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Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208
Address all correspondence and requests for reprints to: Dr. Sonia J. Ringstrom, Department of Neurobiology and Physiology, Northwestern University, 2153 North Campus Drive, Evanston, Illinois 60208-3520. E-mail: s-ringstrom{at}nwu.edu
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 sc 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 FSHß 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 FSHß 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, sc), 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-
(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 FSHß mRNA in
the control group; RU486, on the other hand, reduced FSHß mRNA only
in the anti-I group. The results demonstrate unequivocally that whereas
the effects of the two antiprogestins on serum FSH and FSHß 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.
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