Where are the women? Researchers are on a quest for more representation in medical research
Despite constituting half the population, female subjects are still underrepresented in medical trials. At Northeastern University, a cohort of researchers is trying to close that gender gap.
In the Interdisciplinary Science and Education Complex on Northeastern’s Boston campus, models of human bones line shelves alongside machines that measure how much force it takes to break the real things.
It’s the lab of Sandra Shefelbine, a professor of bioengineering and mechanical and industrial engineering, who studies bone biomechanics. That includes how bone develops, adapts and changes in various conditions, such as with “hip hinge” sports, like hockey, that require players to bend over in a forward position.
Some of her recent research has focused on a hip joint condition called cam morphology, in which young players of these sports develop a bump, or cam, in part of their thigh bone, or femur. The cam forms in what’s known as the femoral neck, the narrower part of the bone directly below the part that fits into the hip joint.
“Bones are smart material,” Shefelbine says, because they adapt when the weight that they carry changes. That’s why children are especially prone to developing a cam in high-impact sports like hockey.
A 3D-representation of the top of the femur. The spherical structure, or head, fits into the hip socket. Cam morphology occurs when the femoral neck, below the head, widens to impinge on the joint. Here, cam morphology is represented by the dark red coloration below the head. Courtesy image.
But during the course of her work, Shefelbine came up against a glaring discrepancy. Even though two-thirds of the patients who experience this hip deformation are female, 95% of the studies on the condition only included men.
The omission was particularly alarming because, over time, a cam narrows the amount of space that the femur has to maneuver within the hip joint and can lead to hip arthritis in adulthood.
“Surely they’ve looked at this in females, surely,” Shefelbine recalls thinking. “Nobody’s looked at the formation of this bump in females, really?”
Shefelbine is not alone in picking up on the omission of women in scientific literature. In recent years, many books have exposed the systemic exclusion of women from science and the scientific process. Medications for conditions that affect men and women equally were approved based on studies that only included men. It was only in 1993, when Congress passed a law requiring the inclusion of women in clinical trials, that things slowly began to change.
The cost of this exclusion, meanwhile, is adding up. Kay Van Wey, a medical malpractice lawyer with over 40 years of trial experience, says that she sees “patterns of preventable errors” in her cases. Part of the problem is that, “Protocols, clinical practice guidelines, algorithms are developed for a wide range of conditions,” she says. Unless it’s something commonly considered “a female issue,” Wey says, “We’re getting health care that’s standardized for a man.”
Researchers at Northeastern are trying to change that. Shefelbine is leading studies that intentionally include female subjects. Other researchers are studying other aspects of the human body, including changes to the cardiovascular system during and after menopause and differences between sexes in how neurological structures develop.
Rebecca Shansky, professor and chair of the psychology department at Northeastern, says that many issues that are specific to women’s health, like reproductive health or menopause, “are seen as ‘niche.’ Even though, you know, we’re half the population.”
Closed doors
The exclusion of women and female subjects in medical research is not for lack of trying. Beyond the 1993 law requiring women to be enrolled in trials, the National Institutes of Health (NIH) in 2015 released guidelines on considering sex as a biological variable in conducting medical research. Researchers who hope to get NIH funding must provide “strong justification” rooted in data to study only one sex.
Other institutions have tried to make changes over the years. In 1999, the American Heart Association published a “Guide to Preventive Cardiology for Women” and a 2014 European Union regulation specified that categories of people likely to use a new medication should be included in the trials for that medicine, with special protections for pregnant and breastfeeding women.
Shansky notes that, anecdotally, from visiting labs and giving talks, there are still a lot of holdouts, which can mean that studies on males and females aren’t “part of the same story, from a publishing perspective,” she says. Studies in female subjects can wind up as an afterthought.
That’s a problem for many reasons. Kejal Kantarci, director of the Women’s Health Research Center at the Mayo Clinic, says that the “historical data that inform current medical treatments are often based on research that was conducted mainly on men. Or, when women were included, the research didn’t account for differences between women and men.”
Without the systematic inclusion of study subjects that can provide insight into the biological differences between male and female subjects, research that forms the basis of medical care will continue to be flawed, researchers say.
“Women go to the doctor because they have a certain set of symptoms, and because the disorder that they might actually have has never been described or studied through a female lens, the doctors are just baffled,” according to Shansky. It’s not just that doctors may not have the right — or any — answers.
Gaps in medical knowledge could also lead to what’s known as medical gaslighting, where a doctor doesn’t believe the patient is experiencing what they claim to be. Approximately 50% of women report having experienced medical gaslighting at some point in their lives, according to independent research platform Worldmetrics.
Medical gaslighting, Shansky continues, occurs far more frequently among “women and people of color because they don’t fit this very specific, textbook, male set” of symptoms.
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Overlooking those symptoms can have deadly consequences. Chiara Bellini, an associate professor of bioengineering who focuses on cardiovascular research, says that “It’s actually shocking when you look at the underrepresentation of female” subjects in her area, she says, especially since heart disease is the leading cause of death among both women and men in the U.S., according to the Centers for Disease Control and Prevention.
