Medicine’s deadly gender gap

New research on pain, medical devices and even PMS reveals big holes in our knowledge of the female body.
Medicine’s deadly gender gap
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In 2004, Barbara Colbourn began experiencing pain in her legs when walking. The 61-year-old London, Ont., office manager tried to ignore the discomfort at first. Six months later, she went to her doctor, who diagnosed peripheral artery disease, or PAD. Colbourn had never heard of it—and was shocked to learn it was a chronic disease caused by atherosclerosis, or hardening of the arteries, of the legs, feet or arms that puts people at higher risk of stroke, heart attack and death. When she was asked to participate in a 24-week international treatment trial organized by London clinical trials nurse Marge Lovell, a PAD awareness advocate, she agreed. Like many women over 60, Colbourn’s health concerns were fixated on breast cancer and heart disease. “Hardening of the arteries was something my grandma had,” she says.

Now 69, Colbourn takes baby aspirin and a cholesterol-lowering drug and exercises daily to prevent the disease’s progression and stave off invasive surgery. There were warning signs she ignored, she says. She had to give up curling in her 50s because her feet were always cold. “Never in my wildest dreams did I think it could be serious.” Just how serious was made clear in a study in the January 2012 American Heart Association journal Circulation: it called PAD an unsung “pandemic” that afflicts more women than men, contrary to previous assumptions. Research in women has lagged behind, says cardiologist Alan Hirsch, a professor at the University of Minnesota medical school who chaired the study. Just as heart disease manifests itself differently in women, so does PAD, says Hirsch, whose study revealed that women with PAD, which afflicts some 800,000 Canadians, are more likely than men to have a limb amputated.

Diagnosed by a simple test that compares arm blood pressure to leg blood pressure, PAD is the “most common, deadly and costly cardiovascular disease that the public hasn’t heard of,” says Hirsch; in 90 per cent of cases, it’s asymptomatic. That so few women have heard of PAD doesn’t surprise Hirsch, who says women have been routinely overlooked in vascular research: “It is embarrassing how many hypertension, lipid studies, and stent trials were done with low [female] enrolment. Every vascular disease I know of except aortic aneurysm is more common in women—venous diseases, lymphedema, PAD—yet we don’t know why and we don’t talk about it.”

A lot of recent research exposes how little we know about the XX body. A report in the February 2010 Annals of Internal Medicine found that women with implantable cardioverter-defibrillators (ICDs) are more likely than men to develop complications. The reason? Testing was done primarily on men, who tend to be physically larger. Stephanie Brister, a surgeon at Toronto’s Peter Munk Cardiac Centre, would like to see women-only randomized clinical trials for ICDs, though she’s not optimistic. “It’s not cost-effective,” she says. “More likely we’ll try to increase the number of women, then hopefully we’ll have a substantial representation with real information.”

It may not seem that surprising to many that women have been so overlooked in vascular research. After all, it wasn’t until 2003 that the American Heart Association issued separate guidelines for women based on the fact that heart disease manifests itself differently in each sex. More shocking are the holes in our fundamental knowledge. A Stanford University School of Medicine study in the January Journal of Pain, for instance, found women reported more intense pain than men in virtually every disease category, and recommended stronger efforts to recruit women in clinical studies to find out why. And the biggest eye-opener: emerging research suggests our entrenched assumption about PMS transforming women into erratic harridans is based on research that didn’t even use women. Rather, to peg hormone levels to mood, most researchers have used theoretical “menstrual cycle phases” which can be wildly imprecise given vast differences between individual women, says neuroscientist Gillian Einstein, a professor at the University of Toronto. Einstein is one of six female authors of a study, “The Role of Ovarian Hormones in Daily Mood,” which was presented as an abstract at the Society for Neuroscience conference in Washington last November. Measuring women’s reported moods directly with their estrus cycles, they found a correlation between mood and hormonal levels exists, but that mood fluctuations are more linked to stress levels and general physical health. The research, which has yet to be published, could be groundbreaking—and not only in ending PMS jokes. It paves the way for a new understanding of half of the population.

