Gender Differences in the Pathogenesis and Risk Factors of Hepatocellular Carcinoma

Abstract

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.

Keywords: HCC; androgens; estrogens; gender; hepatocellular carcinoma; sex hormones.

Figure 1

Schematic representation of the direct role of sex hormones in modulating the risk of developing HCC. AKT: Ak strain transforming; AR: androgen receptor; ATP5J: ATPase-coupling factor 6; CCRK: cell cycle-related kinase; EGFR: epidermal growth factor receptor; ER: estrogen receptor; ERK: extracellular signal-regulated kinase; Fox: forkhead box; GPER: G-protein coupled estrogen receptor; HCC: hepatocellular carcinoma; IL-6: interleukin-6; JAK: Janus kinase; MAPK: Mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; mTORC2: mTOR complex 2; NLRP3: nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3; PI3K: phosphatidylinositol-3 kinase; PTPRO: receptor-type tyrosine-protein phosphatase O; STAT: signal transducer and activator of transcription. * ERs are present both at the level of the cell membrane and of the nucleus.