Sex Specific Differences of Estrogen Therapy in Cardiovascular and Metabolic Function

Abstract

For much of its history as a therapeutic, estrogen (E2) has been studied and applied almost exclusively within the context of female physiology. However, with the growing number of individuals undergoing hormone therapy, particularly among transgender women, there is a significant and rising population of biological males receiving chronic E2 therapy. While E2 has been shown to exert cardioprotective and metabolically beneficial effects in females, it remains unclear whether these benefits translate to the male physiology, or whether sex-specific differences in hormone signaling may lead to distinct or even adverse outcomes. To address this gap, this study was designed to systematically examine the sex-specific effects of chronic E2 therapy through three integrated approaches. First, echocardiography was used to establish baseline sex differences in cardiac structure and function and to assess how chronic E2 treatment influences these parameters in both sexes. Second, the impact of E2 on the expression and posttranslational regulation of connexin-43 (Cx43), a key gap junction protein critical to cardiac electrical conduction, was examined to explore potential mechanisms underlying sex-specific changes in cardiac physiology. Third, whole-body metabolic assessments were conducted to evaluate changes in energy expenditure, oxygen consumption (VO₂), carbon dioxide production (VCO₂), and respiratory exchange ratio (RER), alongside tissue-level analysis of cardiac energy signaling pathways, including LKB1 and AMPK. Together, these studies aim to provide a comprehensive understanding of how chronic E2 therapy affects cardiovascular and metabolic systems in a sex-dependent manner, with implications for both basic biology and the clinical management of individuals receiving estrogen therapy outside the traditional female population. We hypothesize that when taken chronically, E2 deteriorates cardiac function in biological males by down regulating Cx43 and dysregulating posttranslational phosphorylation of Cx43. In addition, we hypothesize that chronic E2 promotes metabolic dysfunction in males by.