Renal Injury and Cross Sex Steroid Therapy in Aging Male Rats

Significance: Transgender females (TGF) are individuals who were born male but identify as female. Gender affrming hormone therapy (GAHT) is used to align physical characteristics with gender identity. In the TGF, GAHT includes 17β-estradiol (E2) combined with surgical intervention (castration, CTX). The long-term effects of GAHT on cardiorenal health are unclear. Thus, using our model of cross sex steroid therapy whereby E2 is significantly elevated in association with a significant reduction in testosterone in E2+CTX male rats, we hypothesized that renal injury is elevated with GAHT, and that age-related increases in renal injury are enhanced in E2+CTX compared to age-matched control. Methods:Male Sprague-Dawley rats were randomly assigned to: Control or E2+CTX with E2 5 mg/day, silastic capsule s.c., replaced every 3 weeks started at 14 (young, Y) or 52-65 (middle-age, MA) weeks of age followed by CTX two weeks later (N=8-10/grp). Experimental protocol: lean and fat mass (EchoMRI), 24-hour metabolic collection for proteinuria, KIM-1, NGAL (ELISA); creatinine (Chemistry Analyzer) up to 14 wks in Y and 20 wks in MA rats post GAHT. Two-way ANOVA with Tukey’s post hoc analysis was performed with P<0.05 considered significant. Results: Body weight and lean mass were significantly decreased in Y and MA E2+CTX vs age-matched Control. Fat mass was significantly reduced in MA E2+CTX vs MA Control. 24-hour urinary protein did not differ in Control vs E2+CTX at either age but was increased with age vs Y groups ( p<0.05). Creatinine was significantly increased in MA groups vs Y but decreased in MA E2+CTX vs MA Control ( p<0.05). NGAL and KIM-1 were significantly increased in MA Control vs all other groups ( p<0.05); NGAL was increased in MA E2+CTX vs its Y counterpart ( p<0.05) but not Y Control. Conclusion: Collectively, these data indicate that markers of renal injury are not increased in Y GAHT males. However, in MA, age-related increases in KIM-1and NGAL are attenuated in GAHT. Future studies will determine if male GAHT are more sensitive to a second hit such as renal ischemia reperfusion and quantitate renal function via a direct method to account for loss of lean mass in E2+CTX males. Formula: see text HL143459, P20-GM-104357, P20-GM121334, AHA CDA 938320, T32-HL105324. This is the full abstract presented at the American Physiology Summit 2024 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.