Transgender individuals comprise roughly 1% of the United States population and include those born one sex but identify as a gender that does not align with their biological sex. Gender-Affirming Hormone Therapy (GAHT) is used to treat these individuals to match secondary sex characteristics to their gender identity. GAHT in transgender females (TGF), individuals born male but who identify as female, involves administration of 17β- estradiol (E2) with an anti-androgen (AA) or castration (CTX). Although long-term studies in this population are limited, recent studies suggest that cardiovascular (CV) risk may be elevated in GAHT-treated TGF versus cis- gender men. However, the mechanisms involved are unknown and potential targets to ameliorate CV risk have yet to be identified. To address this gap in knowledge, the Alexander laboratory has developed a novel model of feminizing hormone therapy in the male rat that involves administration of E2 to mimic physiological levels observed in age-matched female rats in conjunction with androgen suppression. My model mimics the increase in E2, suppression of testosterone and decrease in body weight and lean mass observed in TGF individuals indicating clinical relevance for this experimental model of GAHT. My studies will use two different rat strains, the normotensive Sprague Dawley rat and the spontaneously hypertensive rat. Preexisting chronic disease such as hypertension is contraindicated in GAHT. Yet, GAHT is integral for the treatment of gender dysphoria. To date, basic research utilizing experimental models of GAHT are limited to nonexistent. Thus, a critical need involves the use of innovative animal models to provide reliable risk assessment and in-depth investigation into mechanisms that contribute to increased CV risk in adult TGF individuals that undergo GAHT. Therefore, my F31 will test the following hypothesis that shifting the hormonal milieu with cross sex steroid treatment versus natal sex, elevated estrogen coupled to testosterone suppression in the male, increases susceptibility to target organ injury and cardiovascular risk that is enhanced with aging and involves an estrogen-induced male-specific effect on the vasoconstrictor-vasodilator balance of the renin angiotensin system. Aim 1 will test the hypothesis that the shift in the hormonal milieu in gender affirming hormone therapy in a rodent model of the transfemale rat is associated with increased end organ damage and cardiovascular risk that is further exacerbated with preexisting chronic disease. Aim 2 will test the hypothesis that increased end organ damage and cardiovascular risk in transgender females that undergo gender affirming hormone therapy involves an estradiol induced “male sex-specific” effect on the renin angiotensin system. This grant will also further my training potential as I learn “gold-standard” methods for measurement of blood pressure via radiotelemetry, assessment of end organ damage in response to myocardial ischemia reperfusion with echocardiography by sonography, and ex vivo vascular function studies. Thus, this application will serve towards enhancing my technical skills in scientific communication skills, scientific rigor and networking as I train to become an independent physician scientist.

Narrative: Gender-Affirming Hormone Therapy (GAHT) for transgender women, which involves estrogen supplementation combined with anti-androgen therapy, is associated with an increased risk for cardiovascular diseases compared to the general population. Yet, the mechanisms involved are unknown. This project will investigate the etiology of increased cardiovascular risk in transgender women on GAHT using a novel and innovative model of GAHT in the male rat that mimics the effect of elevated estradiol with androgen suppression.