Sex-differentiated deoxycholic acid promotion of rat liver carcinogenesis is under pituitary control

The influence of continuous growth hormone (GH) infusion and of implantation of ectopic pituitary grafts (PG) to male rats on the sex differences (male greater than female) in efficiency of promotion with dietary deoxycholic acid (DCA; 0.5% w/w) was studied in the livers of diethylnitrosamine (DEN)-initiated Wistar rats. For comparison, liver regeneration after partial hepatectomy (PH) was examined in differently treated animals. The endpoints examined included the number and size of enzyme-altered foci, hepatic c-myc expression and liver weight gain. The area per focus was 2- to 3-fold larger in initiated, DCA-treated males than in the corresponding PG-bearing males, GH-treated males and in females. The expression of the c-myc gene was increased approximately 2-fold in initiated and promoted males, while the increase in females was very small. In both groups of hormone-treated males the expression was at the same level as in females, significantly lower than in the corresponding DEN/DCA-treated males. Liver weight gain in response to PH in initiated as well as uninitiated rats of both sexes was significantly stimulated by DCA. No sex differences or effects of PG on regeneration could be discerned. In conclusion, a sex difference, regulated by a pituitary influence, in focal growth and in c-myc expression was observed during DCA promotion of DEN-initiated rats. This might indicate a correlation between the GH-regulated, proliferation-associated c-myc gene and focal growth during sex differentiated promotion in rat liver. Furthermore, the lack of sex differences in liver weight gain in response to PH during DCA treatment suggests that selective mitoinhibition is not involved, and might in this model indicate hormone-dependent selective stimulation of focal growth as a mechanism for tumor promotion.