Effect of mifepristone and antiestrogens on uterine PGF2 alpha and PGE2 concentrations in ovariectomized and pregnant rats.
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 (PGF2 alpha and PGE2). Antiestrogens administered alone to ovariectomized rats did not effect uterine PGE2 or PGF2 alpha concentrations; whereas the combination of anordiol/mifepristone increased uterine PGF2 alpha concentration, resulting in an increase in the PGF2 alpha/PGE2 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 PGF2 alpha concentrations and in the PGF2 alpha/PGF2 ratio occurred only in anordiol/mifepristone treated group. A decrease in uterine PGE2 concentrations occurred in animals treated with anordiol, tamoxifen and estradiol, resulting in an increase in the PGF2 alpha/PGE2 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 day 7, 8 and 9 of pregnancy induced an increase in PGF2 alpha levels without affecting uterine PGE2 concentration. The changes in PGF2 alpha concentrations induced by anordiol and the combination of anordiol/mifepristone resulted in an increase in the PGF2 alpha/PGE2 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 PGF2 alpha and/or decrease PGE2 concentrations, resulting in an alteration of PGF2 alpha/PGE2 ratio. These findings suggest that there exists a critical balance of PGF2 alpha to PGE2 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.
Li
X J
XJ
Department of Pharmacology, Beijing Medical University, China.
Yu
H
H
Koide
S S
SS
D000021:Abortifacient Agents, Steroidal / Q000494:pharmacology; D000818:Animals; D003283:Contraceptives, Postcoital, Synthetic / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D047108:Embryonic Development / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D015735:Mifepristone / Q000494:pharmacology*; D009635:Norandrostanes / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D000021:Abortifacient Agents, Steroidal; D003283:Contraceptives, Postcoital, Synthetic; D004965:Estrogen Antagonists; D009635:Norandrostanes; D013629:Tamoxifen; C060411:RU 39411; D000077267:Fulvestrant; D015735:Mifepristone; D004958:Estradiol; C023615:anordiol; D015237:Dinoprost; D015232:Dinoprostone