Pituitary grafts modify sex differences in liver tumor formation in the rat following initiation with diethylnitrosamine and different promotion regimens

We previously reported on sex differences in chemical hepatocarcinogenesis studied in the resistant hepatocyte model and on the effects of implantation of ectopic pituitary grafts into male rats on the early stages of liver carcinogenesis. Marked sex differences were found in the area ratio of enzyme-altered foci (mm² foci/cm² liver section) in sexually mature male and female Wistar rats (♂>♀). Pituitary grafts implanted one week before 2-acetylaminofluorene selection in male rats decreased the area ratio to a level near that of sham operated females. The present study was performed in order to investigate the relevance of the results in the short-term experiment in terms of hepatoma formation. To study the importance of 2-acetylaminofluorene selection as a determinant of the observed sex differences an experiment was also performed using the Pitot-model, where male and female rats were initiated with diethylnitrosamine and promotion was performed with phenobarbital. The long-term experiments in the resistant hepatocyte model showed that male rats develop hepatomas earlier than female rats and also showed a tendency towards a prolonged latency time in male rats bearing pituitary grafts. A good correspondence was thus achieved between the short-term and the long-term experiments. The rats treated according to the Pitot-model did not develop hepatomas within the experimental period. Of the rats killed at 13 months, three (out of five) male and five (out of five) female rats had hepatocyte nodules whereas, at 19 months two (out of six) male and five (out of six) female rats had developed such lesions in this model. We therefore conclude that 2-acetylaminofluorene is the factor responsible for the sex differences in the resistant hepatocyte model and that the hypothalamo-pituitary influence during 2-acetylaminofluorene selection is an important modifier of the carcinogenetic process.