The cardiovascular subtleties of testosterone on gender-affirming hormone therapy

The growing number of people who identify themselves as transgender has gained increased attention in recent years and will certainly impact personalized clinical practices and healthcare worldwide. Transgender and gender-nonconforming individuals frequently undergo gender-affirming hormone therapy (GAHT), i.e., they use sex hormones to align their gender identity with their biological characteristics. Testosterone is the main compound used in GAHT by transmasculine people, leading to the development of male secondary sexual characteristics in these individuals. However, sex hormones, testosterone included, also influence hemodynamic homeostasis, blood pressure, and cardiovascular performance by direct effects in the heart and blood vessels, and by modulating several mechanisms that control cardiovascular function. In pathological conditions and when used in supraphysiological concentrations, testosterone is associated with harmful cardiovascular effects, requiring close attention in its clinical use. The present review summarizes current knowledge on the cardiovascular impact of testosterone in biological females, focusing on aspects of testosterone use by transmasculine people (clinical goals, pharmaceutical formulations, and impact on the cardiovascular system). Potential mechanisms whereby testosterone may increase cardiovascular risk in these individuals are discussed, and the influence of testosterone on the main mechanisms that control blood pressure and that potentially lead to hypertension development and target-organ damage are also reviewed. In addition, current experimental models, which are key to reveal testosterone mechanistic aspects and potential markers of cardiovascular injury, are reviewed. Finally, research limitations and the lack of data on cardiovascular health of transmasculine individuals are considered, and future directions for more appropriate clinical practices are highlighted.