as a resource for the IOM committee, whose charge extended beyond assess- ment of women's health to assessment of basic biological differences be- tween males and females that affect human health. It was agreed that another inventory of current research was not needed and was not part of the committee's task. Thus, in addressing its charge, the committee identified and assessed examples of basic biological differences between males and females. It evaluated these differences as they vary over the continuum of the life span of the individual, in addition to how they relate to the under- standing of human disease and health in both males and females. The committee considered how biological function is shaped by experiential influences and identified areas in which additional research would be important to improve the overall understanding of the relationship be- tween sex and human health. The committee also discusses animal (including human) and cellular models in the context of the different examples of sex differences. In light of the evolving understanding of the important role of sex in biological development and the onset of disease, it is particularly important that researchers revisit and revise approaches to studying whole-animal physi- ology. The focus of this report is on sex-based differences, versus sex-based similarities, as they are more likely to successfully 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 parent- hood on the manifestation of some diseases and health outcomes, this report does not directly address these issues, as they are deserving of separate and more in-depth attention. Social status, and the value (or lack thereof) of males or females in certain families or populations, can have a profound effect on health. Low social status, absence of freedoms, limited or no access to health care including family planning and hormone treatments, and poor quality of care are particularly important issues for the health of women in certain cultures and may have a greater impact on their overall health than biol- ogy. As the focus of this report is the health consequences of biologically- based differences between the sexes, these issues are not addressed here. Discussion of some of these issues can be found in In Her Own Right: The Institute of Medicine's Guide to Women's Health Issues (Benderly, 1997) and In Her Lifetime: Female Morbidity and Mortality in Sub-Saharan Africa (Insti- tute of Medicine, 1996~.

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INTRODUCTION 17 Defining the Terms Sex and Gender The committee clarified, for its own purposes, how the terms sex and gender would be used throughout the course of the study and the report (see Box 1-1~. Therefore, using these definitions to discuss differences between males and females, the committee refers to sex differences when the differences appear to have primarily biological origins and to gender differences when they appear to be expressed in response to social influ- ences. The committee acknowledges, however, that it is impossible to know a priori the causes for a particular difference between males and females. Nevertheless, this distinction does have value by signifying that society responds to individuals on the basis of their sex and gender. Males and females differ not only in their basic biology but also in the ways that they interact with and are treated in society. With respect to sex, humans are generally dimorphic. With some ex- ceptions, individuals are either chromosomally XX and developmentally female or chromosomally XY and developmentally male. In defining sex, it is important to distinguish between "genetic sex" and "phenotypic sex," since disorders such as the adrenogenital syndrome and the androgen- insensitivity mutation (Tfm) give rise to phenotypes that seem to contra- dict an individual's genetic sex. In contrast, gender is a continuum. An individual may display char- acteristics considered more typical of the opposite sex, and a person's sense of gender may change over the course of a lifetime. Gender identity and gender role affect individual activities, exposures, and access to care, all of which can affect health and all of which vary widely across cultures. The American Medical Association Manual of Style (Iverson, 1998) de- fines sex as the biological characteristics of males and females. The Ameri-

