Feminizing Hormone Therapy in the Aging Male is Associated with Cardio and Renal Protection that does not Involve a Male-Specific Effect on the RAS

Significance: Whether the long-term use of gender affirming hormone therapy (GAHT) in transgender women (TW), used to achieve feminizing characteristics, is associated with increased cardiac or renal risk is unknown. We hypothesized that cardiac and renal injury would be enhanced in male rats that undergo chronic 17β-estradiol (E2) plus castration (CTX) compared to age-matched male Control via a mechanism that involved a male-specific effect on the renin angiotensin system (RAS). Methods: Male Sprague Dawley rats were randomly assigned to Control or E2+CTX (5 mg/kg via silastic capsules s.c., replaced every 3 weeks) starting 53-65 weeks of age, or equivalent to a middle-aged man. CTX was performed two weeks later to mimic Endocrine Society guidelines (N=5-8/group). At 22-24 months of age, or equivalent to 60-year-old man, rats underwent 24-hour metabolic studies for KIM-1 and Cystatin-C (ELISA), histological analysis for glomerular injury score (GIS) and percent fibrosis; serum troponin and BNP (ELISA) for cardiac injury, mean arterial pressure (MAP) by carotid catheter, ddPCR mRNA expression for estrogen receptor alpha (ERa), GPER, androgen receptor (AR) and components of the RAS: angiotensin type 1 (AT1Ra, AT1Rb) and 2 (AT2R), renin, and MAS receptors. Statistics: Unpaired t-test; p<0.05 considered significant. Results: KIM-1(17660±2483 vs 44100±8984 pg/day, p<0.05) and GIS (2.1±0.2 vs 2.8±0.1, p<0.05) were significantly reduced in E2+CTX versus age-matched male Control. Percent fibrosis (39±5 vs 50±4, p=0.15) and Cystatin C, a renal function marker less effected by lean mass (8.8E+7 ± 2.5E+7 vs 2.8E+8 ± 7E+7 pg/day, p=0.059) did not differ. Serum BNP (68054±19850 vs 117302±9916 pg/mL, p<0.05) and troponin (1041±80 vs 1890±236 pg/mL, p<0.05) were significantly reduced in E2+CTX despite no change in MAP (135±9 vs 155±5 mmHg, p=0.07). E2+CTX was associated with a significant reduction in renal ERa and AR mRNA (91±37 vs 340±27 ERa, 115±53 vs 546±91, AR copies/50ng of RNA, p<0.05) but no change in GPER (497±254 vs 620±201, copies/50 ng RNA, p=0.7). Renal expression of renin (32±7 vs 95±38 copies/50 ng RNA, p=0.3), AT1Ra (851±165 vs 1552±401 copies/50 ng RNA, p=0.2), AT1Rb (208±48 vs 293±75 copies/50 ng RNA, p=0.4), AT2 (267±69 vs 249±65, copies/50 ng RNA, p=0.9) and Mas receptor (566±173 vs 588±133, copies/50 ng RNA, p=0.9) did not differ. Conclusion/Clinical Significance: These data suggest feminizing hormone therapy in the aging male may be protective against renal and cardiac injury providing optimistic findings for transgender women. Moreover, cardiac and renoprotection induced by chronic E2 coupled to androgen suppression may not involve a critical role for the RAS. Future studies will utilize telemetry to investigate circadian rhythm and activity. Funding: T32-HL105324, HL143459, P30GM149404, P20GM104357, P20GM121334 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.