6-ketoprostaglandin-f1-alpha and onapristone

Onapristone (a progesterone receptor antagonist) administered to guinea-pigs on days 11-14 of pregnancy had no effect on uterine PGF2 alpha output and endometrial PGF2 alpha synthesizing capacity when measured on day 15. Peripheral plasma progesterone concentrations were still high on day 15, although the weight of the conceptuses was decreased by 50%. These findings indicate that the lack of increase in PGF2 alpha production by the uterus during early pregnancy is not due to an inhibitory action of progesterone on uterine PGF2 alpha synthesis and release. The output of PGF2 alpha from the guinea-pig uterus remained low during early pregnancy, showing that the uterus is not the source of increased PGF2 alpha secretion, as indicated previously by an increase in PGF2 alpha metabolite concentrations in the urine, after day 24 of pregnancy. Of the conceptual tissues examined, the fetal placenta had the highest PGF2 alpha synthesizing capacity, and it increased 2.3-fold between days 29 and 36 of pregnancy. The fetal placenta may therefore be the source of increased PGF2 alpha production during pregnancy. Onapristone administered to guinea-pigs on days 27 and 28 or on days 34 and 35 of pregnancy resulted in the guinea-pigs being in the early, middle or late stages of abortion when examined on days 29 or 36, respectively. Increased PG production, particularly of PGF2 alpha, by the uterus occurred in those guinea-pigs that were in the middle or late stages of abortion; uterine PG production in guinea-pigs that were in the early stages of abortion remained low.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Abortion, Spontaneous; Animals; Dinoprost; Dinoprostone; Endometrium; Female; Gonanes; Guinea Pigs; Pregnancy; Pregnancy, Animal; Progesterone; Receptors, Progesterone; Uterus

Onapristone (a progesterone antagonist) or ICI 182780 (an oestrogen antagonist) administered to guinea-pigs on days 11-14 of the cycle significantly reduced uterine PGF2 alpha output on day 15. Concentrations of progesterone in plasma of onapristone-treated and ICI 182780-treated guinea-pigs were still high on day 15 indicating that luteal regression had been prevented. These findings indicate that progesterone and oestradiol are necessary for increased PGF2 alpha production by the uterus towards the end of the cycle, and support the hypothesis that oestradiol acting on a progesterone-primed uterus is the physiological stimulus for increased uterine PGF2 alpha synthesis and release in guinea-pigs. The capacity of the endometrium to synthesize PGF2 alpha on day 15 was reduced by treatment with ICI 182780 and, unexpectedly, by treatment with onapristone, indicating that onapristone may also be antagonizing the release or action of oestradiol in some way. Tamoxifen was an agonist in guinea-pigs since it induced vaginal opening. It had no inhibitory effect on uterine PGF2 alpha output and did not delay luteal regression when administered between days 11 and 14 of the cycle. However, it redirected PG synthesis in homogenates of endometrium and myometrium from PGI2 (as indicated by 6-keto-PGF1 alpha) to PGF2 alpha. The output of 6-keto-PGF1 alpha from the uterus of day 15 guinea-pigs was reduced following tamoxifen treatment, but the high output of PGF2 alpha from the uterus was not affected.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Dinoprostone; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Gonanes; Guinea Pigs; Luteolysis; Progesterone; Tamoxifen; Uterus

Antiprogesterone steroid, ZK98299 (Schering, Germany) or RU38486 (Roussel Uclaf, France), has been administered to ovariectomized early pregnant rats receiving continuous steroid replacement. At 24 h later, uterine explants of rats treated with ZK98299 produced significantly greater amounts of prostaglandin E (PGE) than did controls or animals treated with RU38486. The PGE/PGF2 alpha production ratio for uteri of rats treated with ZK98299 or RU38486 was markedly lowered compared to controls, and a significant decrease occurred in the PGE/6-keto PGF1 alpha production ratio for rats treated with RU38486. For ovariectomized early pregnant rats in which progesterone has been withdrawn, a significant reduction in uterine PGE production occurred when compared to control animals. There was also a marked decrease in PGE/PGF2 alpha production ratio, and the PGE/6-keto PGF1 alpha production ratio tended to be lowered relative to controls. The stimulated production (as by ZK98299) or unchanged production of PGE (as by RU38486) indicates a selective action on uterine PGE synthesis among the antiprogesterone steroids, and these findings cannot be explained simply in terms of a blockage of progesterone receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Female; Gonanes; In Vitro Techniques; Mifepristone; Ovariectomy; Pregnancy; Progesterone; Prostaglandins E; Rats; Uterus

Ovariectomized early pregnant rats given continuous steroid replacement therapy have been treated with antiprogesterone steroid, ZK98299 or RU38486. At 24 h following treatment, uterine explants in culture were found to produce significantly greater amounts of PGF2 alpha, but not of 6-keto-PGF1 alpha, when compared to controls. ZK98299 and RU38486 gave almost identical levels of uterine PG production. The 6-keto-PGF1 alpha/PGF2 alpha production ratio for uteri of treated rats was decreased by 45% relative to controls. Similar changes in uterine PGF2 alpha production and 6-keto-PGF1 alpha/PGF2 alpha ratio have been shown for ovariectomized early pregnant rats in which progesterone has been withdrawn when compared to control animals. It has been suggested that inhibiting or withdrawing progesterone in rat uteri exposed to estradiol and progesterone may lead to a stimulation of endoperoxide F-reductase and/or E2 9-ketoreductase activities. The presence of luminal fluid in the uteri was observed for animals treated with antiprogesterone steroid or in which progesterone had been withdrawn. This was associated with a decrease in % dry weight for the uteri of these animals.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Drug Implants; Epoprostenol; Estradiol; Female; Gonanes; Mifepristone; Organ Size; Ovariectomy; Pregnancy; Pregnancy, Animal; Progesterone; Rats; Rats, Inbred Strains; Uterus