The female body has been subject to rapt scrutiny for millennia—in painting, poetry, even beer commercials. But in terms of scientific research, women remain an unmapped continent. That may seem improbable given the seemingly relentless focus on “women’s health”: nine editions of Our Bodies, Ourselves, pink-ribbon campaigns, advances in breast-cancer screening technology, an HPV vaccine, government-funded studies. Yet female under-representation in scientific research mirrors that in politics and executive suites, with two significant differences: it puts women’s health directly at risk; and it limits our scientific knowledge.

The imbalance has been discussed for decades, notably in Rebecca Dresser’s landmark 1992 essay, “Wanted: Single, White Male for Medical Research” (one of her examples is a pilot project studying the role of obesity in breast and uterine cancer that featured only white men). The bias is “nakedly discriminatory,” Dresser wrote, given the knowledge that even “gender-neutral” conditions—heart disease, depression, AIDS—manifest differently in men and women. Twenty years later, the gap remains, despite legislation in the U.S. and less enforceable “guidelines” in Canada. As Anne Zajicek, a clinical pharmacologist at the U.S. National Institutes of Health (NIH), put it in 2010: “Things have been tested in 70-kilo, 22-year-old men since forever, basically.”

Back in the 1980s, the NIH established a policy that all research it funds must include female subjects when appropriate; Congress made it law in 1994. In 2000, when Canada’s scientific funding body, the Canadian Institute of Health Research (CIHR), was founded, so too was an Institute for Gender and Health. Joy Johnson, scientific director of the latter institute, says there’s a long way to go in terms of educating people about the importance of studying differences in sex and gender, but she’s optimistic: “My experience has been that once you make the case and explain that this is not ideologically driven, that this is about good science, then people get it.”

Yet even with more women being included in trials, we don’t have good data, Johnson says, because sex-specific results don’t have to be reported separately. That’s also the case in the U.S., where a 2010 Institute of Medicine report concluded that progress in women’s health has been slowed as a result. A 2011 study from George Washington University spells it out: average enrolment of women in clinical trials rose to 37 per cent between 1995 and 2010. But only 28 per cent of publications referred to sex/gender-specific results.

Hirsch blames an entrenched status quo for some of the bias: “Middle-aged white male physicians have not made the effort to make clinical trials representative—whether it’s women, Native Americans, immigrants. We tend as clinicians to recruit people who look like us and speak the language we speak.” Ruth Faden, executive director of the John Hopkins Berman Institute of Bioethics, has put it more bluntly: “Scientists need to realize women are not men without penises.”

Even the influx of female doctors and scientists hasn’t made a dent in some fields. Stephanie Brister says that when she started as a cardiac surgeon 25 years ago, only 20 per cent of her patients were female. That hasn’t changed, despite awareness campaigns. “It’s retrograde,” says Brister. “For 25 years we’ve been trying to get the message out that more women should be [given] more aggressive treatment because if they are, they do well. Yes, the risk might be higher than for men, but it’s not so high that it negates the benefit [for women].” A similar gender imbalance exists in surgery referrals for osteoarthritis, a condition afflicting far more women than men. A 2008 study in the Canadian Medical Association Journal that sent a man and a woman with moderate osteoarthritis to 67 different physicians found that orthopaedic surgeons were 22 times more likely to recommend surgery to a man than a woman and that GPs were twice as likely to recommend surgery to a man.

The issue is complex, Brister says. One of the limitations of her ICD study was that researchers couldn’t determine whether doctors use different criteria to refer men and women to cardiologists. “It’s hard to sort out whether it’s a referral bias or a protocol bias, even in drug trials,” she says. “Perhaps women aren’t interested in participating—maybe they have too many demands. Or they’re not available for follow-up. It’s not clear.”

