THE ANTIPROGESTINS RU486 AND ZK98299 AFFECT FOLLICLE-STIMULATING-HORMONE SECRETION DIFFERENTIALLY ON ESTRUS, BUT NOT ON PROESTRUS

Previous in vivo studies from our laboratory indicated that administra tion of the antiprogestin RU486 on proestrus suppresses both the preov ulatory gonadotropin surges and the secondary FSH surge, suggesting a role for the progesterone receptor (PR) in the generation of these sur ges. The present study was designed to test the effects of another ant iprogestin, 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 sc at 1230 h on proestrus; uterine intraluminal fluid content, serum gonadotropins , and gonadotropin subunit messenger RNAs (mRNAs) were determined at 1 830 h on proestrus and at 0900 h on estrus. At 1830 h on proestrus, bo th RU486 and ZK98299 at both doses caused equal suppression of the pre ovulatory FSH surge and FSH beta mRNA. Both antiprogestins also equall y attenuated the preovulatory LII surge at this time, with the higher doses causing greater suppression. In contrast, at 0900 h on estrus, t he antiprogestins affected serum FSH differentially; only RU486 suppre ssed the secondary FSH surge despite the fact that both drugs prevente d the release of uterine intraluminal fluid, confirming blockade of pr ogesterone action at the level of the uterus, Neither drug had a signi ficant effect on FSH beta mRNA at 0900 h on estrus. ZK98299 at the hig her dose caused a small, but significant, increase in serum LR. In a s ubsequent experiment, we compared the effects of RU486 and ZK98299 (6 mg/kg, sc), administered at 1230 h on proestrus, on serum FSH raised a bove the natural secondary FSH surge on the morning of estrus by passi ve immunization with an antiserum to inhibin-alpha (anti-I) at 1700 h on proestrus. Consistent with the results of the first experiment, bot h antiprogestins blocked the release of uterine intraluminal fluid, bu t only RU486 lowered serum FSH in both the normal sheep serum-treated controls and anti-I-treated rats; in contrast, ZK98299 actually increa sed serum FSH in the normal sheep serum-treated control animals. ZK982 99 also increased FSH beta mRNA in the control group; RU486, on the ot her hand, reduced FSH beta mRNA only in the anti-I group. The results demonstrate unequivocally that whereas the effects of the two antiprog estins on serum FSH and FSH beta mRNA are similar on proestrus, they a re divergent on estrus. The data suggest that the functional state of the PR/transcriptional activation complex in the gonadotrope on the mo rning of estrus is different from that on the evening of proestrus.