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The transgender, gender-diverse, and nonbinary (TGD) community is a growing population currently estimated at 25 million worldwide who are at higher risk for poor health outcomes compared to the cisgender population (1). Contributing factors include gender minority stress, socioeconomic inequities, and discrimination within the healthcare system.

A significant impediment to improving care for this population is a lack of high-quality studies on TGD health. For example, reference ranges and protocols used to guide TGD treatment are based on binary, cisgender populations and may not be appropriate. There also is limited literature examining the mechanisms by which gender-affirming hormone therapy (GAHT), commonly used for the acquisition of secondary sexual characteristics aligning with affirmed gender, may affect other aspects of health.

This leaves gender-affirming care providers facing a complex task: caring for a growing, high-risk demographic with evidence-based protocols from a different source population (e.g., cisgender individuals).

Researchers from all disciplines can help improve care for TGD patients by considering their unique health concerns and accounting for sex and gender in their studies—an effort that ultimately mobilizes health equity for all.


A significant body of research shows that social (pronouns, self-expression) and medical (GAHT, gender-affirming surgery) transitions effectively treat the gender dysphoria experienced by transgender individuals (those whose sex assigned at birth does not align with their gender identity) (2).

Ideally, clinicians determine GAHT formulation, dose, and route of administration using a patient-centered approach. Higher doses often translate to more pronounced masculinization or feminization, while lower doses may be used in gender-diverse and non-binary individuals or depending on co-existing medical conditions.

The type and route of GAHT administration varies based on lifestyle preference or local protocols and availability. For example, transgender women (individuals assigned male sex at birth who identify as women) with a history of cardiovascular disease may consider using non-oral estrogen GAHT, such as transdermal patches or intramuscular injection (2). This practice is extrapolated from experimental data in cisgender women (individuals assigned female sex at birth who identify as women) which suggests that oral estrogen therapy, whether for contraceptive or postmenopausal use, is associated with an increased cardiovascular risk compared with non-oral estrogen.

Whether this is appropriate is uncertain: A 2022 systematic review reported that only 5 out of 3,113 studies assessed the association of gender-affirming estrogen therapy (GAET) route of administration on measures of cardiovascular risk in transgender women (3). The review revealed conflicting results that likely relate to the heterogeneity of studies that preclude firm conclusions of the effect, if any, of GAET on cardiovascular health.


Gender-affirming hormone therapy variability

Significant attention has been directed to the potential impact of GAHT on health. Route of GAHT alone has pharmacokinetic (drug absorption, distribution, metabolism, and excretion) and pharmacodynamic (drug action and mechanism) considerations that are crucial in assessing any potential relationship between drug and disease. Researchers should consider these factors carefully when studying the impact of GAHT on measures of health. They also should balance the significant improvements in mental health and quality of life associated with GAHT use with the ultimate goal of providing information for informed and shared decision-making between patients and their healthcare providers.

Cisgender populations are not appropriate controls

The psychological benefits provided by GAHT render traditional randomized treatment allocation unethical. Researchers often have used cisgender individuals matched by a sex/gender approach as the referent group. For example, Valentine, et al., matched cisgender women to transgender men (individuals assigned female sex at birth who identify as men) (4). Does matching by sex assigned at birth appropriately highlight the differences observed in cardiovascular outcomes? Perhaps, although it is known that gender also plays an important role (5).

Nota, et al., compared incidence ratios for acute cardiovascular events in transgender individuals using GAHT to presumed cisgender reference women and men from the general population (6). Although this is a novel approach, using cisgender participants as controls does not account for the potential confounders such as psychosocial stressors that the TGD population experience (7).

Non-representative exclusion criterion and data collection

The health inequities observed between TGD and cisgender individuals are rooted in interpersonal, social, and structural stressors, and they are exacerbated by a lack of inclusion of TGD individuals in health research (8). While strategies to increase culturally-sensitive and safe participation in research are outlined in detail elsewhere, all researchers should examine each step of the research process to ensure inclusive practices are employed, including plans for real-world implementation of their findings (9).

Careful examination of the rationale for exclusion criteria is necessary to ensure the population studied is as reflective of the population most likely to be affected by the results of the study (10). Likewise, accurate collection of sex assigned at birth and how this was ascertained—as well as self-identified gender identity—followed by appropriately stratified data analysis, represent a crucial step in allowing for maximal generalizability of the results of research.

The reevaluation of study protocols to promote inclusivity of the TGD population in research is the first step in overcoming these barriers (9). All research should include TGD participants to allow for greater rigor and reproducibility in health research (7, 9, 10).


Sex (biological factors) and gender (sociocultural factors) are important determinants of health not only in the TGD population, but all populations. Incorporating these factors into all aspects of research—while also addressing social determinants of health contributing to quality of life, morbidity, and mortality—is the first step in achieving health equity across the lifespan for persons of all genders.


  1. Reisner SL, Poteat T, Keatley JA, et al. Global health burden and needs of transgender populations: A review. Lancet 2016; doi: 10.1016/S0140-6736(16)00684-X.
  2. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2017; doi: 10.1210/jc.2017-01658.
  3. Turino Miranda K, Kalenga C, Saad N, et al. Gender-affirming estrogen therapy route of administration and cardiovascular risk: A systematic review and narrative synthesis. Am J Physiol - Hear Circ Physiol 2022; doi: 10.1152/ajpheart.00299.2022.
  4. Valentine A, Nokoff N, Bonny A, et al. Cardiometabolic parameters among transgender adolescent males on testosterone therapy and body mass index-matched cisgender females. Transgender Heal 2021; doi: 10.1089/trgh.2020.0052.
  5. Ahmed SB, Dumanski SM. Do sex and gender matter in kidney and cardiovascular disease? Am J Kidney Dis 2021; doi: 10.1053/j.ajkd.2021.05.002.
  6. Nota NM, Wiepjes CM, de Blok CJM, et al. Occurrence of acute cardiovascular events in transgender individuals receiving hormone therapy. Circulation 2019; doi: 10.1161/CIRCULATIONAHA.118.038584.
  7. Goldstein Z, Streed CG, Resiman T, et al. Cross-sex hormones and acute cardiovascular events in transgender persons. Ann Epidemiol 2019; doi: 10.1097/MPG.
  8. Lefevor GT, Boyd-Rogers CC, Sprague BM, et al. Health disparities between genderqueer, transgender, and cisgender individuals: An extension of minority stress theory. J Couns Psychol 2019; doi: 10.1037/cou0000339.
  9. Rytz CL, Beach LB, Saad N, et al. Improving the inclusion of transgender and non-binary individuals in the planning, completion and mobilization of cardiovascular research. Am J Physiol - Hear Circ Physiol 2023; doi: 10.1152/ajpheart.00494.2022.
  10. Chang DH, Dumanski SM, Ahmed SB. Female sex-specific considerations to improve rigor and reproducibility in cardiovascular research. Am J Physiol - Hear Circ Physiol 2022; doi: 10.1152/ajpheart.00462.2022.

Keila Turino Miranda, BSc, is a master in medical science student at the University of Calgary in Calgary, Alberta, Canada. +Email:[email protected]

Dina N. Greene, PhD, DABCC, is an assistant professor in the department of laboratory medicine at the University of Washington and the associate laboratory director at LetsGetChecked in Seattle. +Email: [email protected]

Sofia Ahmed, MD, MMSc, is a professor of medicine at the Cumming School of Medicine, University of Calgary, in Calgary, Alberta, Canada. +Email: [email protected]