UTERINE CARCINOMA IN MICE TREATED NEONATALLY WITH TAMOXIFEN

The induction of preneoplastic and neoplastic lesions by the widely us ed antiestrogen Tamoxifen was studied in female mice, Outbred CD-1 mic e were treated with Tamoxifen (1, 2, 5, 10, 25 or 50 mu g/pup/day) for the first 5 days after birth, At 14-17 months, reproductive tract tis sues were examined for pathological changes, In the ovary, corpora lut ea were lacking while cysts were quite common in Tamoxifen-exposed mic e at all doses; cystadenomas mere seen in two mice, Structural malform ations and epithelial hyperplasia of the oviduct were seen in 100% of the treated mice, Malformations of the uterus, cervix, and vagina were also seen, Excessive vaginal keratinization was not a common feature although vaginal adenosis was observed more often after Tamoxifen trea tment than previously reported after similar treatment with diethylsti lbestrol (DES), The most striking histological features, however were seen in the uterus, One hundred percent of the Tamoxifen-treated mice at all doses exhibited uterine hypoplasia with focal areas of basal ce ll hyperplasia in the lining endometrium. Progressive cellular atypias were seen in the lining endometrium ranging from atypical hyperplasia to uterine adenocarcinoma; the highest incidence of uterine adenocarc inoma was 7/14 (50%) observed in the Tamoxifen 10 mu g/pup/day dose gr oup, No similar tumors were observed in corresponding control mice, Th e induction of atypical uterine hyperplasia and adenocarcinoma combine d with other abnormalities observed in genital tract structure followi ng neonatal treatment with Tamoxifen suggests the developing reproduct ive tract is exquisitely sensitive to perturbation by compounds with h ormonal activity, These studies provide the basis for future investiga tion into the mechanisms of Tamoxifen's carcinogenic effects in experi mental animals, and to the risk benefit analysis for the prophylactic use of Tamoxifen in healthy women who are at risk of developing breast cancer.