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Previous in vivo studies from our laboratory indicated that administration of the antiprogestin RU486 on proestrus suppresses both the preovulatory gonadotropin surges and the secondary FSH surge, suggesting a role for the progesterone receptor (PR) in the generation of these surges. The present study was designed to test the effects of another antiprogestin, ZK98299, which has been reported to block the PR through a mechanism different from that of RU486, on gonadotropin secretion in vivo. RU486 and ZK98299 (2 and 6 mg/kg) were administered s.c. at 1230 h on proestrus; uterine intraluminal fluid content, serum gonadotropins, and gonadotropin subunit messenger RNAs (mRNAs) were determined at 1830 h on proestrus and at 0900 h on estrus. At 1830 h on proestrus, both RU486 and ZK98299 at both doses caused equal suppression of the preovulatory FSH surge and FSHbeta mRNA. Both antiprogestins also equally attenuated the preovulatory LH surge at this time, with the higher doses causing greater suppression. In contrast, at 0900 h on estrus, the antiprogestins affected serum FSH differentially; only RU486 suppressed the secondary FSH surge despite the fact that both drugs prevented the release of uterine intraluminal fluid, confirming blockade of progesterone action at the level of the uterus. Neither drug had a significant effect on FSHbeta mRNA at 0900 h on estrus. ZK98299 at the higher dose caused a small, but significant, increase in serum LH. In a subsequent experiment, we compared the effects of RU486 and ZK98299 (6 mg/kg, s.c.), administered at 1230 h on proestrus, on serum FSH raised above the natural secondary FSH surge on the morning of estrus by passive immunization with an antiserum to inhibin-alpha (anti-I) at 1700 h on proestrus. Consistent with the results of the first experiment, both antiprogestins blocked the release of uterine intraluminal fluid, but only RU486 lowered serum FSH in both the normal sheep serum-treated controls and anti-I-treated rats; in contrast, ZK98299 actually increased serum FSH in the normal sheep serum-treated control animals. ZK98299 also increased FSHbeta mRNA in the control group; RU486, on the other hand, reduced FSHbeta mRNA only in the anti-I group. The results demonstrate unequivocally that whereas the effects of the two antiprogestins on serum FSH and FSHbeta mRNA are similar on proestrus, they are divergent on estrus. The data suggest that the functional state of the PR/transcriptional activation complex in the gonadotrope on the morning of estrus is different from that on the evening of proestrus.

The Antiprogestins RU486 and ZK98299 Affect Follicle-Stimulating Hormone Secretion Differentially on Estrus, but not on Proestrus*