Historically, medical research has been male-dominated in terms of subjects as well as researchers, even though women make up half of the world’s population. As a result of this gender bias, insights into various diseases and findings about medications have often been extrapolated from men and applied to women. But women aren’t just smaller men. Women’s bodies are decidedly different from men’s, with unique organs, genes, hormones, and other key differences.
It’s not surprising, then, that men and women experience many of the same diseases but develop different symptoms. With heart attacks, for example, the most common symptom is chest pain for men and women—but women may be more likely to experience other symptoms, such as shortness of breath, nausea or vomiting, or jaw pain. Women and men also metabolize and respond to many drugs differently. And there are gender-based variations in the physiological mechanisms underlying pain.
Some of these differences have been revealed through research that features gender parity. But many basic questions remain about how different health conditions and responses to drugs, vaccines, and other interventions are influenced by biological sex. “Within the last 10 years, there has been major progress on sex-informed research,” says Dr. Hadine Joffe, executive director of the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a professor of psychiatry in the field of women’s health at Harvard Medical School. But “it’s a mixed story because there’s still such a long way to go.”
Still, progress is being made. In March of 2024, a major advance occurred when President Joe Biden signed an executive order for the White House Initiative on Advancing Women’s Health Research and Innovation with the goal of “getting women the answers they need about their health” and providing greater funding for this research. This follows the passage of a 1993 law, mandating the inclusion of women in human clinical trials for all research funded by the National Institutes of Health. That was a big step in the right direction, but the same standard didn’t apply to animal studies—and a gender gap persists in non-human research, too. In a study in a 2017 issue of the journal ENeuro, researchers reviewed 6,636 research articles in six journals and found that while sex omission in studies using mice or rats declined from 2010 to 2014, sex bias persists, as more articles focus exclusively on males.
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On the upside, Joffe points to the National Institutes of Health (NIH) initiative Sex as a Biological Variable (SABV), which launched in 2016: It spells out the expectation that when researchers are seeking funding from the NIH for studies with animals and humans, they will factor sex into their research design, data analysis, and reporting of results. This is a tremendous development in principle but it doesn’t always play out the way it could or should. “Sometimes people don’t follow through on it because this is complicated research to do,” Joffe says. The gap may be even wider for women of color, research suggests.
In general, “women are still under-represented in research—female representation isn’t proportionate to the burden of disease in many clinical trials,” says Dr. Jecca Steinberg, a maternal-fetal medicine fellow at Northwestern University Medical School in Chicago. In a study published in a 2021 issue of JAMA Network Open, Steinberg and colleagues reviewed female participation in 20,020 clinical trials that had more than five million participants: They found that clinical trials in oncology, neurology, immunology, and nephrology had the lowest female representation relative to the burden of disease in women.
The findings in that study aren’t a fluke. In a 2022 study in Contemporary Clinical Trials, researchers evaluated the enrollment of female participants in 1,433 clinical trials of drugs and devices in the U.S. between 2016 and 2019. Of the 302,664 participants, on average 41% were female; this was true in cardiovascular disease and cancer. In psychiatry, the gap was even greater: While women comprise 60% of people with psychiatric disorders, the mean participation of women in psychiatric clinical trials was 4%.
These days, “many investigators are reluctant to emphasize sex differences in their research because of the emotional turmoil surrounding the evolving complexity of what gender means and what sex means,” says Dr. Marianne J. Legato, emerita professor of clinical medicine at Columbia University and founder and director of the Foundation for Gender Specific Medicine. “It’s one of the elephants in the room of why gender-based research or male-female differences are not being more courageously investigated.”
The issues of gender self-identification and gender fluidity are compounding these challenges. “It’s an extraordinarily and emotionally fraught topic,” Legato says.
Where progress has been made
The good news is that research on women’s health issues has brought many positive developments in specific areas. One relates to a better understanding of genetic factors in disease, particularly the role of high-risk genes, for breast cancer, notes Marcia Stefanick, a professor of medicine at the Stanford Prevention Research Center at Stanford University and director of the Stanford Women’s Health and Sex Diversity in Medicine Center. These insights have transformed the approach to prevention, early detection, and treatment of breast cancer, which has led to better outcomes for many women.
Another example of improvements: “I think the pharmaceutical industry is more cautious now to look in drug trials at the biological impact in males and females,” says Legato. This is a welcome development, she says, given that from 1997 to 2000, eight of the ten drugs that were removed from the market had greater risks for women, including unacceptable side effects. Indeed, research has found that women experience adverse reactions to drugs nearly twice as frequently as men do.
