Project Description Narrative:
Transgender individuals have a gender identity discordant from the sex they were assigned at birth. As such, transgender men were assigned female sex at birth (due to the presence of female-typical genitalia) but have a male gender identity while transgender women were assigned male at birth but have a female gender identity. While most people are cisgender (gender identity concordant with sex assigned at birth), ~1% of the population is transgender, equating to ~60,000 transgender Wisconsinites, of whom 13,000 are over 18 years old. The 2015 U.S. Transgender Survey highlighted the vulnerabilities of this marginalized group at the national and Wisconsin state level, with high rates of poverty, school drop-out, and victimization. These patterns extend to health care in that 30% of Wisconsin’s transgender population reported negative healthcare experiences, 30% avoided accessing healthcare, and 80% felt they did not have a provider of any kind proficient in transgender-related needs. These inequities propagate poor health outcomes, as evidenced by a 9-fold higher rate of suicide attempt than the general population. In recognition of all these factors, the NIH designed transgender individuals a health disparity population in 2016.
MCW faculty responded to these health disparities by forming The Inclusion Clinic at Froedtert and the Gender Health Clinic at Children’s Wisconsin. Together, providers at these clinics see ~35 new transgender youth and adult patients/month for comprehensive evaluation, genderaffirming hormone therapy, and behavioral health interventions with educational and clinical care missions. MCW is primed to become the statewide leader of gender-affirming medical and surgical care; but, as an academic medical center, a research mission is critical towards growing our national impact. Given the extramurally funded research programs of Drs. Cabrera and Widlansky, we are well-positioned to tackle the critical knowledge gap of cardiometabolic outcomes among transgender individuals, as outlined below.
The Endocrine Society and WPATH provide guidelines for gender-affirming medical interventions in transgender men, but the absence of robust clinical evidence behind many recommendations have resulted in significant practice variation, with providers, particularly in pediatrics, relying on the anecdotal expertise of others. Pubertal blockers (GnRH analogs) can be used in early- to mid-puberty to reversibly pause secondary sex characteristic development, reducing gender dysphoria and improving cosmetic outcomes. Masculinizing testosterone therapy can be started age less than 13 years with mental health provider support, informed consent of the patient and, in minors, of legal guardians. Informed consent relies on communication of all risks and benefits and, for providers, this discussion highlights several significant knowledge gaps in near-term and long-term health risks and outcomes.
Relevant to our group’s research expertise, little is known about the effects of testosterone therapy on cardiometabolic health in transgender men, particularly in those started on testosterone at younger ages and/or previously treated with GnRH agonists. Existing data are based on limited retrospective or cross-sectional studies, many using now-antiquated dosing schedules or in those receiving parental testosterone undecanoate, a formulation not available in the US. While low-level evidence suggests testosterone increases muscle mass, decreases fat mass, and results in a more atherogenic lipid panel, the effects on insulin sensitivity and overall cardiometabolic outcomes are conflicting. For example, a meta-analysis showed no increased incidence of cardiovascular events in transgender men on testosterone, but a systemic review found insufficient evidence to assess patient-important outcomes such as death, stroke, myocardial infarctions, or stroke. Further, no studies have addressed possible mechanisms by which sex hormones affect vascular physiology and sex hormone receptors in 8 transgender men. These gaps limit our ability to accurately counsel families, determine risk surveillance strategies, and design treatment regimens to mitigate risk. It is unknown, for example, if parental testosterone delivery mode or dosing frequency has different cardiometabolic effects than transdermal formulations or if testosterone has different effects when given to transgender boys without any prior estrogen-mediated puberty as compared to post-menarchal transgender men with years of prior estrogen exposure. Given that estrogen stimulation leads to long term transcriptional and translational changes that are vasculoprotective, the impact of testosterone therapy on vascular health may differ when given to an individual whose vasculature has not been exposed long-term to adult levels of estrogen compared with an individual whose vascular tree matured in the setting of adult levels of estrogen. In recognition of these knowledge gaps, we hypothesize that transgender boys and men treated with gender-affirming testosterone therapy will develop a cardiometabolic profile intermediate to that of their cisgender peers.
We will address this hypothesis with the following Specific Aims:
Aim 1) Determine the impact of the initiation and titration of testosterone therapy in transgender boys and men on in vivo and ex vivo vascular endothelial function, vascular structure and on the expression of circulating microRNA involved in the regulation of estrogen receptor expression.
Aim 2) Characterize the systemic metabolic and inflammatory impact of testosterone therapy of transgender boys and men.
Knowledge gained by this proposal would help identify (1) if there are near-term cardiometabolic risks to testosterone initiation in transgender men, (2) if there are differences in the cardiometabolic impact of testosterone therapy when initiated prior to versus after completion of an estrogen-driven puberty. These data will also identify future opportunities to test different dosing regimens to maximize testosterone’s masculinizing effects while minimizing any potential cardiometabolic risks posed by such therapy. While any data generated here should not be used to deny transgender individuals testosterone therapy, our findings will be valuable to transgender men and their providers by providing greater quantitative specificity regarding the impact of testosterone on cardiometabolic risk factors. This will improve the informed consent process for testosterone therapy and allow providers to better understand potential cardiometabolic risks posed by therapy that may require closer follow-up than current practice.