Effect of mifepristone and antiestrogens on uterine PGF 2α and PGE 2 concentrations in ovariectomized and pregnant rats

Abstract

Four antiestrogens (anordiol, tamoxifen, RU 39411, ICI 182780) and the antiprogestin, mifepristone (RU 486), were administered to the following three animal models: (1) ovariectomized rats, (2) mated rats treated post-coitally; and (3) pregnant rats treated post-implantation. The antiestrogens were administered alone or in combination with mifepristone at doses effective in preventing and/or terminating pregnancy in rats. The objective of the study was to determine whether these drugs influenced uterine concentrations of prostaglandins (PGF 2α and PGE 2). Antiestrogens administered alone to ovariectomized rats did not effect uterine PGE 2 or PGF 2α concentrations; whereas the combination of anordiol/mifepristone increased uterine PGF 2α concentration, resulting in an increase in the PGF 2α/PGE 2 ratio. Mated rats were treated post-coitally for three consecutive days with anordiol, tamoxifen, estradiol and mifepristone alone and with the combination of anordiol/mifepristone and tamoxifen/mifepristone. An increase in uterine PGF 2α concentrations and in the PGF 2α/PGE 2 ratio occurred only in anordiol/mifepristone treated group. A decrease in uterine PGE 2 concentrations occurred in animals treated with anordiol, tamoxifen and estradiol, resulting in an increase in the PGF 2α/PGE 2 ratio. Anordiol (5.0 mg/kg/day) and mifepristone (4.0 mg/kg/day) alone and the combination of anordiol/mifepristone (2.5/1.0 mg/kg/day) administered to pregnant rats on days 7, 8 and 9 of pregnancy induced an increase in PGF 2α levels without affecting uterine PGE 2 concentration. The changes in uterine PGF 2α concentrations induced by anordiol and the combination of anordiol/mifepristone resulted in an increase in the PGF 2α/PGE 2 ratio. The antiestrogens tested except for ICI 182780 possessed agonist activity when assayed by measuring their capacity to increase the uterine weights in ovariectomized rats. Also, ICI 182789 was the only antiestrogen that did not influence uterine PG concentrations. It can be concluded that ICI 182780 is the only “pure” antiestrogen among those tested. The present results show that antiestrogens and the combination of mifepristone plus anordiol at doses preventing implantation and terminating pregnancy increase uterine PGF 2α and/or decrease PGE 2 concentrations, resulting in an alteration of PGF 2α/PGE 2 ratio. These findings suggest that there exists a critical balance of PGF 2α to PGE 2 concentrations in the uterus required for the normal passage of fertilized ova through the oviduct, initiating implantation of the blastocysts, development of embryos, and maintenance of pregnancy.