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6 The Future of Research on Biological Sex Differences: Challenges and Opportunities ABSTRACT Being male or female is an important fundamental variable that should be considered when designing and analyzing basic and clinical research. His- torically, the terms sex and gender have been loosely and sometimes inap- propriately used in the reporting of research results, a situation that should be remedied through further clarification. Conducting studies that account for sex differences might require innovative designs, methods, and model systems, all of which might require additional resources. Studies that rely 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 analysis of data by sex. Once studies are conducted, data regarding sex differences, or the lack thereof, should be readily available in the scientific literature. Interdisciplinary efforts are needed to conduct research on sex differences. A common, recurring message emerged as the committee addressed the current state of knowledge about sex differences in health and illness and scientific evidence related to sex differences in health and illness and as it met with scientific experts from diverse disciplines. This message is that sex that is, being male or female is an important basic human variable that should be considered when designing and analyzing the results of studies in all areas and at all levels of biomedical and health- related research. Differences in health and illness between individuals are 173

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74 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH influenced not only by individuals' genetic and physiological constitu- tions but also by environmental and experiential factors, all of which interact. As discussed in Chapter 2, the cells of males and females have many basic biochemical differences, and many of these stem from genetic rather than hormonal differences. As reviewed in Chapters 3 and 4, sex differences are evident and evolve across the life span; however, these differences cannot be attributed solely to sex hormones. In addition, naturally occurring variations in sexual differentiation and development can provide unique opportunities to obtain a better understanding of the basic differences and the similarities between and within the sexes. As described in Chapter 5, the incidence and severity of disease vary between the sexes and may be related to differences in expo- sures, portals of entry and processing, and cellular responses. 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. In addition to assessing the available scientific data on sex differences in health and illness, the sponsors asked the committee to consider cur- rent and potential barriers to progress, including ethical, financial, socio- logical, and scientific factors. Committee members raised a wide variety of concerns during the committee discussions. It is the committee's opin- ion that meeting the challenges described in the following sections will, in particular, help to advance scientific knowledge about sex differences in health and illness. TERMINOLOGY One of the first barriers that the committee faced was the inconsistent and often confusing use of the terms sex and gender in the scientific litera- ture and the popular press. Use of sex and gender varies widely among disciplines and authors (National Institutes of Health, Office of Research on Women's Health, 1999a; Kim and Nafziger, 2000~. Anthropologists Walker and Cook (1998) consider the distinction between sex and gender in their field of anthropol- ogy to be very important, as it is possible to determine sex by analyzing skeletal remains and to obtain information on gender roles through the study of artifacts. A 1998 study by Walker and Cook demonstrates that although the rate of use of the term sex in the biomedical literature has not changed significantly since the late 1960s, the rate of use of the term gender has increased markedly, especially since the early 1980s (Walker and Cook, 1998~. Upon further examination, they found that most articles published in the late 1960s and early 1970s made a distinction between sex and gender. However, among the more recent articles that Walker and Cook surveyed in their examination of articles indexed in MedLine under

