Understanding the Gender Disparity in Bladder Cancer Risk: The Impact of Sex Hormones and Liver on Bladder Susceptibility to Carcinogens

It has long been known that bladder cancer (BC) incidence is approximately four-fold higher in men than in women in the United States, and a similar disparity also exists in other countries. The reason for this phenomenon is not known, which impedes progress in BC prevention. However, BC incidence is also significantly higher in male animals than in their female counterparts after treatment with aromatic amines, which are principal human bladder carcinogens. These animal studies and related studies in the context of available human data provide significant insight into what may drive the excessive BC risk in men, which is the focus of this article. The carcinogenicity and biotransformation of bladder carcinogens as well as the impact of sex hormones on these processes are discussed, highlighting the novel concept that the gender disparity in BC risk may result primarily from the interplay of androgen, estrogen, and liver, with the liver functioning via its metabolic enzymes as the main decider of bladder exposure to carcinogens in the urine and the male and female hormones exerting opposing effects on carcinogenesis in the bladder and likely also on liver enzymes handling bladder carcinogens. The findings may facilitate further investigation into the mechanism of gender disparity in BC risk and may also have important implications for BC prevention.