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18 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH can Medical Association (AMA) acknowledges that gender includes more than sex and is a cultural indicator of an individual's personal and social status. The World Health Organization (WHO) (1998b) defines sex as "ge- netic/physiological or biological characteristics of a person which indi- cates whether one is female or male" and defines gender as referring to "women's and men's roles and responsibilities that are socially deter- mined" (p. 10~. WHO notes that "gender is related to how we are per- ceived and expected to think and act as women and men because of the ways society is organized" (p. 10~. The committee's chosen definitions are in line with those of AMA and WHO. Although such definitions are helpful, two committee members ar- gued that they imply that the idea of biological difference suggests a predominance of physiology, with a subsequent fine-tuning by environ- ment.4 Moreover, the two committee members were concerned that di- viding biological and environmental events into separate spheres could make researchers less likely to ask solid mechanistic questions about, for example, how diet and mechanical stress affect bone development. To illustrate, a variety of factors, including behavioral habits, hor- mones, genetics, and environmental influences, affect the development of bone mass. Some of these are generally understood to be internal to the organism (genes and hormones), and some are generally understood to be external. In one sense, some might be called "sex related" and others might be called "gender related." Closer examination, however, shows that this distinction is less clear-cut. Exercise and body weight, for ex- ample, both contribute to bone formation. In the United States, current conventions promote extreme thinness as an appropriate body image for young girls, whereas vigorous weight-bearing exercises are still less com- monly performed by girls and young women than by boys. Both of these factors result in difference in weight-bearing impacts on bones and thus contribute to differences in the development of bone mass. In other words, culture and behavior (gender) become contributing causes to differences in bone mass between males and females (sex). Some questions that might be addressed at the developmental and molecular levels include the following: Does mechanical stress activate particular genes in osteoclasts or osteoblasts? How is physical stress trans- lated into cellular, bone-shaping activity (via hormones? via other types of receptors?. (For examples of model systems that study mechanical stress and bone development, see Cullen et al. [2000], Marie and Zerath 4Two committee members raised concerns that the definitions adopted by the full com- mittee were appropriate but that the subsequent analysis did not fully put the definition into action.

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INTRODUCTION 19 [2000], Mosley [2000], Pedersen et al. [1999~.) Does diet affect circulating hormone levels, the synthesis or turnover of hormone receptors on critical cell types in the bone, or other aspects of bone metabolism? More theoreti- cally, these questions ask how social gender intersects with bone develop- ment at the molecular and cellular levels. The ability to look at sex and gender as part of a single system in which social elements act with biological elements to produce the body has important consequences for medical treatment. In this example, when more is understood about the mechanism of bone formation including how the many factors interact to either promote or impede bone develop- ment researchers and clinicians can begin to formulate an arsenal of new approaches to increase bone mass well before menopause. This example illustrates how biological questions that are posed as a result of an approach that examines how factors outside the body are translated into differences between male and female bodies will break new scientific ground. Throughout the report, the committee presents data where avail- able that genes, physiology, and the physical and social environments operate in concert to produce a phenotype. Researchers are just beginning to unravel these complex interactions, revealing how these factors work together to produce differences between males and females that provide many new opportunities for investigation. SEX DIFFERENCES BEYOND THE REPRODUCTIVE SYSTEM Although an individual can be characterized initially by the presence of particular reproductive organs, sex differences encompass much more than that. Evidence suggests that the distinct anatomy and physiology that develop as a result of having been dealt two X chromosomes (XX) or an X chromosome and a Y chromosome (XY) at fertilization can have a much broader influence on an individual's health than was previously thought. Although it is anatomically obvious why only males develop prostate cancer and only females get ovarian cancer, it is not at all obvious why, for example, females are more likely than males to recover language ability after suffering a left-hemisphere stroke (Shaywitz et al., 1995) or why females have a far greater risk than males of developing life-threat- ening ventricular arrhythmias in response to a variety of potassium chan- nel-blocking drugs (Ebert et al., 1998~. Recent research has shed some light on these puzzles. In the case of stroke, for example, functional magnetic resonance imaging has shown that females rely on both sides of the brain for certain aspects of language, whereas males predominantly rely on the left hemisphere (Shaywitz et al., 1995~. In the case of drug-induced arrhythmias, data suggest that sex

