Yes, Biologically Speaking, Sex Does Matter

Editor's Note: This is the first article in a series on sex-based differences in the biology of males and females, a topic that has gained momentum over the last decade. Subsequent articles will cover sex-based differences in brain structure and strokes, genetics, autoimmunity, and drug metabolism. Lisa Damiani When I was a kid, I always wanted to know why there were two sexes," recalls Florence Haseltine, director of the Center for Population Research at the National Institute of Child Health and Human Development. "From the time I was 4, I used to drive my father crazy. He said, 'Well, when you grow up, you figure it out.'" Haseltine, who has devoted much of her career to pursuing such questions, was heartened last April when the Institute of Medicine validated this budding area of investigation by issuing its report, "Exploring the Biological Contributions to Human Health: Does Sex Matter?"1 The IOM's overwhelming conclusion: it most certainly does. But to what extent, and how? The most often studied differences are in the reproductive system. However, over the past 20 years, and most rapidly in the last 10, scientists have accumulated data on differences between the sexes at many levels, from the cellular to the behavioral, from the clinical to the pharmaceutical. For example, health educators have been trying for years to tell the public about sex differences in heart disease using the general media: on average, men experience heart attacks 10 years earlier than women, and have a better rate of survival after one year. Symptoms also vary by sex: women experience shortness of breath, fatigue, and chest pain; most male heart attacks come on as a sudden, striking pain in the chest. But a recent survey, conducted by the Society for Women's Health Research (SWHR), is proof-positive that efforts to get the word out aren't working (www.womens-health.org/death.html). One in three women respondents at risk for a heart attack were unaware that they may exhibit different symptoms than men, and 17% of women who did know learned about them from their physicians. Courtesy of Raymond WoosleyRaymond Woosley Women and men also metabolize some drugs differently. Seldane, an antihistamine, was taken off the market for this reason a few years ago because it was causing arrhythmias, and in more women than men. "That means that if we had understood why women were responding differently, then maybe we wouldn't have had these problems," says Raymond Woosley, vice president of the Arizona Health Sciences Center in Tucson. "We would have dealt with them before the drugs ever got on the market and would have been able to prevent this problem." No agencies fund sex-based biology per se, except SWHR, a Washington-based advocacy group that Hazeltine helped found. A major force behind the IOM report, SWHR sponsors annual conferences on sex-based biology, funds a scholars-grant program in partnership with Pfizer Inc., and publishes the Journal of Women's Health and Gender-based Medicine. Health and Human Services agencies, including the National Institutes of Health, fund such work through their grant system, but under the heading of specific disease or basic biological areas. For example, in fiscal year 2000 the total budget for heart disease research was $566.2 million, with $80.7 million(US) allocated for women, $56.9 million for men, and $428.6 million for both. In comparison, the total for heart disease research in 1993 was $36.4 million, with $27.7 million earmarked for men. "The big picture is that we believe that there's a major benefit to medicine and society by understanding the natural differences between men and women," concludes Woosley. "It's not just being politically correct; it's good business, good health, and good science." A Coming Together In the past, most findings on sex-based differences were serendipitous, resulting from research that did not emphasize or concentrate on sex as a variable. These investigations either focused entirely on one sex or grouped males and females together, considering them a single population. Since the mid-1990s the situation has changed according to professor of clinical medicine Marianne Legato, Columbia University. Thanks to congressional legislation and a new focus on the sexes by governmental agencies like the Food and Drug Administration (FDA) and NIH, men and women are being looked at differently in the lab, says Legato, who is also director of the Partnership for Women's Health at Columbia.2 "We now look specifically at the difference biological sex makes and are finding differences in every system of the body, including how drugs are absorbed, metabolized, exert their effect, and are excreted from the body," she says. Rheumatologist Michael Lockshin, professor at Weill College of Medicine, Cornell University, New York, convened a meeting in 1999 about sex differences in immune disorders with basic biologists and physicians that included his twin brother, biologist Richard Lockshin from St. John's University, and his brother's wife, Zahra Zakeri, a basic biologist from Queens College. The proceedings were published as a special