Effects of neonatal and adult castration and of testosterone substitution in male rats on growth of enzyme-altered hepatic foci in the resistant hepatocyte model.

Marked sex differences in the growth of enzyme-altered hepatic foci have been observed in rats treated according to the "resistant hepatocyte model." The present study was performed to investigate the effect of neonatal and adult castration of male rats, with or without testosterone substitution, on the growth rate of foci during selection of initiated cells with 2-acetylaminofluorene and partial hepatectomy. Neonatal castration of male rats decreased focal growth to the same level as in female rats. Castration of adult male rats 2 wk before initiation with diethylnitrosamine also decreased the growth rate of foci, but less markedly than in neonatally castrated rats. Testosterone substitution of male rats castrated as neonates or as adults, from 10 days after initiation with diethylnitrosamine, restored focal growth to that of sham-castrated controls. Previous investigations concerning the role of gonadal hormones in sex differentiation of various liver functions indicated a role of the hypothalamo-pituitary-liver axis in mediating the effects of androgens. It is therefore also suggested that the effects of androgens on early steps of hepatocarcinogenesis observed in the present study are mediated by similar mechanisms, possibly through an influence on the metabolism of 2-acetylaminofluorene.