EFFECTS OF ONAPRISTONE, TAMOXIFEN AND ICI 182780 ON UTERINE PROSTAGLANDIN PRODUCTION AND LUTEAL FUNCTION IN NONPREGNANT GUINEA-PIGS

Onapristone (a progesterone antagonist) or ICI 182780 (an oestrogen an tagonist) administered to guinea-pigs on days 11-14 of the cycle signi ficantly reduced uterine PGF2alpha 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 regressio n had been prevented. These findings indicate that progesterone and oe stradiol are necessary for increased PGF2alpha production by the uteru s towards the end of the cycle, and support the hypothesis that oestra diol acting on a progesterone-primed uterus is the physiological stimu lus for increased uterine PGF2alpha synthesis and release in guinea-pi gs. The capacity of the endometrium to synthesize PGF2alpha on day 15 was reduced by treatment with ICI 182780 and, unexpectedly, by treatme nt with onapristone, indicating that onapristone may also be antagoniz ing the release or action of oestradiol in some way. Tamoxifen was an agonist in guinea-pigs since it induced vaginal opening. It had no inh ibitory effect on uterine PGF2alpha output and did not delay luteal re gression when administered between days 11 and 14 of the cycle. Howeve r, it redirected PG synthesis in homogenates of endometrium and myomet rium from PGI2 (as indicated by 6-keto-PGF1alpha) to PGF2alpha. The ou tput of 6-keto-PGF1alpha from the uterus of day 15 guinea-pigs was red uced following tamoxifen treatment, but the high output of PGF2alpha f rom the uterus was not affected.