Post-pubertal testosterone implants in female rats, a model of gender-affirming hormonal therapy, induce hypertension that is exaggerated with aging

Abstract

Introduction: Early pre-pubertal exposure to androgens induces an increase in blood pressure (BP) and renal injury in females, as seen in polycystic ovary syndrome females. However, it is not clear whether treatment with gender-affirming hormonal therapy (GAHT) in trans-men have an impact on their BP and renal health as adults and with aging. Therefore, the present study was undertaken to test the hypothesis that chronic androgen supplements (starting post-pubertal, model of GAHT) in female-to-male trans-sex rats will increase BP and promote renal injury that are exaggerated with aging. Methods: Female SD rats were implanted with testosterone propionate-filled silastic implants (TP, 7.5 mg/10 mm silastic tube/rat, replaced every 3 wks) starting at 7 wks of age (post-pubertal) until 17 months (mos) of age and compared to controls (CON, empty silastic implants). Serum testosterone was measured by LC/MS at 3 mos of age (n=4/grp). Radiotelemetry transmitters were implanted and mean arterial pressure (MAP) was measured at 3 and 17 mos of age (n=3-6/grp). Body composition was determined at 3 and 17 mos of age (n=3-4/grp). Proteinuria was determined at 3, 5 and 7 mos of age (n=4/grp). Serum and urinary creatinine (Cr) were measured at 7 mos of age and Cr clearance was calculated (n=4/grp). Urinary kidney injury molecule-1 (Kim-1) was measured at 12 mos of age (n=3-4/grp). Results: TP had significantly higher serum testosterone compared to CON (6.4 ± 1.5 vs 0.2 ± 0.05 ng/ml; p<0.05). Despite the similar fat mass, lean mass was significantly higher in TP compared to CON starting at 3 mos of age (253.9 ± 6.7 vs 217.7 ± 5.8 g; p<0.05), until 17 mos of age (325.7 ± 15.1 vs 253.5 ± 3.9 g; p<0.05). Proteinuria was significantly higher in TP compared to CON at 5 and 7 mos of age (7.6 ± 1.1 vs 2.4 ± 0.5 mg/24 h and 10.1 ± 1.6 vs 2.4 ± 0.4 mg/24 h, respectively, p<0.05). Cr clearance was significantly lower (0.24 ± 0.03 vs 0.32 ± 0.02 ml/min/100 g, p<0.05) and urinary Kim-1 was significantly higher (6.3 ± 1.5 vs 3.5 ± 0.2 ng/24 h, p<0.05) in TP compared to CON. Importantly, MAP was significantly higher in TP compared to CON starting at 3 mos of age (112 ± 3 vs 106 ± 4 mmHg, p<0.05), with further increases at 17 mos of age (133 ± 1 vs 117 ± 6 mmHg, p<0.05). Conclusion: Post-pubertal testosterone in female sex promotes renal injury and increases BP, independent of adiposity. Aging promotes further increases in BP, suggesting increased risk of cardiovascular diseases. Future studies should determine the mechanisms behind the increase in BP in the female-to-male trans-sex model. P20GM121334, AHA Career Development Award 938320, P20GM104357, R01HL135089, P01HL051971 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.