Sex Differences in MASLD

This review focus on sex-related differences in Metabolic dysfunction-associated steatotic liver disease (MASLD), the most recent term used to describe the range of “nonalcoholic” fatty liver disorders with metabolic causes. The review discusses data on epidemiology, mechanisms, and treatment outcomes. Men are more susceptible to MASLD than women, although premenopausal women have a lower risk that increases with age and is influenced by reproductive status. Additionally, women have higher rates of MASLD-related cardiovascular disease and extrahepatic cancers compared to men. Both hormones and chromosomes play a role in MASLD susceptibility. Hormone imbalances, such as hypogonadism, polycystic ovary syndrome, and chromosomal abnormalities like Turner and Klinefelter syndromes, contribute to hepatic steatosis through metabolic and lipid dysregulation. Sex hormones also modulate key molecular and cellular pathways in MASLD, impacting liver-resident cells, gut microbiota, and innate immunity. Reproductive factors, including age at menarche, menopause, hormone therapy, and lactation, further influence disease risk. Breastfeeding not only lowers maternal metabolic risk but also protects infants from MASLD-related complications. Sex also influences how individuals respond to lifestyle changes and pharmacotherapy for obesity, diabetes, and dyslipidemia. While testosterone replacement therapy may benefit liver health in hypogonadal men, evidence on other hormone therapies is limited. More research is needed to better understand the roles of sex hormones and chromosomes in MASLD development and progression at different life stages. Clinical trials should routinely include sex-based analyses to enhance generalizability and ensure equitable care.