Abstract

PIP: A study begun by a drug company and taken over by the FDA (Food and Drug Administration) in 1970 attempted to assess the role of oral contraceptives in tumorigenesis and clotting abnormalities in animals. The study used ethynerone (MK 665) + mestranol; chloroethynyl norgestrel (Wy-4355) + mestranol; anagestone acetate + mestranol; ethynerone, and; mestranol administered at levels up to 25 times the human use level to female beagle dogs and 50 times the human use level to female rhesus monkeys. No behavioral changes related to compound or dose were observed in either species. Both species exhibited pharmacologic effects of hormone administration. Inhibition of the estrous cycle and vulvar enlargement were seen in all dosed dogs. Both species exhibited a dose-dependent, nonprogressive decrease in hemoglobin and hematocrits, with the anagestone acetate-mestranol combination showing the greatest effect. More nodules developed in the mammary glands of dogs who received the progestogen-mestranol combinations and who received ethynerone alone than control dogs. The 3 progestogen-mestranol combination showed the greatest tumorigenic effect as expressed by the number of dogs affected and by numbers of mammary nodules. This effect was dose-dependent for the ethynerone-mestranol and chloroethynyl norgestrel-mestranol combinations, but for the anagestone acetate-mestranol combination was maximal at the lower dose. A small number of dogs that received each progestogen-mestranol combination developed clinically malignant tumors; control dogs or dogs that received only mestranol or ethynerone were unaffected. In contrast, none of the drugs was associated with an increased incidence of mammary nodules in the monkeys. Some monkeys that received each drug showed ductal epithelial hyperplasia in mammary gland biopsies. Diabetes mellitus occurred in 10 dogs from the chloroethynyl norgestrel-mestranol and anagestone acetate-mestranol groups and in 3 monkeys from the ethynerone-mestranol high dose and anagestone acetate-mestranol high dose groups. Generalized cystic hyperplasia of the gallbladder mucosa was seen in a small number of dogs from the anagestone acetate-mestranol group. The suitability of the dog as test species for the tumorigenic and carcinogenic study of oral contraceptives is indicated.