Janine Austin Clayton, the acting director of the NIH’s Office of Research on Women’s Health in Bethesda, Md., sees the medical gender gap as systemic. “I don’t believe it’s a malevolent exclusion in most cases,” she says. It begins in basic science, she adds, where tissues and animals studied are predominately male. A 2009 report in Neuroscience and Biobehavioral Reviews looked at nearly 2,000 animal studies and found a bias toward the use of male animals in eight of 10 disciplines: neuroscientists used 5.5 males for every one female, pharmacologists used five and physiologists used 3.7. And though women are twice as likely to be diagnosed with major depression, fewer than 45 per cent of animal studies on these disorders used females.

The reason? Using male rats is easier, faster and less expensive. They don’t have an estrus cycle, they don’t get pregnant, they cost less than female rats and they offer more bang for the buck by providing both Y and X chromosomes. Testing on females is not commensurate with doing science as science is set up, Einstein says—where you have one variable and everything else is kept constant. To properly figure out where a female lab rat is in her estrus cycle, for example, a researcher must go into the rodent colony and do a vaginal smear every single day.

The biggest complication women bring, of course, is also the biggest sex difference: pregnancy. After DES and thalidomide given to pregnant women in the 1950s and ’60s caused birth defects, the U.S. Food and Drug Administration (FDA) banned any woman who could become pregnant from participating in clinical trials in 1977, then revoked the ruling in 1993 under pressure from women’s groups. Yet unless a trial specifically mandates female participation—say, testing a new birth control pill—pharmaceutical companies have little motivation to recruit women due to fear of litigation related to pregnancy or breastfeeding risks. As a result, women remain unknowing medical guinea pigs in some areas. One problem is the fact that a “standard” dose for a man can be excessive in a woman. Also, female QT, or heart rhythm, is slower (we don’t know why), which makes certain drugs—antipsychotics, antibiotics, even heart medications—that prolong the QT rate more dangerous for women. The FDA removed 10 drugs from the market for safety reasons between 1997 and 2001; eight posed greater risks to women.

Yet women are routinely prescribed more drugs than men. A study presented last month at Women’s Health 2012: The 20th Annual Congress in Washington found that women are prescribed an average of five medications, compared to 3.7 for men, even after accounting for prescription contraceptives. It also found women are less likely to be prescribed drugs according to clinical guidelines, or “off-label.”

Attitudes to studying sex and gender in medicine are changing, says Einstein, pointing to the example of high-profile scientist Irving Zucker decrying the male-animal bias in the June 2010 Nature. “When it was just women talking about it, it didn’t make a difference,” she says wryly. Governments are also making noise. Last December, the FDA released a draft guideline recommending sex-specific analyses and calling for more women in clinical studies. Canada, which takes its regulatory cues from the U.S., followed suit. Last year, the CIHR ruled all funding applicants must say whether they’re investigating both sex- and gender-related factors in the research and, if not, why not. In January, Health Canada sent out a draft of a policy paper, “Considerations for Inclusion of Women in Clinical Trials and Analysis of Data by Sex,” for feedback. The first update of the paper since 1997 has broadened its scope to include women of all ages, as well as more therapeutic products. Still, critics contend it’s toothless. “It’s not enough,” says scientist Abby Lippman, a professor emeritus at McGill University. “Plans to ‘suggest’ but not make mandatory the inclusion of women and the treatment of all data with intersectional analyses are not likely to fill the holes that need filling in our knowledge.”

