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  • br Discussion To date no


    Discussion To date, no other population-based studies have examined the role of domperidone and liver cancer risk. Two laboratory studies conducted among mice, however, reported that stimulation of prolactin production decreased risk of liver cancer among males [31]. One of the two studies administered domperidone, thus the results of that experiment are more closely related to the results reported in the current manuscript. Reasons for the dissimilarity in results are unclear, but could potentially be due to domperidone being administered to mice with pre-neoplastic hepatic alterations, suggesting that the effect of domperidone was related to progression of disease rather than initiation [31]. In addition, only male mice were included in the laboratory experiment [31], thus it is unclear what effect domperidone would have had on female mice. Alternatively, the effect of prolactin on liver cancer may vary across species as prolactin has been suggested to act as a tumor promoter in rats [24,32]. In humans, domperidone has anti-dopaminergic, prolactin stimulating effects in both men and women [33], with women reported to have stronger domperidone-dependent prolactin stimulation than men [34]. A prior population-based study reported increased cancer risk among persons with hyperprolactinemia [35]. In specific, there was an increased risk of upper and lower gastrointestinal cancer, with a higher risk among women than men. Other studies have reported higher prolactin levels among persons with several cancer types [[36], [37], [38], [39], [40]], including hepatocellular carcinoma, the dominant histological type of liver cancer [[41], [42], [43], [44]]. In these cross-sectional studies, serum prolactin levels, or protein expression of prolactin in tissue samples, were significantly higher in hepatocellular carcinoma cases than in controls [[41], [42], [43], [44]]. Additionally, in a study of human liver tissue [45], prolactin receptor expression was increased in fibrosis and cirrhosis in CL 316243 to normal liver tissue. While these data suggest that serum prolactin expression may be increased in liver disease [45,46], it is unclear that they are relevant to the current findings as the previous studies examined prolactin levels among persons with liver cancer or liver disease, conditions known to be associated with numerous metabolic perturbations. Domperidone is used to treat a variety of gastrointestinal disorders [47], including nausea and vomiting. As these symptoms may be due to different underlying etiologies, confounding by indication could conceivably be related to the elevated risk of liver cancer among women. Furthermore, domperidone was available over-the-counter for a brief period in the U.K. (sold under the brand name Motilium), and studies have reported other “off-label” uses, including treatment of gastroesophageal reflux disease or indigestion [48,49]. However, the most common indication for off-label use among women is stimulation of lactation in the presence of inadequate breast milk production [49]. In the current study, fewer than 20% of women first took domperidone before 50 years of age, the average age of menopause, suggesting that the use of domperidone to stimulate breast milk production is unlikely to explain the sex-specific effect on liver cancer risk. It is unclear whether the findings in the current study support sex-specific differences in results, but if so, it is possible that the differences are related to sex-differences in the activity of enzymes involved in the metabolism of domperidone [50,51]. Domperidone is catabolized primarily by cytochrome P450 (CYP) isozyme CYP3A4 [52,53]. While CYP3A4 is expressed at 2-fold higher levels among women [54], the clinical significance of this, in relation to domperidone use, is unknown. Another possible explanation for the sex difference in the current study is that the male cases were more likely than the female cases to have one or more known risk factors for liver cancer (e.g., obesity, diabetes, chronic HBV/HCV infection, alcohol-related disorder, rare genetic disease). It is thus, conceivable, that any small additional risk of liver cancer among males would be harder to detect on a background of higher overall risk.