Cross-sex hormone therapy in rats induces sex-specific adaptations of renal function and sodium transporters expression.

Introduction: Cross-sex hormone therapy (CHT) has been used in the gender identity-affirming process. Nevertheless, the literature about the renal repercussions of this therapy is scarce. Objective: Evaluate the effects of CHT on blood pressure (BP) and renal function. Methods: Male and female Wistar rats were distributed into groups: M + H (male + hormone), M + V (male + vehicle), F + H (female + hormone), and F + V (female + vehicle). CHT: M + H received algestone-acetophenide (3 mg/kg) plus estradiol-enanthate (0.18 mg/kg); F + H, testosterone-cypionate (3 mg/kg). The vehicle was sesame oil. After 2 months of treatment, BP and renal function [inulin clearance (GFR), ions, and acid excretions] were evaluated. Sodium transporters expression (NHE3, NCC, α-ENaC, and β-ENaC) was assessed by immunohistochemistry. Results: Compared to M + V, M + H presented reduction in BP and GFR but increase in sodium and potassium excretion. GFR did not change in F + H, but sodium and potassium excretions were reduced. Ammonium excretion was decreased in M + H but increased in F + H. The NHE3 expression decreased in M + H and increased in F + H; females showed higher expression of NCC, while CHT did not change it. The β-EnaC expression was higher in females; CHT increased it in males and females. Conclusion: CHT induces sex-specific renal adaptations. Testosterone in females reduces the excretion of sodium and other ions, which may predispose to hypertension. Conversely, estradiol + algestone in males decrease the glomerular filtration rate and alter sodium handling, suggesting maladaptive responses. The expression of sodium transporters was altered in a sex- and nephron segment-specific manner. These findings highlight the need for further studies on the renal consequences of hormone therapy in transgender individuals.