issue in the journal Lupus.3 "It was a small meeting, but it was one where you saw light bulbs going on in people's heads," recalls Michael Lockshin; the brothers were both IOM report committee members. At the meeting, physicians did learn that "sex does matter and does apply to a large number of clinical questions that have yet to be addressed," says Lockshin. In October 2001, the American Physiology Society sponsored a conference that looked at the integration of genetics and hormones in explaining physiological differences.4 Conference organizer Virginia Miller of the Mayo Clinic says that one of the meeting's main purposes was to "bring together people who don't normally talk with one another." Barriers to Progress According to Legato, the next step in this area of research--determining whether applying sex-based biology to patient care influences patient outcome--remains to be proven. "I have seen [this] impact change the care of women for the better in the field of cardiovascular medicine," she says. Although Legato and others have seen progress in some arenas, the IOM report spells out many barriers to progress in this nascent field, including the lack of additional sex-based research at the cellular level, clarifying the terms sex and gender, making sex-specific data more publicly available, and stating the origin of biological research materials, such as cell lines. "At this point, there's been a lot of focus on differences at the clinical level," says Theresa Wizemann, IOM study director. In 1994 the IOM issued a report on women in clinical research and subsequent changes were made in NIH-funded trials.5 Some outcomes from that study, says Sherry Marts, SWHR's scientific director, are that the NIH began including more women in clinical trials and requiring a scientific justification if they weren't. The goal of the April 2001 IOM report is to promote study of sex differences at the cellular and genetic levels, going beyond the hormonal. One of the report's recommendations is to have the sexes considered as a basic variable at all levels of biomedical and health-related research, instead of a field unto itself. But this can't happen until journals start asking authors to report differences between sexes in their articles, an IOM report recommendation. Denise Faustman, an associate professor of medicine at Harvard Medical School and the SWHR's board of directors' chair, does not blame any one particular publication. "It's more of a general theme from basic biology all the way up to the clinical viewpoint," she says. When space is limited, editors may opt, for example, only to include data from the strain of mice that does contract the studied disease, even if genetically identical cohorts didn't. "So things get cut out, even if you're very vigilant and concerned about this topic," remarks Faustman. In her field of autoimmune diseases, a huge difference exists in the penetrance of disease between men and women. While biomedical journals are not jumping on the bandwagon to include sex- difference questions in research, drug development seems to be getting on board. The FDA has widely disseminated the April 2001 IOM study to those who review basic and clinical drug data to educate these scientists about the underlying scientific validity of sex differences in drug metabolism. For example, says Susan Wood, director of the FDA's Office of Women's Health, her office conducted a retrospective study to see if there were any sex-based differences in the pharmacokinetics or pharmacodynamics of new drug applications. Wood's office went through about 300 new applications and found that a substantial number did have differences in the metabolism of a drug, but there was no clear pattern when broken down by metabolic pathway. Some drugs were metabolized faster than others in women. No changes in dosage were recommended. Says Wood: "We need to be able to take the next step" to determine in which cases sex-based differences are relevant, and to come up with a clear way to convey that information to patients and providers. For now, the IOM report is helping her to demonstrate to reviewers and the research community at large that addressing differences in sex is an important question to ask. Karen Young Kreeger (kykreeger@aol.com) is a contributing editor. References 1. Institute of Medicine, Exploring the Biological Contributions to Human Health: Does Sex Matter? T.M. Wizemann, M. Pardue, eds., Washington, D.C.: National Academy Press, 2001. 2. Legato is also editor of the online publication Journal of Gender Specific Medicine (www.mmhc.com/jgsm/index.shtml) 3. Lupus, 8[5]:335-416, 1999. 4. Original papers and review articles can be found in the October to December 2001 volumes of the Journal of Applied Physiology. 5. Institute of Medicine, Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies Vol. 1, A.C. Mastroianni et al., eds., Washington D.C.: National Academy Press, 1994. For More Information Institute of Medicine's report entitled "Exploring the Biological Contributions to Human Health: Does Sex Matter?"

Yes, Biologically Speaking, Sex Does Matter

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