Hormone prevention of mammary carcinogenesis by norethynodrel-mestranol

The observation that the susceptibility of the mammary gland to chemical carcinogenesis is inversely related to its level of hormonally induced differentiation led us to test whether treatment of virgin rats with an estrogenic-progestagenic hormone combination protected the gland against this carcinogenesis. Virgin Sprague-Dawley rats aged 45, 55, 65, or 75 days had implanted subcutaneously for 21 days a pellet containing norethynodrel-mestranol (NM) (98.5%-1.5%) at two doses, a physiological or low dose (LD) of 0.5 mg, equivalent to the dose used in Enovid for contraception in humans, and a pharmacological or high dose (HD) of 5.0 mg. Twenty-one days after NM pellet removal, the mammary glands of 5 animals per group were examined for the number of terminal end buds (TEBs), terminal ducts (TDs), alveolar buds (ABs) and lobules, and the DNA labeling index (DNA-LI). The remaining animals received 8 mg 7,12-dimethylbenz(a) anthracene (DMBA)/100 g body weight, and tumorigenesis was evaluated at 24 weeks. The percentage of TEBs decreased with age, and further with NM treatment at both doses. Treatment did not significantly modify the percentage of TDs, but increased that of ABs in most groups. The DNA-LI of TEBs remained constant, even during aging and after treatment, whereas both aging and treatment reduced DNA-LI in TDs and ABs. Tumor incidence declined with increasing age from 75% to 44% in the 45 and 75 day-old control groups respectively. Adenocarcinoma incidence followed the same trend. NM treatment had a dose-related protective effect against development of tumors in general and of adenocarcinomas in particular. LD treatment resulted in a marginally significant reduction in adenocarcinoma incidence, whereas HD-treated animals were 0.24 times as likely as controls to develop carcinomas. There was a statistically significant correlation between the percentage of TEBs present in the gland at the time of carcinogen administration and the incidence of adenocarcinomas. It was concluded that treatment of virgin rats with the hormone combination norethynodrel-mestranol resulted in long lasting structural changes in the mammary gland which protected this organ from a subsequent carcinogenic insult.