Biological determinants and outcomes of sex discrepancies in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) defines the metabolic origin of ectopic accumulation of intrahepatic fatty substrates that affect multiple organ systems. Given the key role of sex in metabolic regulation, this article reviews sex-specific disparities in the epidemiology, pathomechanisms, clinical course, and therapeutic responses associated with MASLD. The influence of reproductive health on the risk of disease in males and females is also examined. Although MASLD is more prevalent in males, the protective effect observed in females diminishes following menopause, highlighting the significant roles that biological sex and reproductive status play in disease progression. Women may face an elevated risk of certain MASLD-related extra-hepatic complications, and ongoing research is elucidating the mechanisms underlying these sex disparities. Biological sex modifies MASLD susceptibility through diverse factors, including fat distribution, adipose tissue pathobiology, hormone signaling pathways, gene-hormone interactions, immune system dynamics, and bile acid composition. Menstrual and reproductive factors, as well as exogenous hormone exposure, further contribute to differential risk profiles. Both endogenous hormone concentrations and sex chromosome composition are relevant for liver health, as evidenced by increased susceptibility in conditions such as polycystic ovary syndrome and certain chromosomal aneuploidies. The review further discusses MASLD in the context of pregnancy and lactation and examines sex-based variation in response to lifestyle modification and pharmacological therapy. Finally, recommendations for future research directions are provided.