When Larry Cahill was studying neurobiology and behaviour as a graduate student in the early 1980s, research labs were bereft of female mice. The accepted wisdom in the scientific community was that whatever findings came from studying male rodents could be applied to both sexes. Females had hormones, which would no doubt muddy the results.
Cahill didn’t challenge that way of thinking until 2000, when his research (a human trial that included women) uncovered a difference between the sexes: While recalling emotional memories, men used the right hemisphere of the brain’s amygdala and women activated the left. Cahill’s colleagues scoffed at his desire to research sex differences in the brain, calling it “a career killer.”
Neurobiology is just one area of research that has excluded females from trials. For decades, everything from dosage calculations for prescription and over-the-counter drugs (including pain relievers, antihistamines and antipsychotics) to treatment protocols (such as heart attack diagnostics and mental health referrals) has depended on research conducted largely on male subjects, be they human or rodent.
But a growing number of doctors and scientists are now challenging the long-held belief that you can apply research findings about one sex (males) to the other. Recent studies have found differences in the way women and men experience pain, metabolize medications, respond to vaccines, suffer brain injuries and present symptoms for conditions like heart disease. There is also evidence that suggests estrogen may play a role in the prevalence of lung cancer in non-smoking women and the high rates of Alzheimer’s disease in women.
Including “an adequate number” of women in clinical trials is a relatively recent development: It was made a requirement by the National Institutes of Health in the U.S. in 1993; similar guidelines were published by Health Canada in 1997, and by the Canadian Institutes of Health Research (CIHR) in 2009. But, to this day, research subjects still skew male, and women of child-bearing years are often left out of trials due to those pesky hormones, the fear of exposing fetuses to experimental drugs and a lack of volunteers. Just last year, a study by drug maker Sprout Pharmaceuticals on the effects of mixing alcohol and Addyi (the female Viagra) was made up of 23 men and two premenopausal women.
Even when a research pool is split evenly between the sexes, there’s no guarantee that the sex-difference data will be reported or applied to the outcome. A report from Boston’s Brigham and Women’s Hospital found that although more women are now included in trials, “researchers often fail to analyze data by sex or include hormone status or other gender-specific factors, making it difficult to uncover differences in incidence, prevalence and survivability between men and women.”“The scientific approach was to be as reductionist as possible,” explains Cara Tannenbaum, scientific director of the Institute of Gender and Health (IGH), an arm of the CIHR. “And therein lies the paradox: Being reductionist doesn’t serve complex human beings of different sexes and gender identities very well.”
Cahill, now a professor of neurobiology and behaviour at the University of California and an advocate for understanding the influence of sex in neuroscience, says ignoring sex in medical research can lead to potentially fatal misdiagnoses, ineffective treatments and unknown side effects. Take heart disease, which kills more women than all forms of cancer combined. We now know that women have different symptoms for heart attacks than men and a higher fatality rate. Yet the Brigham and Women’s Hospital report points out that women constitute only 35 percent of participants in all heart-related studies.
“What concerns me the most is lack of public awareness,” says Tannenbaum. “If you go to the doctor and you have an infection, do you ever ask, ‘Has this pill been tested in women my age?’ ”
Concussions are another area where sex differences are just now being realized, after decades of research being focused on men. Multiple studies have found that female athletes are more prone to concussions than their male counterparts; and, according to a 2013 study out of the University of Rochester, New York, a woman sustaining a concussion in the two weeks before her period is at risk of worse symptoms—and a longer recovery—than a woman whose injury occurs in the two weeks following. (Fluctuating levels of progesterone are to blame.) The researchers also concluded that women of child-bearing age experience mild traumatic brain injuries differently, more severely and for a more prolonged period than men.
“It is quite shocking that there isn’t more gender-based research overall,” says Angela Colantonio, a senior scientist at the Toronto Rehabilitation Institute. She has been studying brain injuries since 2006; her findings show that women experience more headaches and dizziness and report a greater lack of initiative in daily functioning following an injury.
Lynn Posluns, founder of the Women’s Brain Health Initiative (WBHI), became aware of a bias in the research of aging-brain diseases while fundraising for the Baycrest hospital in Toronto. “When they first started looking at Alzheimer’s, they went to veterans’ hospitals to study older patients — and they were [largely] men.”
