ENHANCEMENT OF HEPATOCARCINOGENESIS IN FEMALE RATS BY ETHINYL ESTRADIOL AND MESTRANOL BUT NOT ESTRADIOL

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (9) , 3862-3869
Abstract
The effect of dietary exposure to synthetic estrogens on hepatocarcinogenesis was evaluated. Diethylnitrosamine-initiated and 0.85% NaCl solution-treated noninitiated female Sprague-Dawley rats were transferred to semisynthetic diets containing mestranol (0, 0.1 or 0.5 ppm), ethinyl estradiol (0.5 ppm), estradiol (0.6 ppm) or mestranol plus .beta.-methasone (0.5 and 0.2 ppm, respectively). .gamma.-Glutamyl transferase (GGT)-positive transections and hematoxylin and eosin-detectable nodules and carcinomas were scored at 9 and 12 mo. Quantitative stereological calculations were performed to determine GGT lesion number and size. At 9 mo., in diethylnitrosamine-initiated rats, ethinyl estradiol and mestranol caused 3.5- and 4.4-fold increases, respectively, in the number of GGT lesions per liver and an increased incidence of hepatocellular carcinomas while estradiol had no enhancing effect. Addition of .beta.-methasone to the mestranol-containing diet caused a significant decrease in GGT lesion number but not carcinoma incidence compared to mestranol alone. At 12 mo., in diethylnitrosamnie-initiated rats, mestranol caused a dose-dependent increase in GGT lesion number. The hepatocellular carcinoma incidence was significantly increased at the high mestranol dose. Small increases in the numbers of larger GGT lesions were also observed in non-initiated animals treated with mestranol and ethinyl estradiol and are most probably due to promotion of spontaneously initiated hepatocytes. The synthetic estrogens evidently cause dramatic increases in the number of presumptive preneoplastic GGT lesions. Carcinoma incidence is also enhanced. Synthetic estrogens thus can act as promoters of hepatocarcinogenesis. [Implications with respect to the carcinogenic potential of oral contraceptives in humans are presented.].