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CHALLENGES AND OPPORTUNITIES 175 both sex and gender, more than half did not distinguish between the terms. Haig (2000) obtained similar results on examination of the use of sex and gender in a sampling of the Science Citation Index. The term gender first appeared in the medical and biological literature in the 1960s in publications of research on the individual psychology of "gender identity" and "gender role" (Hampson and Hampson, 1961; Money and Ehrhardt,1996~. Later, in part as a result of the feminist move- ment, gender came to refer to a set of power relationships in society (Lorber, 1994, pp. 30-31~. The resulting use of gender as both an indi- vidual characteristic and a social institution, however, leads to significant confusion. Synonymous use of sex and gender is common in health-related gov- ernment guidelines and regulations. The final U.S. Food and Drug Ad- ministration rule entitled Investigational New Drug Applications and New Drug Applications establishes in law the requirement that applica- tions for approval of new drugs contain "effectiveness and safety data for important demographic subgroups, specifically gender, age, and racial subgroups" (21 CFR Parts 312 and 314, U.S. Department of Health and Human Services, 1998, p.6854 [emphasis added]~. In contrast, a May 2000 U.S. General Accounting Office (GAO) report, Women's Health: NIH Has Increased Its Efforts to Include Women in Research, uses sex when referring to an analysis of the results of different clinical studies conducted with women and men and notes that gender is used to discuss culturally shaped variations (U.S. General Accounting Office, 2000~. The use of sex and gender as synonyms in science is apparent through- out the literature. According to the current scientific literature, rats, mice, guinea pigs, other research animals, and even plants have gender. Ani- mals may have social behaviors and roles often associated with one or the other sex; however, most published reports are using gender as a syn- onym for sex, and investigators have not developed animals models that mimic the uniquely human trait of gender. Medical textbooks perpetuate the confusion. Harrison's Principles of Internal Medicine, the quintessential internal medicine text, uses sex and gender interchangeably. In a discussion of demographic factors and dis- ease, Harrison's states that "by definition, many disorders of the repro- ductive tract occur exclusively in one gender," but later in the same para- graph it states, "other conditions occur regularly in both sexes, but predominate or tend to be more severe in one or the other" (Ernster and Colford, 1998, p. 14 [emphasis added]) The interchangeable use of sex and gender tends to cause confusion not only in the scientific community but also among policy makers and the general public. Consistent usage across disciplines would aid in the accurate measurement and reporting of differences between men and

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176 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH women and help to communicate clearly how the differences apply to biomedical research, patient care, and policy. 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 litera- ture, 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 individual's gender presentation. In most studies of nonhuman animals the term sex should be used. RESEARCH TOOLS AND RESOURCES More Complex Studies and Additional Resources for Research Differences between the sexes may be modest, yet the differences may still result in different outcomes or may point to significant and larger underlying mechanisms of sex differences. Detection of modest differences may require studies with more complex experimental designs, the use of more complex model systems, and the use of more subjects to achieve statistical power; and, thus, in some cases detection of modest differences may require additional financial resources. A recent example is a large population-based study (O'Donnell et al., 1998) that demonstrates an association and genetic linkage of the angio- tensin-converting enzyme (ACE) locus with hypertension and with dia- stolic blood pressure in men but not women. Existing data on the associa- tion of the ACE locus and blood pressure or hypertension have been conflicting. O'Donnell and colleagues have suggested that "many prior studies may have had inadequate power to detect the modest contribu- tion that might be expected from an individual genetic factor to complex traits such as blood pressure" (O'Donnell et al., 1998, p. 1766~. They also note that differences in the genetic makeup or environmental exposures of the different study populations may also play a role in the different results observed. Another example relates to sex differences in sensitivity to noxious stimuli, which overall are relatively small but whose underlying mecha-

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CHALLENGES AND OPPORTUNITIES 177 nisms are wide-ranging and significant for many aspects of treatment (see Chapter 4 and Berkley [1997a,b]~. 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 initiatives on sex differences. Research sponsors and peer-review com- mittees should recognize that research on sex differences may require additional resources. Information from the Published Literature Information on sex differences can be difficult to glean from the pub- lished literature. In 1999, the U.S. Congress asked GAO to assess the National Institutes of Health's (NIH's) progress in conducting research on women's health in the decade since publication of the 1990 GAO re- port on the inclusion of women in clinical trials. Over the course of its audit, GAO experienced difficulties in determining whether analysis of data by sex is occurring. Even when scientists do analyze data by sex, the results are not always published. Often, when an analysis reveals no dif- ference in outcome by sex, journal editors omit this information and gen- erally discourage researchers from including such information in the results (U.S. General Accounting Office, 2000~. GAO noted that the defi- ciency in reporting the outcomes of studies by sex appeared to be due in part to a lack of documentation of negative findings. In addition, when sex differences are reported, they may not be appropriately indexed by abstracting and indexing services, making it difficult to identify articles of interest (Montgomery and Sherif, 2000~. In fact, very few journals have any information or guidelines regard- ing analysis of data by subpopulations, such as sex, in their instructions for authors. Many journals refer to the "Uniform Requirements for Manu- scripts Submitted to Biomedical Journals" by the International Commit- tee of Medical Journal Editors, which states that when writing about meth- ods, researchers should describe their "selection of the observational or experimental subjects (patients or laboratory animals, including controls) clearly. Identify the age, sex, and other important characteristics of the subjects" (International Committee of Medical Journal Editors, 1997, p. 311~. However, the uniform requirements do not say anything about "age, sex, or other important characteristics of subjects" in the requirements for the statistics, results, or discussion sections of articles. The Journal of the National Cancer Institute ONCE has taken the lead in encouraging authors to include information on and analyses of subjects