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20 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH steroid hormones influence the activities of specific cardiac ion channels (Ebert et al., 1998~. Differences in the prevalence and severity of a broad range of dis- eases, disorders, and conditions exist between the sexes (for additional examples, see Box 1-2~. Some of the variations appear to be influenced by physiological differences, such as the role of sex hormones in cardiovas- cular disease and osteoporosis, or by experiential and environmental dif- ferences, such as smoking habits or exposure to the sun's ultraviolet rays as a result of one's occupation, recreational activities, or clothing styles. Observations such as these are important to the development of an un- derstanding of the etiology of and optimal approaches to the diagnosis and treatment of specific diseases, with the ultimate goal being improve- ment of the health of both sexes. It is important to remember, however, that physiological factors and experiential factors do not act indepen- dently and cannot be neatly compartmentalized. Moreover, the distinc- tion between the origins of these differences biological environment versus social environment can be valuable as well as a hindrance. For some disparities in incidence and manifestation, such as for some of the autoimmune diseases, there are far fewer clues, experiential or biological, to explain the observed differences. The relapsing intermittent form of multiple sclerosis, for example, occurs predominantly in females but has a more severe effect on males (Noseworthy et al., 2000~. Differences between the sexes may be modest, yet they may still re- sult in important outcomes. Small absolute differences between the sexes may result in large differences in health and illness among members of the general population. In addition, small differences between the sexes may be informative in providing an understanding of the underlying mechanisms of normal and pathological functions. Sex Variability Biologists study variability as part of life, and many biological vari- ables, for example, age and family history, affect health. The committee considered such variables for which data were available and relevant to the discussion. Ultimately, however, this report is about the influence of sex one of the most basic human variables on health. In addition to variability between the sexes, there is also considerable variability within each sex. Factors such as race and ethnicity may affect health as well. A striking aspect of some sex differences is the consistency with which they appear across populations with vastly different health status profiles and environmental circumstances. A simple example of variability within populations is height. On av- erage, males are taller than females. This is apparent across all cultures and has been for thousands of years. Although it is partially dictated by

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INTRODUCTION 21 parentage, height is also influenced by environmental factors, such as nutrition (Valian, 1998~. In other cases, sex differences vary among populations, giving clues to their dependence on the interplay of sex and other variables. Obesity is a condition for which the differences between sexes varies by ethnicity. Females are generally more likely than males to be obese, but the sex difference is much more striking in some ethnic groups and even varies among subgroups within ethnic groups (see Chapter 5~. Recent studies with animals indicate that alterations in hormonal and nutritional expo- sures during fetal development can result in variability in health and illness among males and among females (Barker, 2000; Nathanielsz, 1999; vom Saal et al., 1999~. Age and reproductive status add to variability in health and illness within the sexes as well. Most of the discussion so far has been of "typical" males and females, that is, those with the expected XY or XX sex chromosome constitution and the corresponding expected developmental characteristics. Although sexual dimorphism (two, and only two, distinct forms of sex, male or female) at all levels is the "rule," exceptions are more common than most people realize, resulting in chromosomal, gonadal, hormonal, or genital deviations from the chromosomal, gonadal, hormonal, or genital consti- tution of a "typical" male or female (Blackless et al., 2000~. Study of these exceptions can shed light not only on the clinical implications for indi- viduals with a mixed sex genotype (genetic makeup) or phenotype (vis- ible properties of a person) but also on the role of sex in normal develop- ment. EVOLVING RESEARCH POLICY 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 research. Histori- cally, the research community assumed that beyond the reproductive system such differences do not exist or are not relevant. (One example is the lack of consideration of the sex of origin of cells and tissues used in research [see Chapter 6~.) The conjoint study of males and females to explore sex differences is not a well-established convention in scientific practice. Since World War II and until relatively recently, clinical research was conducted primarily

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22 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH with men. As described below, there have been both conceptual and prac- tical deterrents to the inclusion of women and a tendency to underreport rather than highlight sex differences that might bring about possible sci- entific insights. As a result, the medical community lacks useful, compa- rable data on conditions that occur disproportionately, that manifest dif-

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EDUCE ferently' or that require different approaches to diagnosis and treatment in males and females. For many years it was assumed Mat males' parUcu- larly Caucasian males' provided We ~norm" or 'standard and Mere was a tendency to view females as being deviant or problematic even in studying diseases that affect both sexes" Onsthute of Medicine' 1994' p.

