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 gamma-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.