Beyond Sex-Based Medicine in Cardiovascular Health Research and Practice

Medicine and cardiology, in particular, have a long history of treating sex as a binary construct. From risk estimation and echo parameters to lipid ranges and EKG intervals, binary sex categories are engrained in the research and practice of cardiology.¹ This can be traced to most medical school curricula treating sex as rooted exclusively in biology. While medical school curricula acknowledge multiple dimensions of biological sex, including hormone levels, presence of hormone receptors, chromosomes, secondary sexual characteristics, gonads, and genitals, this teaching rarely interrogates the social nature of sex classification or the limits of binary categories.

Despite these varied components, medical education, research, and clinical practice typically only use external genitalia to categorize people into one of two sexes, ignoring additional potentially more salient components of sex. Further, infants born with variations in sex development that do not fall into the binary “biological sexes” are deemed pathological. These infants - sometimes referred to as infants with differences in sexual development (DSD) or as intersex infants – are instead viewed within medicine as having a disease or disorder. Paradoxically, the medicalized view of sex as a “naturally” binary and biological construct is not rooted in biology, but in dominant social paradigms. These paradigms either view sex and gender as interchangeable (thankfully a view increasingly critiqued for its transphobia) or sometimes characterize sex as “only biological” and gender as “only cultural.”

Both these views privilege a narrative that sex is more “natural” and “unchangeable” than gender. This way of thinking, however, is rooted in culture and not the body. The endocrinology and anatomies of many transgender, non-binary, and gender diverse people who have pursued and received gender affirming care challenge the “sex as biology” and “gender as culture” dichotomies. For example, if and when a transgender woman takes hormone therapy to decrease endogenous androgens and increase estrogen, pursues vocal therapy, and undergoes breast augmentation, orchiectomy, and vaginoplasty, nearly every aspect of her sex, with the exception of chromosomes, has shifted to fall into the typical “female” designation. These are not merely “cultural changes” – they have physical and biological relevance.

The transgender woman’s physiology in the above example is no less biologically rooted or clinically relevant than that of a cisgender woman’s. The journeys or modalities to arrive at similar sex characteristics may differ for these women, but we argue this should not result in viewing the sex characteristics of one woman’s anatomy as “less natural” or “more cultural” than the other’s. The one dimension of sex that could still differentiate transgender and cisgender women in this example is sex chromosomes. Almost certainly, the majority of cisgender women (and transgender women, for that matter) have never been karyotyped; some may certainly be surprised at the results.

Ultimately, what is the value of sex-based medicine, especially when sex is almost always defined in clinical practice through the medicolegal paradigm tied to genital appearance at birth? In cardiology practices today, it is often not possible to administer an echocardiogram to a patient unless “sex” is set on the machine. Risk estimators such as the ACC/AHA ASCVD risk estimation tool cannot assign a 10-year risk value unless sex is specified. In addition, there are hundreds of labs for which reference ranges differ on the basis of sex (e.g., high density lipoprotein (HDL)).² While some clinical trials have investigated the impact of hormone replacement therapy on cardiovascular risk or other variations in sex hormones on ASCVD risk,³ patient sex hormone levels are not routinely tested in primary care or even in specialty care to inform cardiovascular care treatment plans. Instead, the sex of “M” or “F” on identification documents is what is used as the proxy to a variety of factors deemed as binary sex characteristics.

There are education, research, and clinical practice implications of this approach of using sex with no regard for a patient’s specific physiology to define the cardiovascular prevention and care plans for transgender, non-binary, and gender diverse people as well as cisgender people. To the best of our knowledge, no clinical guidance documents contain specific recommendations for how to provide cardiovascular care to transgender, non-binary, and gender diverse people using an approach precisely considering physiology. To make matters worse, it is nearly impossible to track the inclusion of transgender, non-binary, gender diverse and intersex people within NIH-funded studies; the enrollment tables for NIH make this task impossible.

Consequently, it’s time to rethink how sex as a biological variable is best incorporated into education, research, and clinical practice. We call for medical schools and graduate medical education programs to partner with transgender, non-binary, and gender non-conforming community stakeholders and patients to update the way they train students and trainees about sex and gender. This will require evaluation of existing curricula to identify portions of undergraduate and graduate medical education that need to be updated to accurately convey the diversity of sex and gender and their relation to research and clinical care.⁴ By encouraging students and trainees to question what component of sex is clinically relevant, they can begin to interrogate existing guidelines that rely on binary sex categories (e.g., ASCVD, alcohol recommendations, etc.) and recognize the nuance in clinical practice. This may seem revolutionary, but is in fact simply aligning training with patient realities.

Ultimately, to best inform clinical practice, we call for more research that specifies the dimensions of sex, gender, and anatomy that are being tested to inform cardiovascular preventive care and treatment protocols. Researchers will need to be trained to recognize the limitations of existing binary categories of sex and gender as well as to develop more appropriate measures of sex and gender that accurately account for the physiology of transgender and cisgender persons and populations. Transgender and non-binary researchers, clinicians, community stakeholders, and patients should be involved in leading these efforts. This will also require research sponsors, such as the National Institutes of Health, and regulatory bodies, such as institutional review boards and the Food and Drug Administration,⁵ to incorporate appropriate measures of sex and gender.

Until such research is conducted and includes appropriate measures of sex and gender, we cannot in good faith provide recommendations for changing clinical practice without appropriate evidence; we do not have evidence to say when to “switch” someone from “male” to “female” in the ACC/AHA ASCVD risk estimation tool, we do not know what are the best echocardiographic parameters for a non-binary person assigned female at birth. Only through updated education and research practices will researchers and cardiologists be able to meet the promise of precision medicine and more accurately allow us to deploy evidence-based interventions to improve the health and well-being of everyone.