Sexual dimorphism in the liver

Sexual dimorphism, which is defined as systematic differences between male and female individuals not limited to characteristics related to reproduction, has been recognized in many organ systems and is emerging as an important component of hepatic function in health and disease. Oestrogen is considered the predominant driver of sexual dimorphism in the liver. Other molecular mechanisms independent of oestrogen including epigenetic regulation and immune function contribute to differences between sexes as do other as yet unknown mechanisms. Clinically, hepatic sexual dimorphisms manifest in many ways. For example, women have a lower incidence of many liver disorders including metabolic-dysfunction-associated steatotic liver disease and liver cancer but are more susceptible to benign neoplasms and autoimmune liver diseases such as primary biliary cholangitis. Better understanding the diverse contributors to hepatic sexual dimorphism, including sociodemographic factors, could deepen our understanding of liver biology and aid in sex-specific clinical management and disease prevention. In this Review, we describe the molecular mechanisms of sexual dimorphisms in liver physiology, including oestrogen signalling, genes encoded on sex chromosomes, epigenetic effects on metabolism and immune function. We also describe hepatic sexual dimorphisms in liver pathophysiology, including in metabolic-dysfunction-associated steatotic liver disease, autoimmune diseases, viral hepatitis and liver cancer.