With women making up more than 70 percent of Alzheimer’s sufferers, the fact that sex differences weren’t being studied set off alarm bells for Posluns. (And it may not just be that women are living longer; one recent study showed that women with the Alzheimer’s gene are twice as likely to succumb to the disease than men with that same gene.) Posluns launched the WBHI in 2012 to raise both awareness and funds to support sex-specific research. “Analyzing the science is very expensive. So we said, ‘We’ll top up the money so that researches can separate out the sexes, or, if they need female rats, we’ll provide money for the female rats.’ ”
She points to a study, published in March in the journal Neurology, that found that women retain their verbal memory longer than men. “One of the tests they give you for Alzheimer’s is a list of words to study, and 10 minutes later you have to repeat them. If a woman can retain the words longer than a man, it means that by the time she forgets them, she’s at a worse stage of the disease than the man.” This means that women could be missing out on years of treatment. “And, of course, as with many diseases, the earlier you intercede, the better. So is the incidence rate for women higher because they’re catching it later?”
There’s an element of “double jeopardy” for women when it comes to medical research, says Tannenbaum. Sex and gender are two separate factors that need to be studied — sex being the biological and physiological factors (such as chromosomes, biology and hormones) and gender being the socially and culturally accepted norms, behaviours, identities and relationships that can impact how a woman interacts with the medical system.
A campaign by Toronto’s Women’s College Hospital (WCH) — dubbed the Health Gap — is examining both factors. “Sex and gender have to be taken into consideration in the way we set up our programs, treatment recommendations, the way we talk to our patients and the way we design our systems,” says Dr. Danielle Martin, vice-president of medical affairs and health system solutions at WCH and an advocate for the Health Gap. “If we don’t, we are likely to end up designing things that systematically create gaps for women.” For example, women who suffer postpartum depression have, by definition, a newborn — and will likely have trouble making it to a 90-minute psychiatry appointment. Those with low incomes have higher rates of hypertension and chronic conditions related to stress and diet — yet limited child care resources and work scheduling conflicts are all obstacles to accessing health care.
Awareness of these issues is reaching a kind of critical mass: As of January, researchers applying for funding with the National Institutes of Health are now asked if they’ve “considered sex as a biological variable” in the preclinical phase (animal trials) — and to include a justification if they haven’t. In 2009, Status of Women Canada instituted a sex- and gender-based analysis policy for the country’s four federal health organizations, Tannenbaum says. As part of that policy, the CIHR includes two questions in its funding application so that researchers have to disclose whether their work will account for sex and gender differences. If the answer is yes, they have to explain how; if it’s no, they have to justify why not.
“In 2010, only about 25 percent of the researchers answered yes,” Tannenbaum says. “But once we started asking those questions, it made people think about it. And that number has more than doubled over the last five years.” It remains a consideration rather than a hard and fast rule, but the IGH is also involved in training its peer reviewers, who hold the purse strings for grants, on its importance. “It’s a carrot-and-stick approach,” says Tannenbaum, “but if you don’t [account for those factors], you won’t get judged very well.”
For its part, the WBHI joined the Canadian Consortium on Neurodegeneration in Aging, a five-year research program announced in 2014 by then health minister Rona Ambrose, as a funding partner to ensure that studies build in a sex and gender perspective. “It’s actually a core value [of the project], which is better than a priority, because a priority can change,” says Posluns. The program is still in the early stages, but Posluns, who was speaking about the issue at the Corporate State conference in Toronto in May, says the potential for findings is huge. “Is there a difference in how exercise affects the male and female brain? What about food? We know we synthesize drugs like Ambien differently than men because of hormones, so are foods synthesized differently as well, and should we be eating more of something, or less of something, that would be better for our brains? This could open up a huge amount of study. . . . We’re really going to start to make some headway.”
Cahill is optimistic that awareness of this issue has reached a tipping point, and campaigns such as the one by WCH will help spread the word even more. But patients also share responsibility in advocating for change, Martin says — by volunteering for trials, asking questions about medications and putting pressure on the government to address barriers to access and treatment. “That’s how we’re going to shift the balance.”