Sex Hormones and Metabolic Dysfunction-Associated Steatotic Liver Disease
Ralf Weiskirchen, Amedeo Lonardo
Abstract
Positioned at the intersection of sex medicine and endocrinology, metabolic dysfunction-associated steatotic liver disease (MASLD) is often managed by specialists who may not be fully familiar with the complex roles of sex hormones in its pathogenesis and clinical course. To address this gap, we review the molecular actions of testosterone, estradiol, and progesterone on liver functions, as well as the role of sex-hormone binding globulin (SHBG) in MASLD histogenesis, highlighting disparities by sex as well as reproductive status. We also discuss how sex hormones influence fatty acid metabolism, gut dysbiosis, mitochondrial activity, gluco-lipidic homeostasis, lipotoxicity, inflammation, and MASLD-related liver tumorigenesis. Furthermore, we examine observational studies on associations between endogenous and exogenous sex hormones and SHBG with MASLD, with attention to hypogonadism in either sex or polycystic ovary syndrome. We summarize the role of sex hormones in modulating MASLD risk across life stages such as menopause, breastfeeding, and lactation. Lastly, we review the hepatic effects of hormone replacement therapy (HRT) on MASLD in both sexes, prospects, and safety of HRT and contraceptives among individuals with chronic liver disease. In conclusion, sex hormones play significant roles in MASLD pathobiology, underscoring the importance of sex-specific approaches in clinical practice and research.