The morphologic effects of synthetic reproductive steroids on the mammary gland of rhesus monkeys. Mestranol, ethynerone, mestranol-ethynerone, chloroethynyl norgestrel-mestranol, and anagestone acetate-mestranol combinations

Abstract

A total of 213 treated and 16 control monkeys comprising 12 experimental groups was evaluated for determination of the long-term (10 years) effects of various dosages of a variety of synthetic oral contraceptive steroids on the mammary glands of rhesus monkeys. The steroid hormones included mestranol, ethynerone, a combination of mestranol and ethynerone, chlorethynyl norgestrel plus mestranol, and anagestone acetate plus mestranol. Various degrees of physiologic lobular hyperplasia and lactational changes were observed in association with all of these steroid hormones; these changes appeared dose-dependent. Mestranol caused a proliferative atypia ranging from a minimal to a moderate degree in 8 of 34 (23%) animals, but it was not dose-related. Eleven of 15 monkeys (73%) administered ethynerone developed proliferative atypia, ranging in degree from minimal to severe, including one invasive carcinoma and 2 lesions resembling intraductal carcinoma in the human. The mestranol and ethynerone combination produced a proliferative atypia in 22 of 52 animals (42%), including five identical to intraductal carcinoma in the human and one identical to lobular neoplasia. Of the 40 monkeys administered anagestone acetate and mestranol, 20 (50%) developed proliferative atypias; the atypias ranged from mild to severe and included five resembling intraductal carcinoma in human breast. The chloroethynyl norgestrel and mestranol combination induced proliferative atypia in 25 of 52 monkeys (49%); six of these atypias were severe and indistinguishable from intraductal carcinoma of the human breast; and one, if in the human breast, would reflect a solid variant of an invasive carcinoma. Only 2 of the 16 control monkeys (12%) developed proliferative atypias, and these were of minimal to mild degree. The occurrence of severe degrees of atypia identical to intraductal carcinoma in the human breast and invasive carcinoma associated with hormone administration suggests a carcinogenic effect.