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24 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH 8~. Unfortunately, although some reports now treat males and females as being different, but equally "normal," the habit of viewing the male as the norm or baseline can still be found in the current medical literature (Nicolette, 2000~. Over the past several decades, the women's health movement has successfully worked toward achieving a significant increase in the amount of research conducted on women's health issues. Critics argue that the majority of such research has focused on reproductive health. Still others suggest that the pendulum has swung too far in the direction of studies focusing on women, with researchers now collecting data exclusively on females without including the corresponding data on males. Neverthe- less, the study of sex-based differences in biology has yielded information beneficial to the health of both males and females. The justification for excluding females from clinical studies arose par- tially from efforts to protect them. Protection of human research subjects emerged as a policy issue after World War II with the issuance of the Nuremberg Code of Ethics in 1949, which outlined the basic moral, ethi- cal, and legal requirements of conducting research with human subjects (McCarthy, 1994; U.S. Government Printing Office, 1949~. This landmark document led the way for a series of protectionist policies, including hu- man subject protections issued by the U.S. Public Health Service in 1966 that were revised repeatedly and that were ultimately rewritten and pub- lished as the policy guidelines for the entire U.S. Department of Health, Education, and Welfare in 1971 and again, with more stringent federal regulations, in 1974 (45 CFR 46, May 30, 1974~. These efforts were spurred by a series of alarming adverse events, including those caused by thalidomide and diethylstilbestrol (DES), and the exposure of abusive and unethical research practices, such as the Tuskegee syphilis study and the use of U.S. servicemen during World War II as research subjects in studies of the effects of mustard agents and lewisite (a poison gas) (Institute of Medicine, 1993, 1994~. Although none of these provisions excluded specific subpopulations from clinical research, the policies stated that subjects who were vulner- able because of physical, mental, or social circumstances must not be exploited. Hence, few women were included, as pregnant women and their fetuses were grouped into the category of "vulnerable populations" (45 CFR 46, subpart B; Institute of Medicine, 1994~. Thus, although the thalidomide and DES incidents were not related to the participation of women in clinical trials, they fostered an aversion to involving women who were or who could become pregnant in any drug-related research (Institute of Medicine, 1994~. (Although both thalidomide and DES were successfully tested in clinical trials, the side effects were not apparent until the approved drugs were used widely by pregnant women, who were not part of the clinical trial population.)

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INTRODUCTION 25 In 1977 the U.S. Food and Drug Administration (FDA) issued guide- lines recommending that pharmaceutical companies exclude women in their childbearing years from phase I clinical studies (studies with healthy subjects to evaluate the safety of a new drug) (U.S. Food and Drug Ad- ministration, 1977~. In addition, the U.S. Department of Health and Hu- man Services established in 1991 that "no pregnant woman may be in- volved as a subject in an activity . . . unless the purpose of the activity is to meet the health need of the mother and the fetus will be placed at risk only to the minimum extent necessary to reach such needs" (45 CFR 46.207~. Scientifically, women were excluded as clinical research participants because (1) there was a general belief among clinical researchers that men and women will not differ significantly in response to treatment in most situations, and (2) the inclusion of women introduces additional variables (in the form of hormonal cycles) and decreases the homogeneity of the study population (Institute of Medicine, 1994~. Ironically, even as it was acknowledged that the female hormonal cycle is a significant confound- ing variable and test substances might respond unpredictably to hor- monal fluctuations, it was nonetheless widely believed that men and women were similar enough that it was acceptable to then treat women with therapies developed solely on the basis of the results of studies performed with men as research subjects (Haseltine and Jacobson, 1997~. The policy of exclusion continued into the mid-1980s, when, in 1985, the U.S. Public Health Service Task Force on Women's Health Issues con- cluded that health care for women and the quality of health information available to women had been compromised by the historical lack of re- search on women's health issues (U.S. Public Health Service, 1985~. In response, NIH issued a new policy in 1986 that encouraged the inclusion of women in clinical research, requested justification for the exclusion of women, and suggested evaluation of the data for differences by sex. A 1990 investigation by the U.S. General Accounting Office (GAO), how- ever, found that the guidelines were not being implemented with any regularity (U.S. General Accounting Office, 1990~. With government and public interest in the composition of study populations escalating, NIH created a new office, the Office of Research on Women's Health (ORWH), and issued a stronger policy statement on the inclusion of women and minorities in clinical studies. In 1993, with the passage of the National Institutes of Health Revitalization Act (P.L. 103-43), ORWH was authorized statutorily and the guidelines for inclu- sion of women and minorities became law. That same year, FDA lifted the 1977 restrictions on the inclusion of women in their childbearing years in phase I clinical trials and encouraged analysis of clinical data by sex but did not require inclusion of both sexes in clinical trials (Merkatz et al., 1993~. In 1998, FDA published the final rule, Investigational New Drug

