Cross-Sex Hormone Therapy in rats induces sex-specific adaptations of renal function and Sodium Transporters expression

Debora Conte Kimura Lichtenecker¹Nathalia Beserra Silva^1,2Letícia Maria Monteiro^1,2Isabela Borges Da Mota Silveira^1,2Rogerio Argeri^1,2Magnus R. Dias da Silva^3,4Guiomar Nascimento Gomes^1*

• ¹Department of Physiology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, São Paulo, Brazil
• ²Postgraduate Program in Translational Medicine, Department of Medicine, Universidade Federal de Sao Paulo Escola Paulista de Medicina, São Paulo, Brazil
• ³Trans Care Outpatient Clinics; Núcleo de Estudos, Pesquisa, Extensão e Assistência à Pessoa Trans Professor Roberto Farina, Universidade Federal de Sao Paulo, São Paulo, Brazil
• ⁴Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Universidade Federal de Sao Paulo Escola Paulista de Medicina, São Paulo, Brazil

Cross-sex hormone therapy (CHT) has been used in the gender identityaffirming 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 algestoneacetophenide (3mg/kg) plus estradiol-enanthate (0.18mg/kg); F+H, testosterone-cypionate (3mg/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. Conclusions: 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.