Meanwhile, the COVID-19 pandemic yielded some interesting discoveries of how the immune systems of men and women are different. It became apparent, for example, “that men were much more likely to die [while] women were much more likely to survive but develop symptoms of what’s called Long Covid,” Legato notes.
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Through research, it has also been discovered that men and women have different immune responses to vaccines. “In my research, we see that women mount greater immune responses until older ages to vaccines like the seasonal flu vaccine than men do,” says Sabra Klein, a molecular microbiologist and immunologist whose research focuses on sex-based biology, at the Johns Hopkins Bloomberg School of Public Health in Baltimore. “They experience more mild-to-moderate reactions such as malaise, headache, and soreness. But this is not translating into going back to companies to make different dosing recommendations for men and women.” Instead, a one-dose-fits-all-genders approach persists.
Where the gaps are most pronounced
Meanwhile, “female-exclusive conditions such as menopause and endometriosis are not the focus of a lot of research, especially translational research where discoveries are translated into products and treatments,” says Dr. Primavera Spagnolo, director of the Laboratory of Sex/Gender-informed Translational Neuroscience at Brigham and Women’s Hospital and an assistant professor of psychiatry at Harvard Medical School. As an editorial in a 2023 issue of the journal Nature noted, “Despite its importance for the health of half the world’s population, menopause is under-studied.”
In addition, “women’s health issues like obstetrics are under-represented in the medical literature,” says Steinberg. A study in a 2021 issue of the American Journal of Obstetrics & Gynecology Maternal-Fetal Medicine found that while obstetrical complications affect more than 33% of women throughout the world, obstetrical clinical trials represent only 2% of all clinical trials in the U.S., which “creates a huge knowledge gap,” Steinberg says.
Progress in closing the gender gap is also lagging when it comes to autoimmune disorders, such as rheumatoid arthritis and thyroid disorders, which affect more women than men. “We don’t know how to leverage knowledge regarding women’s immune function to improve treatment,” Spagnolo says. In the area of mental health, there are also significant gender disparities. Take post-traumatic stress disorder (PTSD): Women are two to three times more likely to be diagnosed with PTSD and to suffer more chronic and severe symptoms than men are, according to research in a 2024 issue of the journal Nature Mental Health. And yet “a lot of preclinical studies [on treatments] were done in males,” says Spagnolo. “Gaps like this are one of the reasons we encounter so many difficulties in figuring out if a treatment is going to be safe and effective in women. We need more funding on this kind of research.”
Sometimes even when men and women are included in clinical trials, researchers neglect to separate and analyze the findings by gender. “There still is abysmal aggregation of data between men and women,” says Klein.
What needs to change
Fixing the gender bias problem will not happen easily. Aside from the complexity of designing the research, a funding inequity is contributing to the gender gap in medical research. When ranked by funding amount, research on diseases that affect mostly or exclusively women—such as migraine, endometriosis, chronic fatigue syndrome, and anxiety disorders—are underfunded relative to the burden they place on the female population, according to an analysis in a 2023 issue of Nature.
Then there’s the challenge of bringing increased research-based knowledge about gender disparities into clinical practice. Take the issue of drug dosing, for example: “The immune system is different between men and women, and women’s body composition is different so they metabolize drugs differently,” says Stefanick. “The sleep medicine zolpidem [Ambien] is the only drug that has separate dosing recommendations for men and women.”
Gender differences in heart disease is another area where there’s been a disconnect between research findings and clinical practice. Even though the medical field began recognizing that women often experience different symptoms of heart disease than men do in the late 1990s, women are still “underdiagnosed and undertreated” for heart disease, Legato says.
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Indeed, a study in a 2018 issue of Women’s Health found that men with chest pain were 2.5 times more likely to be referred to a cardiologist than women, after presenting in primary care practices or an ambulatory care clinic. More recently, in a 2024 issue of the journal Cureus, researchers found that women with milder symptoms were less likely to be diagnosed with cardiovascular disease or likely to have their symptoms misdiagnosed as being gastrointestinal or anxiety-related; as a result, women received fewer diagnostic tests (such as coronary angiography and electrocardiogram, or ECG) and received fewer prescribed medicines (such as anticoagulants and statins) compared to men.
Clearly, more research needs to be done on gender differences in terms of the risks and manifestations of various diseases, as well as responses to treatments. More education of the public and those rising through the ranks of the medical profession is also necessary. “It’s the exception rather than the norm to teach about these differences in medical school, nursing school, and graduate school,” Klein says. “That needs to change. If you have patient contact, you need to understand these differences.”
