Addressing Gender Disparities in Medical Research

Throughout much of medical history, the typical portrayal of the “average patient” has largely mirrored that of the average male. Medical research, encompassing clinical trials for new treatments, commonly employed male subjects as the primary standard. This male-centric approach, entrenched in societal gender norms and power dynamics, has left significant gaps in understanding the influence of sex differences on health, disease progression, and treatment outcomes.

The historical oversight regarding the importance of sex in health research has led to critical implications. A prime example is the study of estrogen, a key hormone in female reproductive health. Despite its role beyond reproduction, affecting various bodily functions including cardiovascular health, the wider implications of estrogen remained largely unexplored until recently. Carolyn Mazure, the Norma Weinberg Spungen and Joan Lebson Bildner Professor in Women’s Health Research at Yale School of Medicine, noted that “the first major study on the effects of estrogen on coronary heart disease, conducted in the 1970s, included 8,341 men and not one woman.”

The underrepresentation of women in clinical research has posed challenges in fully understanding how biological sex differences affect disease mechanisms and treatment responses. For instance, while it has been assumed that male and female bodies respond similarly to medical interventions, findings suggest that the reality is far more complex. Such misconceptions have had tangible consequences, particularly in treatment protocols. In the past, women diagnosed with hypertension were often prescribed diuretics, while men typically received angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers. Research has now revealed that these medications can elicit different adverse effects based on sex, emphasising the necessity for inclusive research.

Efforts to address these disparities gained momentum in the 1990s, after the U.S. Government Accountability Office published a report highlighting the underrepresentation of women in clinical trials for newly approved drugs. Of fifty-three drugs reviewed, it was discovered that many had female participation rates significantly lower than representative levels, particularly in cardiovascular drug trials.

The legislative response culminated in 1993 when Congress mandated federal trials funded by the National Institutes of Health (NIH) to include women and minorities. This landmark change aimed to enhance treatment accuracy and to meet the distinct health needs of historically underrepresented groups. In 1998, Mazure founded Women’s Health Research at Yale (WHRY) to spearhead comprehensive research on women’s health and its interface with overall health outcomes. “Our goal is [to] integrate those findings into professional practice and clinical education and shape public policy to advance health,” said Mazure.

Among WHRY’s initial projects was an examination of the BRCA1/2 gene mutations and their influence on breast cancer recurrence. Led by Bruce Haffty, this study highlighted that women with these mutations faced a greater risk of cancer recurrence, prompting change in treatment decision-making processes for affected individuals. Haffty remarked, “The funding allowed us to test a larger cohort of women as the testing was quite expensive at the time.”

Current research at Yale continues to uncover important sex differences across various medical conditions. For example, Akiko Iwasaki, Sterling Professor of Immunobiology, is investigating sex disparities in immune responses during COVID-19 infection. Her team is analysing how male and female patients exhibit distinct symptom profiles and severity levels. Julio Silva, an MD/PhD student at Yale, stated, “Distinct immune responses correlate with the distinct symptom profiles that females and males experience.”

Similarly, Caroline Johnson, an associate professor of epidemiology, is exploring sex differences in colorectal cancer metabolism. Her findings indicate that high levels of asparagine are linked to poorer outcomes specifically for female patients. Johnson explained, “We have found that high levels of asparagine are linked to poorer prognosis for female patients only…”

Looking beyond clinical studies, basic and preclinical research has also begun to shift towards inclusivity. The NIH’s 2016 policy, “Sex as a Biological Variable,” aims to ensure that both male and female subjects are represented in biomedical studies. Past research predominantly relied on male models, which may have skewed results. Studies conducted by various labs, such as the Dolan Lab at the University of Chicago, have demonstrated that there are intrinsic differences even at the cellular level between male and female cells.

Research into sex differences in health has made significant strides over the last few decades. Mazure highlighted that focusing on women’s health not only addresses past inequities but also strengthens healthcare for everyone. She stated, “When women’s health improves, the nation thrives.” As researchers continue to delve into understanding these differences, the potential for improved medical care and treatment outcomes for all patients becomes increasingly evident.