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26 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Applications and New Drug Applications (U.S. Department of Health and Human Services, 1998~. This rule allows the agency to refuse to file any new drug application that does not appropriately analyze safety and efficacy data by sex. In 2000, GAO reassessed NIH's progress in conducting research on women's health in the decade since publication of the 1990 GAO report. GAO reported that NIH has made "significant progress in implementing a strengthened policy in including women in clinical research," treating the inclusion of women and minorities as a matter of scientific merit in the review process for extramural research (U.S. General Accounting Office, 2000, p. 2~. However, the GAO report noted that less progress has been made in encouraging analysis of the data by sex. NIH agreed with GAO's overall conclusion. With regard to the criti- cism that NIH has not ensured the analysis of the data by sex, NIH raised concerns that GAO had included in its review unpublished reports based on research that had occurred before the new requirements were enacted (Kirschstein, 2000~. The reports referred to in the GAO audit (which were subsequently published Montgomery and Sherif, 2000; Vidaver et al., 2000~) looked at articles published between 1993 and 1998 in select jour- nals and found that few, if any, data from research funded under the 1993 mandate for the inclusion of women in clinical trials would have been available or published within that period (Pine, 2000~. 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. The availabil- ity of mechanistic explanations is also critical for the effective use of cur- rent knowledge, that is, indicating where existing research done only with a male population or only with a female population is most or least likely to be directly applicable to both sexes. ORGANIZATION OF REPORT Chapters 2 to 5 give specific, in-depth examples of sex differences and discuss how those differences influence the health of both individual males and individual females. The information is presented at increasing levels of organizational complexity, from the cellular level, to the whole- organism level, to the response of the organism to its environment. Spe- cifically, Chapter 2 describes the basic genetic, cellular, and molecular differences between the sexes. Chapter 3 provides background informa-

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INTRODUCTION 27 lion on the development and changes of the whole human across the life span. Chapter 4 presents examples of how basic genetic and physiological differences between males and females might produce phenotypic differ- ences. Chapter 5 looks into the response of the individual to external agents encountered purposefully (e.g., food or medications) or coinciden- tally (e.g., infectious agents or ultraviolet radiation). Discussions of ani- mal (including human) and cellular research models of human conditions appear throughout the report, generally in conjunction with a particular example. Finally, Chapter 6 addresses overarching barriers to valid and productive research on sex and gender differences as they relate to health and discusses the challenges and opportunities that lie ahead in this emerging field of research. The report includes four appendixes to pro- vide the reader with additional information: Appendix A discusses data sources and committee methods, Appendix B describes physiological and pharmacological differences between the sexes, Appendix C includes a glossary, and Appendix D includes IOM committee and staff biographies. The examples used throughout the report were chosen to demon- strate that sex differences occur across a wide variety of interrelated disci- plines. The use of a particular example is not meant to imply that research in that area is more important or should have priority over research in other areas. In each chapter, 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 opportunities in basic and applied research, and fill identified research gaps.