Women’s Health, Research, and Sex as a Biological Variable

Ensuring that women are represented in research studies and in science fields is an important part of advancing science and ensuring that women justly benefit from research. “Both sex and gender affect health and disease…and gendered assumptions affect the nature and practice of research,” notes Janine Austin Clayton, MD, FARVO, the NIH Associate Director for Research on Women’s Health and Director of the NIH Office of Research on Women’s Health. “In the past we were doing what you might call unisex research…the default human model for clinical research was a 70kg man… Despite research being done primarily in men, the knowledge that was garnered by those clinical studies was applied to women, and that [raised] scientific, ethical, and equity concerns.”

Research done using only male animals during preclinical trials and predominantly male subjects in human clinical trials leads to knowledge gaps that negatively impact women’s treatment and health outcomes. “We know that there are a lot of sex-based differences. Men and women can manifest diseases differently, they can experience illnesses differently, they can respond to drugs differently, metabolize drugs differently…” says Melina Kibbe, MD, the Colin G. Thomas Distinguished Professor of Surgery and Chair Department of Surgery University of North Carolina School of Medicine. For example, the FDA had to reduce the dose of Ambien for women after discovering, due to traffic accidents following use of the drug, that women metabolize the drug more slowly than men. And, in fact, about 80% of adverse events reported by users after drug approval are reactions reported by women.

The NIH policy on the Consideration of Sex as a Biological Variable (SABV), established in 2016, is a part of a global movement to account for the possible role of sex in human and vertebrate animal research. Additionally, a report on Measuring Sex, Gender Identity, and Sexual Orientation published earlier this month by the National Academies of Sciences, Engineering, and Medicine recommends that the NIH standardize the collection of data on both sex and gender, including setting consistent language for survey questions that ask about a respondent’s sex, gender identity, and sexual orientation. Considering sex and gender as variables in research studies and reporting results by sex leads to a more complete knowledge base that improves rigor and reproducibility, a tenet of good science. Increased knowledge leads to more productive research, more effective treatments, and better health for women (and men).

In recognition of women’s history month, we’d like to highlight some of PRIM&R’s resources that explore the importance of considering sex as a biological variable and shifting to appropriate sex balance in research studies.

2019 Keynote and 2021 Webinar on Considering Sex as a Biological Variable

Dr. Clayton was appointed Associate Director for Research on Women’s Health and Director of the Office of Research on Women’s Health at the NIH in 2012. She has strengthened NIH support for research on diseases, disorders, and conditions that affect women and is the architect of the NIH policy requiring scientists to consider sex as a biological variable across the research spectrum to enhance reproducibility, rigor, and transparency.

Dr. Clayton gave a keynote address at the 2019 Advancing Ethical Research Conference about advancing a foundational framework for rigorous research relevant to the health of women.

Dr. Clayton also presented a 2021 PRIM&R Webinar, Now is No Time to Relax: Why the Global Pandemic Strengthens the Case for Considering Sex as a Biological Variable. In this webinar, she discusses the NIH policy on SABV and how the coronavirus pandemic has revealed continued gaps in our knowledge base, intransigent health disparities and health inequities, and runs the risk of reversing years of progress toward gender equity. This highlights a pressing need to redouble our efforts to fully integrate the study of sex into the research process and support women’s advancement in biomedical research careers.

Highlights from this webinar include:

PRIM&R members can view the full recording of this webinar for free by logging into the Knowledge Center.

2020 Panel on Sex Bias in Research

Accounting for the role of sex is important not only once research reaches human trials, but also in earlier phases of the research pipeline. Important sex differences that could guide clinical studies in humans may be missed due to the conventional reliance of preclinical animal studies on male animals or cells. For example, “What we think we know about the brain, we really only know about male brains. And that’s because neuroscientists have been studying male animals about six times as much as they study female animals… this is a public health problem,” says Rebecca M. Shansky, PhD, a neuroscientist and professor of Psychology at Northeastern University, where she directs the Laboratory of Neuroanatomy and Behavior. Shifting from a practice of using all-male animals, however, introduces complications for researchers, animal care programs, and IACUCs.

PRIM&R hosted a panel at the 2020 IACUC Conference exploring the need to incorporate an appropriate sex balance in animal studies and sharing insights for how to navigate associated challenges, including husbandry of mixed-sex animal populations, rethinking “unnecessary duplication” in the light of the shortcomings of past single-sex research studies, identifying circumstances where mixed-sex studies are not scientifically appropriate, and negotiating the role of the IACUC.

Discussion Guide: Beyond Sex and Gender Difference in Funding and Reporting of Health Research

“Funding agencies and academic journals are two [additional] gatekeepers of knowledge production and dissemination, including whether and how sex/gender is incorporated into health research,” explains a journal article by Hanvisky et al. (2017) titled “Beyond sex and gender difference in funding and reporting of health research.” The article describes work that found significant inconsistencies in whether and how sex and gender considerations in research were addressed by major health journals and funding agencies in 36 countries. The authors propose two paradigmatic shifts in the conceptualization of sex and gender, and six operational questions to incorporate these considerations to improve the quality of health research.

PRIM&R offers a discussion guide for this article, which can be used as a starting point for group discussion, or to deepen your own understanding. The discussion guide summarizes the article and suggests background resources and further reading.

PRIM&R members can access this discussion guide for free by logging into the Knowledge Center; nonmembers can purchase for $20.

Hankivsky, O., Springer, K.W. & Hunting, G. Beyond sex and gender difference in funding and reporting of health research. Res Integr Peer Rev 3, 6 (2018). https://doi.org/10.1186/s41073-018-0050-6