Induction of mammary tumors, estrous cycle abnormalities and endometrial hyperplasia in rats exposed to different doses of N-nitrosomethylurea.

Groups of female Sprague--Dawley strain rats were given 3 i.v. injections of N-nitrosomethylurea in doses of 0.5, 1, 2, 3, 4 or 5 mg/100 g body weight at 4-week intervals. The first dose was given when they were 50 days old. By 23 weeks after the first injection, mammary tumors had developed in 0, 0, 33, 54, 72 and 100% of animals respectively. There was a direct relationship between the total dose of carcinogen administered and the degree of tumor anaplasia observed on histological examination. All of the tumors contained assayable amounts of estrogen and progesterone receptors, and the receptor concentrations were not related to the dose of carcinogen. Twenty-one rats, all exposed to the 4 highest doses of N-nitrosomethylurea, had arrest of the estrous cycle at the stage of estrus. In 15 of the 21 the walls of the uterine horns were thickened and grossly distended by fluid. Histological examination demonstrated the presence of endometrial hyperplasia. These uterine abnormalities were usually accompanied by polycystic disease of the ovaries. Both endometrial hyperplasia and abnormal estrous cycles without uterine changes were associated with elevated progesterone receptor to estrogen receptor ratios in the corresponding mammary carcinomas.