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  • A role for endogenous hormones in


    A role for endogenous Prostaglandin J2 in the gender discrepancy in liver cancer risk has been hypothesized, with most speculation focusing on testosterone or estradiol [[5], [6], [7], [8]]. However, the role of estrogenic exposures remains unclear, as studies have reported mixed results for parity [[9], [10], [11], [12], [13], [14], [15]], oral contraceptive use [16], and menopausal hormone therapy [15,17,18], although two studies have shown an increased liver cancer risk associated with bilateral oophorectomy [15,18]. Other hormones could also play a role in liver cancer development. Prolactin is an estrogen-responsive hormone secreted by the pituitary gland that is expressed at higher levels among women than among men [19]. While its role in reproduction, including lactation, menstruation, and sexual behavior, is well characterized, prolactin also plays extensive roles in numerous other processes including immune response regulation [20]. Prolactin exhibits immunostimulatory properties and protects against inflammation under severe stress, such as trauma [21]. Whether the higher levels of prolactin found in women could underlie the gender difference in liver cancer risk is not known. Prolactin secretion, however, can be increased by domperidone, a dopamine antagonist that is commonly prescribed for the amelioration of nausea and vomiting [22,23]. Experiments in mice, one of which employed domperidone, have reported that stimulation of prolactin production decreased liver tumorigenesis [24,25]. As liver cancer rates are rising and survival rates remain poor, identification of possible chemopreventive agents could provide an effective intervention in high-risk populations. Thus, to examine the hypothesis that domperidone use, and by extension higher prolactin levels, is associated with decreased liver cancer risk in humans, a large study in a medical records database was undertaken.
    Materials and methods
    Results Overall, the median length of enrollment in CPRD was 10.3 years (range 6.5–14.6 years), with the median being slightly longer among men (10.4 years) than among women (9.9 years). Characteristics of the cases and controls are shown in Table 1. Among both men and women, cases were more likely than controls to be current smokers, have chronic HBV and/or HCV infection, have diabetes, have an alcohol related-disorder and have a rare genetic disorder. Male cases, compared to female cases, were more likely to be obese, to be ever smokers (current and former), and to have chronic HBV and/or HCV infection, diabetes, alcohol-related disorders and rare genetic disorders. The associations between domperidone use and liver cancer are shown in Table 2. Among the cases, 4.8% had received prescriptions for domperidone, with an average cumulative dose of 2315 mg. Among the controls, 3.9% had received prescriptions for domperidone, with an average cumulative dose of 4176 mg. Comparing ever versus never use, there was no association between domperidone and liver cancer risk among men (OR = 1.06, 95% CI: 0.76, 1.48) or among women (OR = 1.21, 95% CI: 0.82, 1.76). In addition, there was no meaningful difference in liver cancer risk when stratified by time since last use. The analyses of number of prescriptions and cumulative dose, however, resulted in somewhat discrepant findings among men and women. Among men, there were no significant associations between risk and either cumulative dose (p-trend = 0.62) or number of prescriptions (p-trend = 0.57). Among women however, there was an elevated risk of liver cancer with increasing cumulative dose (p-trend = 0.02) and number of prescriptions (p-trend = 0.02). In particular, higher risk was found among women Repetitive DNA received the highest cumulative dose (OR2700 mg vs. 0 mg = 2.52, 95% CI: 1.18, 5.41) and the greatest number of prescriptions (OR≥11 Rx vs. 0 Rx = 3.17, 95% CI: 1.07, 9.40). Stratification by age at first use among women (<50 yrs. vs > = 50 yrs.), however, did not identify any differences in results (data not shown). To determine whether the differences between men and women were meaningful, an interaction analysis was conducted which found little evidence of heterogeneity. In examining cumulative dose, the p-value for interaction was p = 0.19, while the p-value for interaction of the number of prescriptions was p = 0.21.