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The Antiprogestins RU486 and ZK98299 Affect Follicle-Stimulating Hormone Secretion Differentially on Estrus, but not on Proestrus¹

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

	Abstract

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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 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.

	Introduction

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THE SUSTAINED elevation of serum FSH on the morning of estrus, the secondary FSH surge, plays an important physiological role in the recruitment of a cohort of follicles for the next estrus cycle (1); nevertheless, the factors underlying the generation of the secondary FSH surge are still incompletely understood. Foremost among these factors is a fall in circulating inhibin from the high levels present on the evening of proestrus, reaching a nadir on the morning of estrus, coincident with the peak of the secondary FSH surge (2, 3); the cellular mechanisms by which a fall in circulating inhibin leads to stimulation of FSH secretion, however, are unclear. Furthermore, whereas a fall in circulating inhibin is required for generation of the secondary FSH surge, it alone is insufficient to account for the sustained elevation of serum FSH on the morning of estrus. Previous in vivo studies from our laboratory demonstrated that the antiprogesterone/antiglucocorticoid RU486 (mifepristone), in addition to attenuating the preovulatory gonadotropin surges on proestrus, suppresses the secondary FSH surge on the morning of estrus (4) as well as the rise in serum FSH that occurs in response to passive immunization with an antiserum to inhibin- (anti-I) (5). We demonstrated further that suppression of the secondary FSH surge by RU486 on the morning of estrus persisted when circulating progesterone (P) and corticosterone were markedly reduced by treatment with aminoglutethimide on the morning of proestrus (6). Passive immunization with anti-I on any day of the estrous cycle raises serum FSH (7, 8); suppression of this rise in serum FSH by RU486, however, requires the high estrogen (E) background normally present on proestrus (9). We proposed, on the basis of these findings, that ligand-independent activation of an E-inducible form of the P receptor (PR) in the gonadotrope, susceptible to blockade by RU486, participates in the generation of the secondary FSH surge. To gain further insight into the mechanism(s) by which ligand-independent activation of the PR increases FSH secretion on estrus, in the present study we compared the effects of RU486 on FSH secretion with those of another antiprogestin, ZK98299 (onapristone), which has been reported to have a different mode of action at the molecular level (10). Our data indicate that although both drugs act as PR antagonists in other target tissues, such as the uterus, on estrus and affect the preovulatory gonadotropin surges similarly on proestrus, they have divergent effects on serum FSH on the morning of estrus.

	Materials and Methods

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Animals
Female Sprague-Dawley rats (55–60 days old) were obtained from Charles River (Portage, MI). Animals were housed under a 14-h light, 10-h dark schedule, with lights on at 0500 h, and were provided with standard rat chow and tap water ad libitum. Estrous cyclicity was monitored by daily vaginal cytology; only rats that showed at least two consecutive 4-day estrous cycles were used. Protocols were approved by the animal care and use committee of Northwestern University.

Drug treatments
RU486 (Roussel-UCLAF, Romainville, France) and ZK98299 (Schering, Berlin, Germany) were dissolved in benzyl benzoate-sesame oil (1:4) with slight warming. In Exp I, 2 or 6 mg/kg doses of the drugs were injected sc at 1230 h on proestrus; vehicle alone served as the control. In Exp II, 6 mg/kg doses of the antiprogestins were injected sc at 1230 h on proestrus; sheep anti-rat inhibin--(1–26) serum 795 (0.5 ml) was injected into the tail vein under light metophane anesthesia at 1700 h on proestrus. Normal sheep serum (0.5 ml; ICN ImmunoBiologicals, Costa Mesa, CA) served as the control.

Collection of tissue and serum
Rats were killed by decapitation at the indicated times. Trunk blood was collected from individual animals, allowed to clot, and centrifuged at 24 C for 10 min. Serum was aliquoted and frozen at -20 C until RIA for gonadotropins, steroids, and inhibin-. The pituitary was rapidly removed, frozen on dry ice, and stored at -70 C until RNA extraction. Uterine intraluminal fluid content and uterine weights were determined to confirm blockade of P action on the cervix by treatment with RU486 and ZK98299.

