Problems in evaluating chronic toxicity of contraceptive steroids in dogs

The study investigated the chronic toxicity of contraceptive steroids in female beagle dogs, using doses 1, 10, or 25 times higher than those for humans. It found that dogs treated with norethindrone-ethynylestradiol and dimethisterone-ethynylestradiol developed cystic endometrial hyperplasia, pyometra, and alopecia, but did not show significant mammary development or related hyperplastic/neoplastic changes. However, dogs on high doses of megestrol acetate exhibited significant mammary stimulation, hyperplastic and neoplastic changes, and symptoms of diabetes mellitus. These mammary changes, including nodular hyperplasia and tumors, were not observed in similar studies on monkeys or rats, raising questions about their relevance to human tumorigenesis.