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178 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH by sex. In October 2000, JNCI amended its Information for Authors to say, "Where appropriate, clinical and epidemiological studies should be ana- lyzed to see if there is an effect of sex or any of the major ethnic groups. If there is no effect, that should be stated so in Results" (Arnold, 2000; Jour- nal of the National Cancer Institute, 2000~. On the basis of the recent GAO report and other related reports, encouraging the inclusion of "negative data" (the absence of a finding of a sexual dimorphism may be an indica- tion of a similarity between the sexes) would be an important step. The phrase "where appropriate" regarding the need for analysis by sex, how- ever, may be interpreted and applied quite differently by different re- searchers. RECOMMENDATION 9: Make sex-specific data more readily available. 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 and researchers should give an informative statistic (e.g., means and standard deviations, t-test value for comparison, exact P value) rather than simply indicating that the comparison was not statisti- cally significant. Reporting of exact statistics allows the findings to be taken into account far more effectively in later meta-analyses. When de- signing or updating databases of scientific journal articles and other infor- mation, informatics developers should devise ways of reliably accessing sex-specific data. Information on Sex of Origin of Cell and Tissue Culture Material All somatic cells have a full complement of chromosomes, including the sex chromosomes. Despite this, useful information on the sex of origin of cell lines or tissue cultures is often lacking in the literature. Data sug- gest that many cells throughout the body display sex specificity. For ex- ample, human primary osteoblasts (a type of bone cell) isolated from pre- and postmenopausal women show age-dependent changes in their ex- pression of biochemical markers and responsiveness to hormones that are not observed in the same bone cells from younger or older men (Katzburg et al., 1999~. Receptors for sex hormones are present on a wide variety of cells. Arterial wall macrophages derived from circulating blood mono- cytes are known to take up lipoproteins and to form large foam cells. Such foam cell formation is an early event in atherosclerosis, and recent research suggests that the earlier onset and higher incidence of athero- sclerosis in men may be related to the presence of androgen receptors on

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CHALLENGES AND OPPORTUNITIES 179 the immune cells and androgen-mediated lipid loading (McCrohon et al., 2000). A great deal of research on human cell lines involves newborn fore- skin cells, which are obligatorily male. There is no equivalent source of female newborn tissue. Reviewers often ask whether the genital location of foreskin fibroblasts or keratinocytes modifies their behavior and makes them invalid models for the behaviors of cells derived from a nongenital location, but reviewers do not ask if male versus female sex is similarly relevant. The fetal fibroblast-like cell lines commonly used in aging re- search (e.g., WI-38 and IMR-90 cells) are nowhere characterized as male versus female, nor has anyone questioned the relevance of cellular sex in studies with these lines. (The large number of malignant immortal cell lines available from the American Type Culture Collection and similar sources are rarely identified by sex, but even if they were it would be extremely difficult to interpret differences among donor lines, as the ex- pression of many genes is presumably abnormal by virtue of the malig- nant transformation process.) Few to no data are available for determination of whether cell sex matters when studying such functions as cell life span and the response to stresses. Information about the sex of origin of cells and tissues, however, could be very useful and even critical for interpretation of results and for comparison of results across disciplines. Because the sex of the source of eukaryotic cells used in research can readily be determined by DNA se- quencing, it need not remain an unknown. Many published studies, how- ever, do not report such information even when it is known. RECOMMENDATION 10: Determine and disclose the sex of origin of biological research materials. The origins 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 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. (The committee acknowledges that inclusion of people, animals, or cells and tissues of or from 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. Deter- mining and disclosing the sex of origin of biological research materials are important steps in that direction.)

