Gender Differences in the Pathogenesis and Risk Factors of Hepatocellular Carcinoma

Simple Summary Significant gender disparities have been highlighted in the incidence, aggressiveness, and prognosis of HCC. A different epidemiological distribution of the risk factors of liver damage and, above all, the actions of sex hormones are at the basis of these differences. Accurate knowledge of gender disparities in HCC would lead to adequate surveillance strategies and the potential implementation of current treatment schemes. Several chronic liver diseases are characterized by a clear gender disparity. Among them, hepatocellular carcinoma (HCC) shows significantly higher incidence rates in men than in women. The different epidemiological distribution of risk factors for liver disease and HCC only partially accounts for these gender differences. In fact, the liver is an organ with recognized sexual dysmorphism and is extremely sensitive to the action of androgens and estrogens. Sex hormones act by modulating the risk of developing HCC and influencing its aggressiveness, response to treatments, and prognosis. Furthermore, androgens and estrogens are able to modulate the action of other factors and cofactors of liver damage (e.g., chronic HBV infection, obesity), significantly influencing their carcinogenic power. The purpose of this review is to examine the factors related to the different gender distribution in the incidence of HCC as well as the pathophysiological mechanisms involved, with particular reference to the central role played by sex hormones.