EFFECTS OF TOREMIFENE ON NEONATAL RAT UTERINE GROWTH AND DIFFERENTIATION

In the developing rodent uterus, the estrogen agonist activity of trip henylethylene antiestrogens such as tamoxifen alters uterine luminal e pithelium morphology and inhibits uterine gland genesis. We examined u terine growth and differentiation in female offspring from date-mated Sprague-Dawley rats given the structurally related antiestrogen, torem ifene, by s.c. injection in 10 mu l of sesame oil on postnatal days (P ND) 1-5, 10-14, or 20-24. Toremifene given on PND 10-14, a period of r apid uterine gland differentiation, caused a dose-related increase in uterine weight, tripled luminal epithelium cell height, and completely inhibited uterine gland development on PND 14 at doses of 10 mu g or higher. Based on this dose-response analysis, a 10-mu g dose of toremi fene was chosen to assess uterine development after neonatal exposure (PND 1-5). Uterine weights and luminal epithelium cell heights were si gnificantly increased by toremifene on PND 5 but returned to control l evels by PND 26. Uterine gland numbers were reduced to 50% those of co ntrols on PND 26. Dose-related uterine weight and luminal epithelium c ell height increases were also observed in rats given toremifene on PN D 20-24. This estrogen agonist activity of toremifene, revealed primar ily in the uterine luminal epithelium, indicates that toremifene is de velopmentally toxic.