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180 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Lack of Data on Sex Differences Across the Life Span from Longitudinal Studies 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. Several longitudinal studies, some spanning more than 40 years, have provided vitally important data that demon- strate sex differences, ranging from genetic differences to differences in diagnostic and therapeutic interventions, as individuals age (such as the Framingham Study and the Bogalusa Heart Study [Berenson et al., 1992; Dawber et al., 1951; Kannel et al., 1976; O'Donnell et al., 1998~. These studies have provided such information not only about the original par- ticipants but about their offspring as well. Those studies, however, were designed with specific disease end points, such as the risk factors for and the development of coronary artery disease, thereby precluding consider- ation of many other relevant developmental issues and other diseases, disorders, and conditions. Unfortunately, few such longitudinal studies exist. As a result, the lack of longitudinal studies has limited understand- ing in particular of sex differences throughout the life span. RECOMMENDATION 11: Longitudinal studies should be conducted and should be constructed so that their results can be analyzed by sex. Lack of Consideration of Hormonal Variability Data on cycles (menstrual, circadian, etc.) are often lacking. Most studies with women do not define which part of the cycle the participants were in at the time of study, note the participants only by age and not whether they are pre- or postmenopausal, or are based on only one cycle. Furthermore, characterization of the phases of estrous and menstrual cycles across studies is inconsistent and can lead to considerable confu- sion. For example, in studies with humans some investigators assess a phenomenon or condition during the luteal phase and take their mea- sures near the end of that phase, when progesterone levels are dropping or are at low levels, whereas others take their measures near the midpoint of the luteal phase, when progesterone levels are rising or are at their peak. Problems with timing the menstrual cycle for research are not insur- mountable, and several studies (including studies determining timing of the menstrual cycle for surgery for breast cancer prognosis) are under way (Hagen and Hrushesky, 1998; Jatoi, 1998; Macleod et al., 2000~.

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CHALLENGES AND OPPORTUNITIES 181 RECOMMENDATION 12: Identify the endocrine status of research subjects (an important variable that should be considered, when pos- sible, in analyses). INTERDISCIPLINARY AND COLLABORATIVE RESEARCH Uniformity in Application of Federal Regulations Interpretation and application of federal regulations regarding pro- tection of human subjects are at the discretion of university and industry institutional review boards (IRBs) and can be highly variable. For ex- ample, current federal guidance describes policies for inclusion of women in research protocols that may be applied more restrictively at the discre- tion of local IRBs. Similarly, the policies for the use of research animals set by institutional animal care and use committees (IACUCs) vary by insti- tution. Thus, the ability to study sex differences is not uniform across institutions, and there is a question of fairness, as some oversight bodies allow procedures that others do not. This lack of uniformity can inhibit collaborative work between institutions with different IRB and IACUC regulations. Uncertainties about how best to protect women in their childbearing years contribute significantly to the inconsistencies in the application of guidelines. A 1999 statement by the Committee on Ethics of the American College of Obstetricians and Gynecologists (ACOG) notes the valid con- cerns for the well-being of the fetus but states that "the resulting sense of restraint has limited the growth of knowledge in some areas of normal physiology, pathophysiology, and therapeutic approaches during preg- nancy" (Chervenak and McCullough, 1999, p. 206~. The ACOG commit- tee affirmed the need for research with pregnant women and offered guidelines for selecting, informing, and caring for pregnant women in clinical research studies. IRBs are a topic of great interest to the members of the Institute of Medicine (IOM) Clinical Research Roundtable (www.iom.edu/crr). In addition, the Office of Human Research Protection of the U.S. Depart- ment of Health and Human Services has commissioned IOM to do a two- part study on the future of IRBs. The first report will be a 6-month fast- track study that addresses accreditation standards for IRBs (expected release date, summer 2001~. The second part will be a full-length study of the overall structure and functioning of activities used to protect human subjects and the criteria used to evaluate the performance of activities used to protect human subject (expected release date, fall 2002~. The committee is encouraged by the attention that the problems of IRBs will receive from these two IOM activities and looks forward to their published proceedings and recommendations.

