Induction and promotion of gamma-glutamyltranspeptidase-positive foci in the liver of female rats treated with ethinyl estradiol, clomiphene, tamoxifen and their associations.

The objective of the present study was to determine whether a short exposure (6 weeks) to high doses of ethinyl estradiol (EE) could not only promote but also initiate hepatocarcinogenesis, and whether two antiestrogens, clomiphene (C) and tamoxifen (T), could influence EE activity. 2-Acetylaminofluorene (AAF), which has been shown to produce rat liver hyperplastic lesions characterized by the presence of estrogen receptors, was used either as a promoter to test for initiating activity, or as an initiator to test for promoting activity. Putative preneoplastic lesions were identified by means of a positive gamma-glutamyltranspeptidase (GGT) reaction. The results revealed that when administered alone in female Sprague-Dawley rats, not only E, but also C and T were clearly active in both initiating and promoting the development of GGT-positive foci. Moreover, in rats of the same strain treated with EE + C or EE + T a significant increase in the incidence of GGT foci demonstrated the occurrence of an additive effect in terms of both initiating and promoting activity. Fischer 344 rats were more susceptible than Sprague-Dawley rats to promotion by EE, C and T, but any substantial evidence of an additive effect was absent when the two anti-estrogens were administered in association with the estrogen.