One of the biggest gaps surrounds pregnant women, says Françoise Baylis, a professor of bioethics and philosophy at Dalhousie University and an advocate for including pregnant women in clinical trials. “Pregnant women get sick and sick women get pregnant,” she says. “And we have a moral obligation to recognize that women are as entitled to health care while they’re pregnant as when they’re not.” Without research, you can’t give good advice, she says, citing the H1N1 vaccine as an example of pregnant women being prescribed a medication that hadn’t been tested on pregnant women. “If you were pregnant and your doctor told you to take it, wouldn’t you have rather been told ‘This works’ or ‘This doesn’t work?’ ” she asks. Baylis is working on proposals that would allow pregnant women to be integrated into trials after safety and efficacy have been established, though getting regulators, scientists, corporations and women on side will be a challenge, she says, noting Health Canada’s new draft guidelines provide vague “initial guidance” on the inclusion of pregnant and breastfeeding women in trials.

Pregnant women use a swath of medications, many of which are untested on them, says Barbara Mintzes, an assistant professor of pharmacology and therapeutics at the University of British Columbia. Mintzes, who believes testing on pregnant women is ethical but urges caution, is concerned about creating an incentive to extend the marketing of unnecessary products. “There should be good suggestive evidence that a treatment is going to have a real benefit in pregnancy before starting a randomized trial,” she says, noting that 12 per cent of pregnant women are prescribed selective serotonin re-uptake inhibitors (SSRIs) for depression “off-label,” even though limited scientific evidence suggests that neither pregnant women nor their babies benefit.

Studying sex differences provides new insight into disease, says the NIH’s Clayton, an ophthalmologist. Women comprise two-thirds of the visually impaired or blind population worldwide, she says: “We know autoimmune eye diseases are more common in women. What’s less known is that retinal diseases are too. We don’t know why. Age is a risk factor for ocular diseases, but that doesn’t account for all of the difference.”

Mapping the female brain is also rich uncharted terrain, says Einstein, that could provide vital clues into Alzheimer’s, which afflicts more women than men. Wilder Penfield’s famous “homunculus” brain map is based only on men; a corresponding “her-munculus” doesn’t exist. “We don’t know how the female brain changes with the ovulatory cycle and age,” she says. “We’re already seeing evidence that ovaries are playing a protective role, even post-menopause.” Walter Rocca, a professor of neurology and epidemiology at the Mayo Clinic, has found women who have their ovaries removed prior to natural menopause have a higher risk of all causes of death.

The power of estrogens has been vastly underrated, says Einstein, who believes they’ve been given a “bum rap” by science, especially after hormone replacement (HRT) trials were shut down in 2002 when estrogen and progestin taken together were found to increase the risks for heart disease and breast cancer. Subsequent studies, including one in the April 2011 Journal of the American Medical Association, found estrogen-only HRT actually reduced the risks of heart attack and breast cancer. Yet getting funding to study estrogens remains difficult, she says: “They’re treated like a toxic chemical.” It’s an attitude based on ignorance, she adds. “It irks me when people say that estrogen is a female hormone. It’s also incredibly important in males.”

Einstein’s currently at work on a “re-theorizing” of women’s health, investigating biological and societal factors. The biomedical model in place now is a car-mechanic model, she says: “If something’s wrong with the carburetor, you replace it.” But that approach doesn’t work as well on chronic “autoimmune” conditions—multiple sclerosis, lupus, rheumatoid arthritis—which are far more common in women. Studying women can teach us a lot about the treatment of and care for chronic diseases, which place far more of a burden on the health care system, she says.

It could also yield new measurements for subjective complaints dismissed as “psychological” because they don’t match objective measures based on men, such as poor sleep. “More women than men complain of poor sleep, but when they have [a sleep study], their sleep architecture is fine, so people interpret it as women just complaining when maybe the measurement isn’t what it should be.”

A call to action is required, says Hirsch, who cites PAD as an example: “If women got the message, attitudes would change within one or two years because women would demand it.” Women’s risk of breast cancer is one in 11, and women can’t imagine not being screened, he says. “But the risk of PAD is higher and no one is warning them. Women should be aghast.” He has a point. But for women—and men—to be aghast requires knowing what we don’t know. Barbara Colbourn, for one, says her PAD diagnosis has made her more militant about her health. “We don’t know enough,” she says. Even knowing that is a starting point.