Special Treatment

Studies of men guide many medical therapies for women, but diseases often hit the sexes unequally. New efforts to tease apart physiological differences between the sexes promise to improve health care for women--and for men.

In polling booths and in paychecks, women deserve to be treated the same way as men. But there's at least one place where equal treatment is inappropriate--even dangerous: in the doctor's office. Some age-related illnesses manifest themselves differently in the two sexes. Yet most medical treatments for women are based on studies of men. Now, researchers are working to understand and exploit these sex differences. Such discoveries could lead to therapies customized for men or women, improving everyone's health in old age.

Medical science has suffered from "the cult of the typical 70-kilogram man," says Sherry Marts, vice president of scientific affairs at the Society for Women's Health Research, a nonprofit organization based in Washington, D.C. "Anything you didn't find in a 70-kilogram man was somehow atypical, and women were just small men with different plumbing and a hormone problem."

Researchers have excluded women from health studies for a variety of reasons. They've been reticent to risk putting a fetus in harm's way, should a female subject become pregnant during the course of a study. Scientists have also been concerned that women's cycling hormonal patterns would confound the data.

But a movement to include women in clinical research and develop sex-specific treatments has gained momentum. In 1993, the National Institutes of Health (NIH) mandated that clinical studies include women as study subjects; now, more than 50% of participants in trials funded by NIH are women.

Some of the biggest differences to fall out of these inclusive studies concern the heart. Women lag behind men in incidence of heart disease by about 10 years. In addition, women don't have the same kinds of heart attacks as men do. They tend to get angina--squeezing chest pain--rather than the massive myocardial infarctions that often lead to sudden death in men. And women frequently experience heart attack symptoms that aren't typical for men. Rather than the classic "crushed chest" sensation and numb left arm, they often feel jaw and shoulder pain and suffer nausea and heartburn. "Women are much less likely to get the Hollywood heart attack," says Marts.

"For a long time, if you were a woman in your late 30s to early 60s, ... it was very hard to get anyone to consider that you may be having a heart attack," she says. "There are stories of women showing up in the emergency room complaining of symptoms like this, being given a bottle of Maalox, and dropping dead in the parking lot of a heart attack." But heightened awareness of female-specific symptoms has dramatically improved the diagnosis and treatment of heart trouble in women.

Physiological distinctions between men and women--and cells from the two sexes--provide further support that treatments should sometimes be customized according to sex. One obvious factor is estrogen. Women lose their protection against heart disease after menopause--when estrogen quantities plummet and their rate of heart attack begins to approach that of men. So researchers have implicated a dearth of estrogen in the rise in the rate of heart attacks. At the cellular level, that idea has merit. Estrogen softens and relaxes blood vessels, for instance, and discourages the formation of fatty plaques by helping bodies maintain a healthy balance of cholesterol-carrying molecules. Yet hormone replacement therapy increases the risk for heart attack in women over 65 (see "Hot Flash!"), suggesting that something else is at work.

That something could be mechanical. Women's hearts are smaller and tend to beat faster because they can't push as much blood with each pump, says cardiologist Marianne Legato of Columbia University in New York City. This and other features can render them susceptible to abnormal rhythms and also might explain why such stutters are a more common side effect of certain drugs in women than in men.

Strokes also hit women in different ways than men. Because women live longer, they experience more total strokes--and stroke deaths. Yet for most of their lives, women suffer strokes at lower rates than do men of the same age; the rates don't start to converge until people reach their 70s.

And animal studies suggest that women need different stroke treatments than men do. In experiments on male mice, a protein called PARP in neurons was found to heighten stroke damage. Blocking PARP in males quells destruction, suggesting that the molecule is a promising target for stroke drugs. However, such compounds, it turns out, worsen strokes in female animals, Patricia Hurn of Oregon Health and Science University in Portland and colleagues reported in April.

Hints for novel treatments might lie in fundamental differences in how cells from males and females behave. For example, Robert Clark, a cell biologist at the University of Pittsburgh School of Medicine in Pennsylvania, and colleagues grew separate cultures of brain cells from male and female rats and found that those from males die more readily when exposed to a compound that exacerbates stroke damage. The cells even die differently: Male cells are messier, says Clark. "The male cells explode, and female cells shrivel," he says.

In addition to stroke, the findings might illuminate sex differences in age-related brain deterioration, Clark says. For instance, variations in death mechanisms between cells from males and females might help explain incongruities in neurodegenerative diseases, such as the observation that men are more likely than women to develop Parkinson's disease, and that women respond less well than men do to some PD treatments. The findings also suggest that conditions involving brain damage most likely require treatment with sex-specific therapies, says Clark.

Considering the sex of a subject can benefit not only women but men as well. For instance, in the 1990s researchers halted trials of one promising medication to minimize stroke damage, called tirilizad, because the drug didn't perform better than the placebo did. But subsequent analysis suggested that the treatment failed because women did exceedingly poorly on it: They frequently suffered seizures, for instance. Had scientists processed the data from men and women separately from the outset, the treatment might have proved successful in men despite failing in women, Hurn says.

"Men and women are different enough to study both sexes," says Legato, "and they are different enough that we should change the practice of medicine." In this enterprise, a little inequality might help improve health care for everyone.

R. John Davenport is an associate editor of SAGE Crossroads' sister site, SAGE KE. He's been known to bake and dust.

Note: This article addresses issues that will be discussed during a special debate on "Women and Aging" cosponsored by the Women's Bioethics Project and SAGE Crossroads. The live event will take place in Seattle, Washington, on June 8, and the discussion will be rebroadcast in a webcast on June 21.