Evaluation of autonomic cardiovascular responses evoked by restrain stress in an experimental model of testosterone hormone therapy

• Grant number: 25/03123-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2025
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Jeimison Duarte Santos
• Grantee: Stefanie Carolina Azevedo Martins
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/12013-1 - Effects of Testosterone as a Gender-Affirming Hormone Therapy (GAHT-T) in the cardiovascular system: molecular mechanisms and potential biomarkers of cardiovascular risk, AP.TEM

Abstract

Sex hormones play a fundamental role in cardiovascular homeostasis. Female sex hormones exhibit cardioprotective effects, whereas androgens promote a pro-hypertensive status. Part of the hypertensive effects of androgens is associated with their modulatory effects on the autonomic nervous system (ANS). Supraphysiological levels of androgens increase sympathetic activity and reduce parasympathetic activity under basal conditions or in adverse contexts, including stress. Restriction stress, a classic experimental model of ANS activation, is characterized by increased blood pressure (BP) and heart rate (HR), and preliminary data suggest that male-related sexual factors exacerbate these responses. Transmasculine individuals use testosterone as gender-affirming hormone therapy (GAHT-testo) to develop male secondary sexual characteristics. Although considered safe, GAHT-testo may increase cardiovascular risk for this population due to the high testosterone levels achieved. Our hypothesis is that, in an experimental GAHT model, testosterone exacerbates autonomic cardiovascular responses evoked by the stress restrain, favoring pro hypertensive outcomes. The aim is to evaluate whether cardiovascular parameters mediated by the central nervous system through autonomic components are modulated by testosterone in female rats subjected to stress restrain. Female, 8-week-old Sprague-Dawley rats will receive testosterone cypionate (24 mg/Kg/week) for eight weeks. A control group will be treated with vehicle. Additionally, a group of male rats will be treated with vehicle, mimicking the cisgender men population, to validate the experimental GAHT model. The validation will be assessed by increased body mass index, muscle mass, and elevated serum testosterone levels. For cardiovascular evaluation, after the treatment period, the femoral artery and vein will be cannulated to acquire BP and HR recordings under the following conditions: 1) basal, 2) during restriction stress, and 3) post-stress recovery. The effect of testosterone on autonomic activity involved in cardiovascular responses will be analyzed through heart rate variability (HRV) and spontaneous baroreflex sensitivity. To assess the influence of ANS components on cardiovascular responses, adrenergic receptor (¿ and ¿) and muscarinic (M2) antagonists will be administered to cannulated animals after the treatment period. Cardiovascular recordings will be acquired under basal conditions, during restriction stress, and in the post-stress recovery phase. We aim to provide critical insights into the impact of supraphysiological testosterone levels on the biological components involved in cardiovascular responses to stress stimuli. From a translational perspective, these findings may contribute to optimizing GAHT-testosterone protocols, positively impacting the cardiovascular health of the transmasculine population.