RIAs
Serum FSH and LH were determined by double antibody RIA, as described previously (4), except that rat LH RP-3 instead of ovine LH S-25 was used as the standard in the LH RIA; reagents were supplied by National Hormone and Pituitary Program. Intra- and interassay coefficients of variation were 2.3% and 7.8%, respectively, for FSH and 3.0% and 6.1%, respectively, for LH. Serum inhibin- was determined by a homologous double antibody RIA as described previously (11). This assay detects, in addition to dimeric inhibins A and B, the free -subunit, precursor forms, and binding protein-complexed forms of inhibin; serum concentrations are thus higher than those obtained using the two-site assay for dimeric inhibin (2, 3). Nevertheless, the utility of this first generation RIA for inhibin- in monitoring biologically relevant inhibin in the circulation is well documented (2, 12). Results (picograms per ml) are expressed in terms of the rat inhibin--(1–27) standard. Serum P was measured using a kit from ICN Biomedicals (Irvine, CA); serum estradiol was measured with a kit from Diagnostics Products Corp. (Los Angeles, CA).

RNA extraction and Northern blot analysis
Total RNA from anterior pituitary was isolated by the single step acid guanidium thiocyanate-phenol-chloroform extraction (13), using the TRI reagent kit (Molecular Research Center, Cincinnati, OH). Each anterior pituitary was homogenized in 1 ml TRI reagent; additional details of RNA isolation and Northern blot analysis of steady state levels of messenger RNA (mRNA) for the FSHß, LHß, and -subunit were previously described (14).

Statistical analysis
Data were evaluated by ANOVA using the CRISP statistical software package (CRUNCH Software, San Francisco, CA). In Exp I, drug treatment was the only between-subject factor; results obtained at each time were analyzed separately. In Exp II, treatment with antiprogestins and anti-I were the two between-subject factors. Post-hoc comparisons of the effects of antiprogestins were performed using the Newman-Keuls test. P < 0.05 was considered significant.

	Results

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Exp I: gonadotropin and gonadotropin mRNA responses at 1830 h on proestrus and at 0900 h on estrus to RU486 and ZK98299 administered at 1230 h on proestrus
At 1830 h on proestrus, all animals exhibited the normal E-induced accumulation of uterine intraluminal fluid, which, consistent with our earlier results, was unaffected by RU486; ZK98299 was similarly without effect (Fig. 1A). At 0900 h on estrus, both antiprogestins blocked the release of uterine intraluminal fluid (P < 0.005), with the higher doses of both drugs having a greater effect (P < 0.05).

View larger version (25K): [in this window] [in a new window]   Figure 1. Uterine intraluminal fluid (A), serum FSH (B), anterior pituitary FSHß mRNA (C), and serum LH (D) levels in female rats given vehicle, RU486 (2 or 6 mg/kg), or ZK98299 (2 or 6 mg/kg) at 1230 h on proestrus and killed at 1830 h on proestrus or 0900 h on estrus. Each bar is the mean, and the error bar is the SEM of four or five rats. Significant P values are indicated in the text.

At 1830 h on proestrus, both drugs, at both doses, lowered steady state levels of FSHß mRNA equally (P = 0.0015; Fig. 1C). At 0900 h on estrus, there was no significant effect of antiprogestin treatment on FSHß mRNA overall; when only the higher doses of RU486 and ZK98299 were compared with vehicle, however, ZK98299 significantly increased FSHß mRNA levels (P < 0.05). Steady state levels of mRNAs for LHß and -subunit were not significantly affected by either antiprogestin at either time examined (data not shown).

Both antiprogestins suppressed the preovulatory surge of LH at 1830 h on proestrus (P < 0.01; Fig. 1D). Although the suppression appeared to be dose related, the differences between the effects of the higher and lower doses did not reach statistical significance. Drug treatment tended to increase basal levels of LH at 0900 h on estrus (P < 0.02); by post-hoc analysis, however, only the higher dose of ZK98299 significantly increased the serum LH concentration (P < 0.05).

Serum levels of inhibin- were higher at 1830 h on proestrus than at 0900 h on estrus, as expected, and were not significantly affected by treatment with the antiprogestins. On estrus morning, however, there was a significant overall effect of drug treatment on serum inhibin- levels (P = 0.017), with the higher dose of RU486 tending to suppress and both doses of ZK98299 tending to increase circulating inhibin- (Table 1). The difference between serum inhibin- levels in animals that received 6 mg/kg RU486 and those that received 6 mg/kg ZK98299 was significant by post-hoc comparisons (P < 0.05). Serum levels of P and estradiol were not affected by treatment with the antiprogestins at either time studied (data not shown).