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182 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Opportunities for Interdisciplinary Collaboration The need for greater use of interdisciplinary collaboration in not unique to the study of sex differences. The committee refers the reader to the recent IOM report Bridging Disciplines in the Brain, Behavioral, and Clini- cal Sciences (Institute of Medicine, 2000~. Although the report is primarily concerned with brain research, the discussion of the issues and barriers related to interdisciplinary research and training and to translational re- search is relevant to the study of sex differences as well. The committee that prepared that report concluded that researchers sometimes perceive interdisciplinary research as impure or "second rate," with each disci- pline having a sense of superiority and believing others to be less rigor- ous. Moreover, students fear that interdisciplinary training will not prop- erly prepare them for a career. The National Research Council's Committee on National Needs for Biomedical and Behavioral Sciences noted in its recent report (National Research Council, 2000) that the number of researchers in the basic bio- medical workforce is sufficient to meet the nation's needs. It also encour- aged NIH to gradually shift the focus of its predoctoral programs from single-discipline to interdisciplinary training and increase opportunities for postdoctoral training through interdisciplinary training grants. In the study of sex differences, synergy is needed between and among basic scientists, epidemiologists, social scientists, and clinical researchers. There is a need for better translational or bench-to-bedside research. Data on interlevel integration (cellular, to animal, to human) are often limited. At the human level, collaboration across medical specialties is also needed. As noted in a 1994 IOM report, Women and Health Research, such col- laborations can be difficult as researchers from different disciplines look at different points along a causal pathway, use different tools, and obtain different results (Institute of Medicine, 1994~. Strategies for more effec- tive communication and cooperation are needed. As an example of mutual benefits that can come from interdiscipli- nary research, consider epidemiology and basic biological research. Epi- demiological studies can be used to identify areas in which basic research is needed. Information about environmental exposures that affect disease risk and pathogenesis could point to genes and biological mechanisms that modify risk. In the opposite and equally beneficial scenario, under- standing the biological basis of differences or similarities could help iden- tify unrecognized environmental risk factors (Hoover, 2000~. Collection of better data on exposures, including multiple exposures, could enhance analysis.

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CHALLENGES AND OPPORTUNITIES 183 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). NON-HEALTH-RELATED IMPLICATIONS OF RESEARCH ON SEX DIFFERENCES IN HEALTH Lack of Awareness That the Consequences of Genetics and Physiology May Be Amenable to Change A problem with discussing sex differences is that such differences, when shown to have a genetic or physiological influence, are thought to be immutable. Such sex differences are interpreted as being a direct result of chromosomes. Since an individual's sex chromosomes, either XX or XY, cannot be changed, people tend to think that differences between the sexes are also unchangeable (Valian, 1998~. Valian (1998) notes that "it is odd that we should interpret sex differences as immutable, when we do not accept biology as destiny in other aspects of human existence" (p. 67) and cites aging as an example. The human life span is set by biology, but people do not accept the average life span as their fate. Biology incorpo- rates mutually interacting factors, from genetic to psychosocial, across the life span. Great amounts of time and many resources are put into research on understanding mechanisms of disease and developing cures. People eat certain foods, take vitamins, exercise, and take preventive treatments such as vaccines, all in attempts to prolong life. Discriminatory Practices Based on Sex Differences Historically, studies on race, ethnicity, age, nationality, religion, and sex have led to discriminatory practices. Participants in the Research De- signs and Gender working group at the NIH Scientific Meeting and Pub- lic Hearing on Influences of Sex and Gender on Health in 1996 noted that

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184 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH in the past it has been difficult to publish findings on sex differences. "The paucity of studies on neuroendocrine aspects of female functions may be attributable to a belief that it was not politically correct to acknowledge different functioning at different times of the month for fear of discrimi- nation based on the differences" (National Institutes of Health, Office of Research on Women's Health, l999d, p. 97~. Scientific research is not separate from other practices of society. Bias in interpretation or reporting by observers is well documented in the social sciences but is less obvious in the basic and clinical sciences. Yet, scientific theories, questions, and data are also subject to biased interpre- tation (Institute of Medicine, 1994~. Such biases and the tendency to per- ceive one sex (classically, males), race, age group, or other subpopulation to be the norm can portray differences displayed by others as "deviant" (Institute of Medicine, 1994~. To acknowledge and explore nonreproduc- tive aspects of sex differences in health and illness requires a view of males and females as different but equally "legitimate" biological entities without respect to whether there is (or should be) equivalence or equality in all other domains. 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 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.