Post‐Pubertal Testosterone Implants Induce Hypertension in Female‐to‐Male Trans‐Sex Rat Model

Introduction Androgens induce increases in blood pressure ( BP ) and risk of cardiovascular diseases ( CVDs ) in females, as seen in polycystic ovary syndrome females. However, it is not clear whether treatment with gender‐affirming hormone therapy in trans‐men have an impact on their BP or risk of CVD. Therefore, the present study was undertaken to test the hypothesis that chronic androgen supplements (starting post pubertal) in a rodent model of transgender men, will increase BP and promote metabolic dysfunction. Methods Female SD rats were implanted with testosterone propionate ( TP , 7.5 mg in 5 mm silastic tubes, replaced every 3 wks, n = 10) starting at 7 wks of age (post‐puberty) and compared to controls (empty silastic implants, n = 10). Rats were weighed weekly. Radiotelemetry transmitters were implanted at 13 wks of age (n = 5‐6/group) and mean arterial pressure ( MAP ) was measured at 15, 21 and 25 wks of age. Body composition was determined at 15, 21 and 23 wks of age and proteinuria was determined at 15 and 21 wks of age (n = 4/group). Serum testosterone was measured by LC/MS at 15 wks of age (n = 4/group). Oral glucose tolerance test was performed at 11 and 22 wks of age (n = 4/group). Results TP supplements increased serum testosterone at 15 wks of age by 30‐fold compared to female controls (6.4 ± 1.5 vs 0.2 ± 0.05 ng/ml, respectively; p<0.005). Body weight ( BW ) increased significantly in TP group compared to controls by 10 wks of age (241 ± 4 g vs 220 ± 2 g, respectively; p<0.05) and was sustained through 26 wks of age (311 ± 7 g vs 276 ± 5 g, respectively; p<0.05). Fat mass and fat mass/BW were similar between TP and controls. Lean mass was significantly higher in TP group compared to controls at 15, 21 and 23 wks of age (254 ± 7, 268 ± 12 and 273 ± 12 g vs 218 ± 6, 227 ± 5 and 229 ± 5 g, respectively; p<0.01); however, when factored for BW, there were no differences between TP and controls. Proteinuria was significantly higher in TP group compared to controls at 15 wks of age (4.9 ± 1.2 vs 2.1 ± 0.3 mg/24 h, respectively, p<0.05) and 21 wks of age (7.6 ± 1.1 vs 2.4 ± 0.5 mg/24 h, respectively, p<0.005). Importantly, MAP was increased significantly in TP group at 15 wks of age (112 ± 3 vs 106 ± 4 mmHg, p<0.05), 21 wks of age (114 ± 3 vs 105 ± 2 mmHg; p<0.05) and 24 wks of age (115 ± 3 vs 104 ± 2 mmHg, p<0.05), compared to controls, respectively. Oral glucose tolerance test at 11 and 22 wks of age was similar between groups. Conclusion Testosterone used in a form of sex‐affirming therapy in female rats induced increases in BP that are independent of adiposity or Insulin resistance and maybe associated to renal injury. Future studies should determine whether these changes are sustained with aging, and the mechanisms responsible for the increase in BP in the female‐to‐male trans‐sex model.