Sex differences in dehydroepiandrosterone-induced hepatocarcinogenesis in the rat

Dehydroepiandrosterone (DHEA), a steroid secreted by the adrenal gland, is a peroxisome proliferator and a hepatocarcinogen. Previously, we have shown that 15-week-old male rats given DHEA in AIN-76 diet without vitamin E developed liver tumors. In the present study, we have examined the carcinogenic effect of DHEA in 5–6-week-old male rats and in intact and ovariectomized female rats. Rats were fed Purina chow containing DHEA at a concentration of 0.45% for 100 weeks and livers were evaluated for tumor incidence and multiplicity. In male rats the incidence of total tumors and hepatocellular carcinomas (HCC) was 94 and 81%, respectively, with 1.9±0.3 (mean±SD) tumors per liver. In intact and ovariectomized females the total tumor incidence was 46 and 60%, respectively. However, the incidence of HCC and the mean number of tumors were similar in both intact and ovariectomized groups. Phenotypically the neoplastic nodules and HCC in female rats were negative for γ-glutamyltranspeptidase. The results of these studies further confirm that DHEA is a hepatocarcinogen in male and female rats. The possible reasons for the decreased incidence of liver tumors in females in relation to the peroxisome proliferative effect of DHEA is discussed.