We examined the effects of short-term estrogen and progesterone treatment mimicking pregnancy in aged female Lewis rats on the development of N-methyl-N-nitrosourea (MNU)-induced mammary carcinoma. Rats were administered a single intraperitoneal injection of 20 mg/kg MNU at 7 weeks of age and half of those rats were administered a subcutaneously implanted 21-day release pellet containing 0.5 mg 17β-estradiol and 32.5 mg progesterone (E/P) at 24 weeks of age. The rats were then monitored for the occurrence of mammary tumors. Rats were sacrificed when the largest mammary tumor became ≥1 cm in diameter, or when the rat reached 48 weeks of age. Development of MNU-induced mammary carcinomas was accelerated after short-term E/P treatment, compared with E/P-untreated rats: the incidence of ≥1-cm mammary carcinomas tended to increase (60 vs. 44%); the latency tended to shorten (28.7 vs. 34.6 weeks); and cancer multiplicity (number of all-sized carcinomas per rat) significantly increased (1.8 vs. 0.8). In E/P-treated rats, comedo necrosis was frequently seen and the incidence of estrogen receptor and/or progesterone receptor-negative mammary carcinomas was significantly increased. Early age at full-term pregnancy or short-term hormone treatment mimicking pregnancy may suppress the risk of breast cancer, but the age of hormone exposure is a crucial factor, because hormone exposure mimicking pregnancy in aged individuals may exert effects opposite of those exerted in younger individuals.

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