Bellini studies a condition known as aortic stiffening, where the aorta — the largest artery in the human body — loses its elasticity as it ages. That flexibility is important as it allows the aorta to maintain blood pressure levels. An aorta that stiffens too quickly, Bellini explains, can be a sign of premature aging.
Bellini notes that aortic stiffening can happen in anyone, regardless of sex, but not at the same rate. Notably, female subjects experience aortic stiffening at a slower rate until they hit menopause, but then “their cardiovascular risk kind of matches that of men,” she says. Figuring out why is part of her lab’s work.
Bellini studies these effects in mice for several reasons. For one, mice do not naturally experience menopause. Because scientists have to induce menopause, this provides a natural control group of animals that never go through the process. Additionally, some of her other studies — for instance, how smoke inhalation affects the cardiovascular system — would be dangerous for human subjects.
One of Bellini’s graduate students, Hannah Wilker, wrote in her dissertation that, despite clear differences in the cardiovascular risk factors between males and females the “research in animal models remains overwhelmingly biased, with over 70% of studies solely including male mice.” Fewer than 1% of the studies included menopause as a factor in their analysis.
In Bellini’s lab, they compare the difference in the rate of aortic stiffening of male and female mice as they age. In both male mice and female mice without menopause they find no difference, she says. In male mice and females that have been induced into menopause, however, they see a “big difference between early and late stage menopause,” she says. The later they are into menopause, the faster the stiffening occurs.
Wilker, who studied the effects of smoke inhalation on arterial stiffness, notes in her dissertation that accounting for sex-specific differences like “menopause is crucial when evaluating the cardiovascular impact of environmental stressors.”
Of mice and women
Bellini isn’t the only one dealing with a mouse problem. Mice and humans share about 80% of the same genes, and the genetic modification of mice is easily accomplished with today’s technology, making them ideal subjects for experiments that would be dangerous, or fatal, to humans. But scientists often still default to male mice in their studies.
Why do the boys get all the attention?
Shansky says that there are several reasons. One is the additional expense — in time, effort and money — of running the same experiment on two separate groups.
“Now, especially with the state of federal funding for science, money is tight for everyone,” she says.
She added that the current state of science, with its publish-or-perish pressures, is also not favorable to doing rigorous work. “It’s just not, because people’s careers and lives are on the line,” she says.
That problem may be compounded by a plethora of new, high-tech techniques, where “the expectations for high-profile papers now are that you use every technique under the sun,” she says. “Those kinds of experiments are very time consuming, they’re very labor intensive, they’re very costly.”
Then again, the resistance might also just be that it’s hard to move on from old habits, and that, for a long time, many scientists simply assumed that there wasn’t enough of a difference between males and females to warrant the additional effort or expense in many experiments.
But that’s not what her work has found. In some of Shansky’s current research, she says that they have identified neural fight-or-flight circuits in the brain that are different between the sexes, with areas of the prefrontal cortex that are thicker in females than in males. This kind of research shows how the structure of the brain itself develops differently in male and female subjects.
When they stimulate or inhibit this circuit, which originates in the prefrontal cortex and connects to another part of the brain, they observe opposite behavioral responses between the sexes in their mice. For instance, in response to mild foot shocks, male mice are more likely to freeze while female mice are more likely to dart across the chamber.
It all points to the complexity — and need — for really paying attention to sex differences, experts say. “We are in a new era in [female] health. We now understand that the female body is not a smaller version of the male form,” says Kantarci.
The hip bone’s connected to the…
However, the problem may run even deeper in the research community.
Shefelbine and her team knew that the key to understanding why women were more prone to the cam hip abnormality was to study women directly. Because female bones develop differently than male ones, Shefelbine says that the research in one is untranslatable to the other, at least in research like this.
But the first time Shefelbine tried applying for funding for her project studying cam morphology in female hockey players, “We got the response that ‘females don’t play ice hockey,’” she says.
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“That’s the problem we’re targeting.”
Shefelbine and Laura Wang, a Ph.D. student, are now running two concurrent studies, one using female ice hockey and soccer players between the ages of 7 and 17 and another between 18 and 35. In the first set, they use MRI scans to identify how early the cam begins developing, while in the latter they look for developed signs of arthritis in current and former athletes. That’s because cams aren’t usually diagnosed until adulthood, when they show up as arthritis.
Just based on the current understanding of female bone development, Shefelbine expects the cam to develop in a slightly earlier period among the young female group than it’s been seen in males.
The goal with all of this is prevention, Shefelbine notes, but “to have an intervention to prevent the formation, we kind of need to know, when does it form?”
The kind of work that Shefelbine, Bellini and Shansky are doing isn’t just helping to close the gap in medical research — it’s also inspiring the next generation of scientists.
When Wang arrived at Northeastern, she was excited to discover that she could conduct research, alongside Shefelbine, into female bone health. During her master’s studies, before joining Northeastern, all she wanted was to conduct medical research, but all the studies she read focused on male subjects.
“Why only males?” she recalls asking. “Where are the women?”
