Gender affirming hormone therapy in the male rat is associated with differential effects on cardiovascular risk factors

Gender-Affirming Hormone Therapy (GAHT) in transgender females (male to female) involves administration of 17ß-estradiol (E2) with an anti-androgen (AA) or castration (CTX). GAHT is used to treat individuals that are born one sex but identify as the other gender. Numerous clinical studies indicate that cardiovascular (CV) risk is elevated in GAHT transgender females. Yet, the mechanisms involved remain unknown. Thus, the purpose of this study was to develop an experimental model of the transgender female and to test the hypothesis GAHT is associated with increased CV risk. Methods: Male Sprague Dawley rats were randomly assigned to the following groups: Control (n=8), E2 [5 mg/day, pellet sc, replaced every 3 weeks, N=6], E2+AA [E2 + Spironolactone, 10 ng/kg/day, diet, N=8], and E2+CTX (N=8). AA and E2 were initiated at 14 weeks of age; CTX rats were exposed to AA for 2 weeks prior to CTX at 16 weeks of age. At 28 weeks of age, EchoMRI for measurement of body weight, fat and lean mass was followed by 24-hour metabolic studies. E2 (ELISA), testosterone (RIA) and analytes (Chemistry Analyzer) were analyzed end of study at 28 weeks of age. Data were analyzed using GraphPad Prism 9 with one-way ANOVA with multi-group comparisons. Statistical significance was set at a P value of <0.05. Results: ( Table 1 ) E2 alone was sufficient to decrease testosterone in male rats. Administration of E2 in the male rat was associated with a significant decrease in body weight, lean mass and average kidney and testes weight. Creatinine was decreased in E2 alone. Yet, BUN was decreased in E2+CTX. E2 + AA was associated with a significant increase in total cholesterol compared to Control; an increase not observed in E2 or E2+CTX. HDL was elevated in E2+AA, whereas LDL-C was decreased in E2, E2+AA and E2+CTX mimicking what is observed in the transfemale population. Collectively, these results demonstrate differential effects of E2+AA versus E2+CTX on CV risk factors in male rats indicating that long-term studies are needed to determine the effect of GAHT on CV risk across the lifespan. [Table: see text] Funding: HL143459, P20-GM-104357, P20-GM121334, T32-HL105324, and LGBTQ Fund of MS This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.