Mammary nodules in beagle dogs administered investigational oral contraceptive steroids.
Of 172 beagle dogs administered oral contraceptive steroids for 5-7 years, 114 developed 1,156 nodules in the mammary gland region. Most of these nodules arose 2.5-3.5 years after initiation of treatment. Approximately 16% of the nodules were transient and disappeared spontaneously from the mammary gland during the study. A total of 925 nodules were present in 99 dogs at the time of death or necropsy. These nodules were classified as benign mammary dysplasias (7.0%), lobular or intraductal hyperplasias (31.4%), simple adenomas (20.8%), complex adenomas (25.4%), benign mixed tumors (5.3%), malignant tumors (3.6%), or nonmammary lesions (6.5%). Histologically, the mammary nodules were representative primarily of the hyperplasias and tumors that occur spontaneously in the mammary glands of the dog. The only major exception was the presence of 82 simple adenomas that had basaloid features. Most of the contraceptive-related mammary nodules developed in dogs receiving the combination of progestion and mestranol at 10 or 25 times the proposed human dosage. Control dogs and dogs receiving mestrenol alone had few mammary nodules. Combinations of anagestone acetate and mestranol and chloroethynyl norgestrel (WY-4355) and mestranol produced large numbers of nodules at 10 and 25 times the proposed human dosage, whereas ethynerone plus mestranol produced large numbers of nodules only at 25 times the proposed human dosage. Ethynerone, when given alone at 25 times the proposed human dosage, was associated with fewer mammary nodules. Malignant neoplasms were seen in dogs given 10 and 25 times the proposed human dosage of anagestone acetate plus mestranol and 25 times the proposed human dosage of WY-4355 plus mestranol and ethynerone plus mestranol. This study strongly associates certain combinations of progestin and mestranol with mammary neoplasia in dogs.
D000236:Adenoma / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D003276:Contraceptives, Oral / Q000633:toxicity*; D003277:Contraceptives, Oral, Combined / Q000633:toxicity; D003280:Contraceptives, Oral, Synthetic / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008656:Mestranol / Q000633:toxicity; D009365:Neoplasm Regression, Spontaneous; D009644:Norgestrel / Q000633:toxicity / Q000031:analogs & derivatives; D009649:Norpregnadienes / Q000633:toxicity; D011283:Pregnenes / Q000633:toxicity; D045167:Progesterone Congeners / Q000633:toxicity; D013258:Steroids, Chlorinated / Q000633:toxicity; D013997:Time Factors
D003276:Contraceptives, Oral; D003277:Contraceptives, Oral, Combined; D003280:Contraceptives, Oral, Synthetic; D009649:Norpregnadienes; D011283:Pregnenes; D045167:Progesterone Congeners; D013258:Steroids, Chlorinated; C007891:chloroethynyl norgestrel; D009644:Norgestrel; D008656:Mestranol; C017235:anagestone