ICI 182,780 acts as a partial agonist and antagonist of estradiol effects in specific cells of the sheep uterus

We assessed the ability of ICI 182,780 (ICI) to block the estradiol (E2) re sponses of genes within the sheep uterus. Ovariectomized ewes in the 'ICI E2' treatment group received a uterine infusion with 10(-7) M ICI for 14 h , an injection of 50 mug E2 6 h after the infusion started, and were hyster ectomized 18 h postinjection. Other groups received only ICI or E2, or neit her treatment ('Con'). Both E2 and ICI increased the wet weight of dissecte d endometrium: averaging 10.0 +/- 1.2 g for ICI + E2, ICI, and E2 groups co mpared to 6.8 +/- 0.6 g for Con. Slot blot analyses of endometrial RNA show ed that estrogen receptor-alpha (ER), progesterone receptor (PR), glycerald ehyde 3-phosphate dehydrogenase (GAPDH), cyclophilin, actin and c-fos mRNAs responded to E2 treatment: the first five increased an average of 60% whil e the last decreased 38%. In situ hybridization identified more subtle ICI effects: agonistic up-regulation of GAPDH mRNA in superficial endometrial c ells, and antagonistic down-regulation of ER and PR mRNAs in the inner laye r of the myometrium. Thus, we conclude that the agonist versus antagonist e ffects of ICI relative to those of E2 are a function of the gene examined a s well as the specific cell within the uterus. (C) 2001 Elsevier Science Lt d. All rights reserved.