Sex Differences Used to Study Disease

Compared to men, women are two to three times more likely to suffer from depression or anxiety disorders, 20 to 70 percent more likely to develop lung cancer from smoking, 10 times more likely to contract HIV during unprotected sex with an infected partner, and twice as likely to die within the first year after a heart attack. Women and men are different--and these differences may lead the way to a better understanding of health and disease in both men and women, says Phyllis Greenberger, executive director of the Society for the Advancement of Women's Health Research (SAWHR), source of the above statistics. On Nov. 2, the nonprofit organization sponsored a meeting in Washington, D.C., to encourage researchers to identify sex differences and to consider how these differences may be exploited to develop better treatments for human disease. Many advances in the understanding of gender differences have been made in the past decade, especially in the fields of mental health, immunology, and pharmacology. The push for more research on women's health started in the late 1980s as an "equity issue" to get more women enrolled in clinical trials, says Florence Haseltine of the National Institute of Child Health and Human Development in Rockville, Md. Now researchers can take advantage of recognized gender differences as a "scientific opportunity" to learn more about human physiology and disease. At the heart of the matter are the sex hormones. "Estrogen rules," says Gillian Einstein, a neuroscientist at Duke University Medical Center in Durham, N.C. "Estrogen acts on virtually every neuron in the brain." And estrogen's effects on the brain--and on every organ and tissue in the female body--may underlie fundamental differences in behavior, disease prevalence and progression, and drug response that distinguish women from men. Perhaps the most obvious place to look for the sex differences that underlie male and female behavior is in the brain. "The brain has a sex," says Einstein. And that sex-specific circuitry is largely determined by hormones that bathe the brain during development. But even in mature animals, estrogen can change the density of contacts between neurons. Working with female rats that had had their ovaries surgically removed, Einstein and her collaborators, Christina Williams and Phillippa Miranda, found that a brief treatment with estrogen increased the density of inputs to neurons in the hippocampus, a brain region involved in learning and memory. Chronic administration of estrogen, however, did nothing. The results suggest that physicians treating women with estrogen might need to consider when or how to administer the hormone to achieve the best effects in terms of brain function, says Einstein. Estrogen definitely affects mood and cognitive brain functions, says Donna Stewart, chair of Women's Health at Toronto University and the Toronto Hospital in Ontario. The hormone influences the amount of the neurotransmitter serotonin available in the brain, which may explain, in part, why women are more susceptible to depression and other mood disorders. The onset and severity of these conditions are usually greater after the onset of menstruation and after pregnancy, which suggests that hormones are involved. Female hormones probably also play a role in the development and progression of multiple sclerosis (MS), says Peter Riskind, associate professor of neurology and director of the multiple sclerosis program at the University of Massachusetts. This autoimmune disorder attacks the myelin that sheathes the axons of neurons, destroying their ability to transmit messages. Hormones such as estrogen may somehow modulate the immune reaction, protect the brain from injury, or help repair the damaged myelin. In fact, when estrogen levels are high, during pregnancy, the number of disease flare-ups decreases. "Some would argue that pregnancy is the most effective treatment we have for MS," says Riskind. Although MS is generally not as severe in women, more women get the disease than men, says Riskind. Women are more likely to experience a first episode indicative of MS, which could be visual loss, slurred speech, or muscle weakness. And based on one small study, they're three times more likely to have a second episode within 15 years of the first. But MS is not the only autoimmune disorder that preferentially attacks females. Women are more likely to suffer from rheumatoid arthritis, lupus, autoimmune thyroid disease, and a host of other autoimmune disorders. Why? A genetic mutation may derail T-cell education, particularly in women, says Denise Faustman, associate professor of medicine at Harvard Medical School and director of immunology labs at Massachusetts General Hospital. For decades, scientists believed that autoimmune diseases were caused by T cells running amok, mistakenly attacking the body's own tissue. But these lymphocytes probably misbehave because they were not properly trained to tell the difference between "self" and "nonself," says Faustman. Studying a mouse model of autoimmune disease, Faustman has found a mutation that precipitates disease in most of the female mice--but in less than 15 percent of the males. Understanding how males compensate for this defect may lead to novel drug treatments for autoimmune disease. Gender also affects the way people react to drugs. For women, the activities of certain enzymes that metabolize drugs change during the menstrual cycle, says Stewart. And oral contraceptives decrease the effectiveness of many drugs. Further, women are more likely to experience cardiovascular side effects from drugs--particularly from drugs that block potassium channels in the heart, says Raymond Woosley, professor and chair of pharmacology at Georgetown University Medical School. If you're interested in women's health, Pfizer Women's Health program and the Society for the Advancement of Women's Health Research is now sponsoring a grant to stimulate research into the mechanisms of disease in women. They will award three grants of $65,000 per year for three years. Applications are due on Jan. 19, 1999, and the awards will begin July 1, 1999. For more information, contact the program coordinator at (800) 201-1214. Web site: www.womens-health.org According to Woosley, women taking certain drugs are twice as likely than men to develop Torsades de Pointes syndrome, a life-threatening cardiac condition that can be brought on by some 40 different medications that cause the heart muscle to relax. These drugs include antihistamines such as Seldane (now removed from the market), cardiac drugs, and even a drug called cisapride, which is commonly used to treat heartburn. Despite studies such as Woosley's, physicians are not fully aware of the clinical ramifications of the differences between the way men and women metabolize and react to drugs, says Carol Braun Trapnell, director of medical affairs at GloboMax LLC in Hanover, Md. Braun Trapnell recently searched Medline for studies on clinically relevant examples of gender differences in drug response and says she came up with a "big goose egg." But the burgeoning field of pharmacogenomics should change all that. Scientists are now searching the human genome for genetic markers that may reveal how an individual will respond to a particular drug. By identifying and studying the differences in how people absorb and metabolize drugs, and how drugs affect them, physicians should someday be able to tailor treatments to an individual--man or woman--to optimize the benefit and minimize risks of adverse reactions. Clearly, many questions remain to be answered. "And that's great," says Jaqueline Wolf, associate professor of clinical medicine at Harvard Medical School. "It's what science is all about. Each answer leads to ever more questions." Which is why SAWHR, in conjunction with Pfizer Inc., is now offering grants to researchers who wish to study issues related to women's health, particularly in the areas of cardiovascular disease, mental health, or reproductive physiology. "We've come a long way in a short time," says Greenberger. Haseltine agrees. "When my daughter reached puberty, she wondered whether women's sense of taste changes during their menstrual cycle," she says. "She couldn't have asked that kind of question 10 years ago." Karen Hopkin is a freelance science writer based in Silver Spring, Md.

Sex Differences Used to Study Disease

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