ICI-182,780 INHIBITS ENDOGENOUS ESTROGEN-DEPENDENT RAT UTERINE GROWTHAND TAMOXIFEN-INDUCED DEVELOPMENTAL TOXICITY

To assess the effects of the steroidal antiestrogen ICI 182,780 on pos tnatal uterine development, female Sprague-Dawley rats were given s.c. injections of ICI 182,780 (0.1-100 mu g/rat) on each of postnatal day s (PND) 10-14. ICI 182,780 inhibited uterine growth, as measured by ut erine weight, in a dose-dependent manner but had no effect on either u terine luminal epithelium hypertrophy or gland genesis., Immunohistoch emical analysis revealed that ICI 182,780 (10 mu g) markedly reduced u terine estrogen receptor (ER) immunoreactivity in all uterine cell typ es while tamoxifen (10 mu g) increased ER immunoreactivity, most notab ly in the luminal epithelium. In addition, tamoxifen increased uterine weight and induced luminal epithelium hypertrophy but inhibited uteri ne gland genesis-outcomes also seen with synthetic estrogens such as d iethylstilbestrol. To test the hypothesis that these effects are a con sequence of the estrogen agonist activity of tamoxifen, rats were cotr eated with ICI 182,780 (10 mu g, PND 8-14) and tamoxifen (10 pg, PND 1 0-14). ICI 182,780 greatly reduced or completely blocked tamoxifen-ind uced uterine weight gain, luminal epithelium hypertrophy, tamoxifen-in duced ER immunoreactivity, and the inhibition of uterine gland genesis . ICI 182,780 given daily on PND 1-5 did not alter PND 5 uterine weigh t or uterine differentiation on PND 26. We conclude that postnatal exp osure to ICI 182,780 does not affect uterine growth or differentiation at an age when the uterus is not dependent on estrogen for growth, i. e., PND 1-5, but does inhibit later endogenous estrogen-dependent uter ine growth. The blockade of tamoxifen-induced uterine developmental al terations by ICI 182,780 demonstrates that these tamoxifen effects res ult from its estrogen agonist activity.