For the first time, says JoAnn E. Manson, M.D., Dr.P.H., a research program may get "conclusive answers" to questions about women's health. Photograph by Kris Snibbe. Photo illustration by Jim Gipe

Ah, chivalry. We know it as that noble male quality that obligated Saint George to endure a dragon's sulphurous breath so a fair maiden would go free. But chivalry's legacy has been mixed: while it may have opened a few doors for women, historically it has closed many more. And, unfortunately, chivalry has excluded women from serving as study subjects in most biomedical research.

Although few research protocols require anyone to smell dragon breath, new and unknown drugs have had severe and even fatal consequences for women and, particularly, their children. Thalidomide, prescribed to pregnant women in England and other foreign countries as an antidote to morning sickness, deformed more than 8,000 infants before the drug was pulled from the market.

A more insidious story is that of the synthetic hormone diethylstilbestrol (DES), which was prescribed in this country from the 1940s through the 1960s to prevent miscarriages. Mothers who took the drug remained healthy themselves and gave birth to healthy babies. But years later, daughters of women who had taken DES suffered rare vaginal cancers and uterine deformities. Establishing the link between drug and side effect took years. In the aftermath of DES, the U.S. Food and Drug Administration (FDA), in 1977, excluded all premenopausal women from phase I and phase II clinical trials, which are used to establish drug safety and dosing levels. The regulation remained in effect until 1993.

Admittedly, including women of childbearing age in research studies poses many ethical problems. Although neither DES nor thalidomide was an experimental drug at the time these tragedies occurred, the results of their use nevertheless underscored the vulnerability of the developing fetus.

But the ban also reinforced a long-standing bias against including women in biomedical studies, a bias that spans the breadth of academic and industrial research. The FDA's brand of chivalry has been extended to all women, even those who are sickest and at highest risk of mortality. The reasoning seems to run along these lines: "Premenopausal women could become pregnant at any time; postmenopausal women are too frail."

The result has been a notable absence of women in numerous important lines of biomedical inquiry. Several nationwide studies of heart disease--the number-one killer of women (and men) in the United States--enrolled no women at all. It's almost laughable: the first clinical studies of how the female hormone estrogen affects heart disease were performed in men. But, as JoAnn E. Manson '75, M.D., Dr.P.H. '87, points out, the past tendency of medical research to neglect women has been no laughing matter.

"Because these original studies in men were discouraging, there was a loss of momentum," says Manson, an endocrinologist who is associate professor of medicine at Harvard Medical School and the School of Public Health, and co-director of women's health in the division of preventive medicine at Brigham and Women's Hospital. "Consequently, it's taken decades for us to make the commitment to studying hormone replacement therapy in large-scale trials among women."

Part of the problem has to do with how the medical research world uses the word "model." For years, in human physiology textbooks, the unspoken prefix to "model" has been "male": the 70-kilogram human male held the answers and, in many cases, dictated the questions. "When I was in medical school, most teaching focused on the male model," recalls Manson, "and with it came the assumption that everything about the efficacy of drugs--physiological or biological--could be extrapolated from that model."

Although many experts continue to maintain that there are few cases in which men and women respond differently to pharmaceuticals, there is little question now that there are vast differences between the sexes in how certain diseases are manifested. Perhaps the most important of these is heart disease, which kills more than half a million American women each year. It isn't any rarer in women than in men; it's just different, in a number of significant ways:

• Heart disease usually appears much later in women, possibly due to the protective effects of estrogen.
• Women are also much less likely to experience the chest pain typically associated with heart disease in men.
• The relationship between blood lipids and heart disease appears to be different in women than in men: low density lipoprotein, the so-called "bad cholesterol," appears to be less dangerous in women, while high density lipoprotein, the "good cholesterol," appears to offer them more protection.
• Reports that moderate alcohol consumption can protect against heart disease appear to have more relevance for men than for women, because women may incur increased risk of breast cancer from alcohol.
• Diabetes appears to predispose women, more than men, to heart disease.
• A woman's first heart attack is very likely to be her last; studies show that heart attacks are much more likely to be fatal in women than in men.

Better diagnosis and treatment require that we study and understand the natural history of heart disease in women in the same way we have already done in men. Real progess has been made, and many medical studies now include women whenever possible. Researchers have found that women are normally very willing study participants, but certain aspects of their involvement in research--just like their physiology--distinguish them from men.

There are a number of social, financial, and medical barriers to women who want to become research subjects. For instance, women are not only more likely to depend on public transportation, but also may be more threatened by the prospect of venturing out of familiar neighborhoods. More women have lower-paying jobs that may not allow the option of taking discretionary time for a research study. Many women have family members or friends depending on them for daily care and attention, and may be more focused on those duties than on their own medical needs.

But another important reason may have to do with most women's having "grown
up ineligible" for most medical research. According to Deborah Cotten, M.D., an associate professor of medicine at Harvard and an AIDS researcher at Massachusetts General Hospital, an ambivalent mood toward research exists among women. "Women were not invited to join in medical research as independent members of society," she says, "and that was ingrained in us."

Fortunately, the $628-million National Institutes of Health-sponsored Women's Health Initiative (WHI)--the largest clinical trial ever mounted by the federal government--is helping women make up for years of lost ground. JoAnn Manson, who coordinates the WHI effort at Brigham and Women's Hospital, says the study will provide important answers to questions about estrogen therapy's impact on heart disease, breast cancer, osteoporosis, and Alzheimer's disease, as well as information on other crucial issues related to women's health.

"We already have compelling evidence that estrogen therapy has favorable effects on cholesterol, and even some favorable effects on blood flow to the heart," Manson says. "Whether that's going to translate into a reduction in heart attacks and strokes, we don't know for certain. And we also don't know whether these hormones will increase the risk of breast cancer. We really need this randomized trial to get definitive answers to these questions."

Although women have been eager to join the WHI study, and most of the slots are taken, the hormone replacement therapy portion has been the hardest to fill, Manson says. "One reason has been that women in the Boston area are highly medicalized and sophisticated," she explains, "and most of them have made up their minds about whether they want to take estrogen. But we're still trying to reach anyone who wants to come out to participate in this highly important trial, and help get conclusive answers to these important questions."

It may feel a bit uncomfortable at first for many women. After all, they've been used to standing outside the research process for years, while men took the risks--and reaped greater rewards. But the time has come to take chivalry out of the laboratory.

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