From the margins to mainstream: Tackling gender inequality in biomedical research

In the early 2000s, a woman named Mary was suffering from severe insomnia amidst rising pressures from her demanding job. Seeking relief, her doctor prescribed a standard dose of Ambien, a popular sleeping aid. After what felt like a restful night’s sleep, Mary rushed off to work, unaware that her Ambien dose had been too high. On her drive in, her slowed reaction time caused her to run a red light, causing a minor car accident. Thankfully, no one was hurt, but it was a terrifying wake-up call for Mary.

Years later, Mary discovered that Ambien is processed more slowly by women, leading to new recommendations for lowered doses in women. If the initial clinical trials of Ambien had included an equal representation of men and women, Mary and countless other women may have been saved from dangerous situations caused by Ambien overdosages.

This discrepancy in Ambien dosages is not the only instance of a failure to account for differences between men and women. Historically, women’s health research has been underfunded and its importance underappreciated. In March, President Biden signed an executive order that will promote women’s health research and called on Congress to dedicate $12 billion to the cause. So far, $100 million of federal funds have been invested in researchers and startup companies studying conditions that impact women solely, differently or disproportionately.

The tides are changing, but continued public education and advocacy are essential to make gender equality in biomedical research a mainstream practice.

Women are underrepresented in clinical and basic science research
In the past, clinical research studies enrolled only men and used the data as a proxy to inform treatment decisions for women and intersex individuals. In fact, in the 1970’s, the Food and Drug Administration (FDA) actively promoted the exclusion of women from Phase I and Phase II clinical trials, fearing the trials would negatively impact fertility.

"Women are 50% to 75% more likely to have bad side effects to medications compared to men."

-- Rachel Stubler

Following extensive protests, a National Institute of Health (NIH) policy was adopted in the late 1980’s to encourage the inclusion of female participants. A decade later, the NIH Revitalization Act of 1993 made inclusion of women in research trials a legally enforceable requirement. Because of this act, all studies funded by the NIH since 1994 must comply with this policy.

The push for equal representation in clinical trials revealed that men and women respond differently to many different medications. Some of the many biological differences between women and men include increased fat mass, slowed transit of food and drugs through the gastrointestinal tract, and slowed kidney filtration.

These factors greatly influence the way that drugs are absorbed, resulting in women requiring different drug doses. Women experience a pendulum of complications - some medications exhibit increased effectiveness, while other medications show increased sensitivity. These differences contribute to women being 50% to 75% more likely to have bad side effects to medications compared to men. In fact, from 1997 to 2000, unexpected risks to women accounted for 80% of FDA-approved drugs being removed from the market.

The inclusion of women in clinical research has greatly improved our understanding of how sex differences contribute to how well medications are tolerated. However, achieving gender equality in clinical research remains an ongoing challenge. Despite mandates for inclusion of both sexes, a 2019 meta-analysis found that women are still underrepresented in clinical studies in 7 out of 11 disease categories.

While there have been efforts to increase the representation of women in clinical research, this advancement stands in stark contrast to their persistent underrepresentation in basic science and preclinical studies.

Research using animal models provides insights into disease mechanisms and potential treatment outcomes, paving the way for safe and successful clinical trials. However, many animal studies use only male animals. It wasn’t until 2016 that the NIH mandated the consideration of sex as a biological variable in animal studies.

Although this new policy was passed, it is not always implemented. In physiology studies, the ratio of male to female animals is seven to two while in pharmacology studies, it is a whopping five to one. Additionally, while attention has been drawn to considering sex as a variable in animal studies, little work has acknowledged or considered the impact of sex in cell culture models. This factor will be of increasing importance as more and more research uses advanced cell culture techniques such as organoid systems.

More studies are needed on conditions primarily impacting women
In addition to improving the representation of women in clinical trials, increased research on conditions that impact women solely or at a higher rate is desperately needed to improve healthcare outcomes. 

"Women make up 80% of individuals with autoimmune diseases and are twice as likely to be diagnosed with Alzheimer’s disease."

-- Rachel Stubler

Women experience unique health issues including breast and ovarian cancer and pregnancy-related conditions that require specialized research and treatment approaches. Additionally, many conditions impact women much more frequently than men. For example, women make up 80% of individuals with autoimmune diseases and are twice as likely to be diagnosed with Alzheimer’s disease.

Some proposed reasons for these sex biases include differences in sex hormones, having an extra X chromosome and environmental factors; however, research is needed to elucidate the mechanisms underlying these differences and provide tailored therapeutic strategies. Focused research addressing sex biases and the unique medical needs of women promotes gender equity in healthcare.

The path forward
Over the past few decades, we have made great strides in recognizing inequalities in medical research and we are beginning to address them. However, much progress is still needed to reach the point of women’s health equity. In recent years, women have surpassed men in representation of students receiving M.D. and Ph.D. degrees in the biomedical sciences. With increased representation in the field, women must continue to advocate for improved research policies.

Stories like Mary’s serve as a powerful reminder of the real-life consequences of gender disparities in medical research. In 2020 only 10.8% of the NIH budget was allocated to women’s health studies. Biden’s executive order aims to reduce this gap by creating a Fund for Women’s Health Research at the NIH. These funds will prioritize studies on women’s health and improve guidelines and standards for robust research on conditions impacting women. Specific topics of interest include breast cancer, lupus, rheumatoid arthritis, endometriosis and menopause. This executive order opens the door for a new era where women's health research is no longer an afterthought but a central focus of scientific inquiry. Together, we can bridge the gender health gap and create a more equitable and effective healthcare system.

Here are some great resources if you are interested in learning more and getting involved:

Women’s Health Access Matters

Society for Women’s Health Research

NIH – Office of Research on Women’s Health