From the March 31, 2023 issue of the Transformational Times
How Studying Female Rabbits led to Teaching Sex and Gender Topics to Medical Students
Sandra Pfister, PhD
“If we don’t look for differences, then we don’t know that there are differences or that sex and gender are relevant.”
-- Juliana M. Kling, Professor of Medicine, Chair of the Division of Women's Health Internal Medicine, Department of Medicine, Mayo Clinic
In the early 1980s, I was figuring out what it meant to be a basic science researcher as a graduate student in the Department of Pharmacology (University of Texas Health Science Center at San Antonio). What I failed to notice was that all the animals I used in my studies were males. On reflection, the only scientists I knew using female animals were those studying pregnancy or reproduction. I was interested in vascular disease and hypertension, so why would the sex of my animals matter? The year I received my PhD (1984), two publications in PubMed contained the terms sex and hypertension in the title field. By 1993, NIH had mandated women be included in clinical trials. Yet it took until 2016 for a NIH directive to include sex as a biological variable (SABV) in all studies, including those done in cells/tissues/animals. Fortunately, it did not take me 32 years to see the value of using female animals.
In 1992, my career path led me to MCW as an assistant professor in the Department of Pharmacology & Toxicology. My research investigated lipid mediators from arachidonic acid that contributed to contractile responses in pulmonary arteries from rabbits. About the same time, the Office of Research Women’s Health was established at NIH, and the first long-term national health study that included only women was established. It was called the Women’s Health Initiative (WHI) and had a clinical center at MCW led by Dr. Jane Kotchen. One goal was to find strategies for preventing heart disease in postmenopausal women. It was then I knew I should be studying females. I stopped checking “either sex” on my rabbit orders and more importantly, was intentional about comparing the experimental data results between females and males. Not surprisingly, based on all we now know about sex-based medicine, the data showed enhanced pulmonary vascular contractions in females compared to males. This purposeful decision to study female rabbits was the beginning of an exciting new research direction for my laboratory to explore novel mechanisms in pulmonary arterial hypertension, a known sex-based disease.
We need to do better
Despite mandates to study women in clinical trials and incorporate SABV in basic science research studies, it has not been enough. Repeating my PubMed search for publications in 2022 with the terms sex and hypertension in the title field yielded a mere 57 results. I thought by 2022, the number would have generated at least 100s of publications. My “cursory search’’ is unfortunately supported by numerous published reports. Using cardiovascular disease as an example, only 25% of preclinical experiments included females1. Cardiovascular clinical trials did not do better with participation by males continuing to predominate2. When females are enrolled, the results of the studies are often not stratified by sex or gender.
Language is important and the terms sex and gender cannot be used interchangeably. Simply defined, sex refers to the biological and physiological characteristics that define humans and animals as male, female, or intersex. Not as easily defined, Gender is a societal construct by humans that refers to roles, activities, and behaviors, and encompasses a wide range of identities beyond male, female, and intersex3. Not including females in clinical trials -- or including them, but not analyzing the data by sex and gender -- is problematic as it translates to not diagnosing and/or best treating females.
Building sex and gender studies into the curriculum
As a non-clinician, I wondered how I might be more impactful in promoting the importance of studying sex-based differences in health and disease. Could the path be through medical education? A national survey of medical schools (2014) indicated that 86% of medical students were aware of sex and gender medicine differences in medicine, and 94% believed that medical education should include teaching about sex and gender medicine4.
I knew MCW did not have a formal sex and gender medicine curriculum. That motivated me to lead a team to assess our own faculty and students’ knowledge and interest in sex and gender curriculum development. Results showed that approximately 84% of our M1-M4 students said their education should include sex and gender medicine, and that this knowledge would improve patient care. However, more that 50% of students felt the MCW curriculum had not prepared them to treat sex and gender differences in their patients. Faculty surveyed also felt strongly that MCW medical education should include the teaching of sex and gender differences (96%) while only 20% felt their own training had prepared them to teach it to medical learners.
Next steps involved recruiting three M1 (Kendall Trieglaff, Madeline Zamzow, Bryn Sutherland) and four M2 (Peter Johnson, Andrea H. Rossman, Nnenna Nwaelugo, Ramneet Mann) students to audit and analyze the specific sex and gender content of every M1 and M2 didactic lecture (2020-2021 years). Kendall, Maddie, and Bryn (now M3s) continue to participate in the project and their work has recently been accepted for publication in the Wisconsin Medical Journal. Students recognized a major limitation of education materials was sex and gender are mostly presented in binary terms. There was little to no discussion that addressed intersexuality, nonbinary, transgender or any others on the gender spectrum. Looking ahead, there is opportunity to use these identified gaps in sex and gender health topics to innovate and expand content in MCWfusion.
My optimistic hope is that a future survey of students and faculty shows not only faculty are better prepared to teach the sex and gender health topics, but students are better equipped to treat sex and gender differences in their patients. Combined with a dedicated focus on being inclusive of sex and gender in clinical trials and SABV in basic research studies, the chances of misdiagnosing or inappropriately prescribing treatments will be rare in every patient.
“No scientific discovery can save a life without first traversing a learning environment...”
-- Marjorie Jenkins, Founding Director of Laura Bush Institute for Women’s Health, Dean, University of South Carolina School of Medicine Greenville
For further reading:
DH Chang, SM Dumanski, SB Ahmed Female sex-specific considerations to improve rigor and reproducibility in cardiovascular research Am J Phys 324:H279 (2023).
SH Bots, NC Onland-Moret, HM den Ruijter Addressing persistent evidence gaps in cardiovascular sex differences research – the potential of clinical care data. Front. Glob. Womens Health 3:1006425, 2023
L Merone, K Tsey, D Russell, C Nagle. Sex Inequalities in Medical Research: A Systematic Scoping Review of the Literature. Womens Health Rep. 3:49, 2022
MR Jenkins, A Herrmann, A Tashjian, et al. Sex and gender in medical education: a national student survey. Biol Sex Differ 7:45 (2016).
Sandra Pfister, PhD, is a Professor in the Department of Pharmacology & Toxicology at MCW. She is a member of the Faculty Pillar of the Robert D. and Patricia E. Kern Institute for the Transformation of Medical Education.