View this table: [in this window] [in a new window]   Table 1. Effects of RU486 and ZK98299 on serum inhibin- levels on the morning of estrus

View larger version (26K): [in this window] [in a new window]   Figure 2. Uterine intraluminal fluid (A), serum FSH (B), anterior pituitary FSHß mRNA (C), and serum LH (D) levels of female rats given vehicle, RU486 (6 mg/kg), or ZK98299 (6 mg/kg) at 1230 h on proestrus and normal sheep serum (NSS) or anti-I at 1700 h on proestrus. All determinations were made at 0900 h on estrus. Each bar is the mean, and the error bar the SEM of four or five rats. Note that the scale for serum LH is different from that in Fig. 1. Significant P values are indicated in the text.

FSHß mRNA was not significantly affected by treatment with anti-I, but was affected by treatment with the antiprogestin (P = 0.003), and the interaction between the two treatments was significant (P = 0.04; Fig. 2C). By post-hoc test, ZK98299 significantly increased (P < 0.05) FSHß mRNA at 0900 h estrus, whereas RU486 was without effect. Neither LHß nor mRNA was affected by treatment with anti-I or antiprogestins (data not shown).

Serum LH was not affected by treatment with anti-I; the effect of the antiprogestins, however, was significant overall (P = 0.0065; Fig. 2D). Both RU486 (P < 0.05) and ZK98299 (P < 0.01) increased serum LH secretion, in agreement with our earlier report (5).

Serum P was not affected by anti-I, but increased in response to treatment with the antiprogestins overall (P = 0.02), in contrast to the results obtained in Exp I. By post-hoc analysis, however, only the effect of ZK98299 was significant (P < 0.01; data not shown). Neither treatment had a significant effect on serum estradiol levels. Serum inhibin- levels could not be determined in this experiment because of interference by circulating anti-I antibody.

	Discussion

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The key finding of the present study was that whereas in cycling female rats, the antiprogestins RU486 and ZK98299 affected FSH secretion similarly at the time of the preovulatory gonadotropin surges on proestrus, their effects were divergent on the secondary FSH surge on the morning of estrus, when only RU486 lowered serum FSH.

Our previous work examining the effects of RU486, administered on proestrus, on serum gonadotropin levels at the time of the preovulatory gonadotropin surges and the secondary FSH surge (4, 5, 6, 9) suggested participation of PR in the cascade of events that leads to generation of the gonadotropin surges at this dynamic stage of the reproductive cycle. In the present study, we sought clearer insight into this role of the PR through evaluation of the effects of a newer antiprogestin, ZK98299, which, although closely related structurally, differs from RU486 in its action at the molecular level (15). Indeed, ZK98299 has been proposed to represent a distinct type of antiprogestin (type I), which, unlike the type represented by RU486 (type II), prevents the formation of stable receptor dimers and binding of the receptor to its cognate progesterone response element in target genes (10). The conclusion that this fundamental difference existed between the mechanisms of action of the two types of antiprogestins at the molecular level was based on the results of gel mobility shift assays in a cell-free system (15, 16); it was disputed, however, on the basis of subsequent competition (17) or genomic footprinting (18) assays in intact cells and remains controversial.

Additional differences between the actions of the two types of antiprogestins reported in the literature are 1) that ZK98299 has greater specificity for the PR (19) than does RU486, which binds to both PR and glucocorticoid receptor (GR) with high affinity (20); 2) that RU486, but not ZK98299, can function as an agonist when cAMP-mediated cellular signaling is activated (16, 21, 22), although evidence has also been presented that ZK98299-occupied human PR_B is capable of inducing transcriptional activation (23); 3) that RU486 binds to PR with 10-fold (17) or 5-fold (24) greater affinity than does ZK98299; and 4) that ZK98299-occupied PR is underphosphorylated relative to those occupied by the agonist R5020 or RU486 (25).

None of these reported differences provide a ready explanation for our finding of divergent actions of the two drugs on estrus, but not on proestrus. Glucocorticoids directly stimulate FSH secretion in vivo (26) and in vitro (14, 27), and a role for glucocorticoids in generation of the secondary FSH surge has been proposed (28); thus, blockade of the GR by RU486, but not ZK98299, could account for the present findings. The results of our previous in vivo study using treatment with dexamethasone and aminoglutethimide, however, argue strongly against the possibility that RU486 lowers serum FSH on the morning of estrus through blockade of the GR (6). Similarly, for reasons enumerated in a previous communication (9), we consider it unlikely that RU486, but not ZK98299, acts as an agonist in lowering serum FSH on estrus. Finally, the lower affinity of binding of ZK98299 to PR, relative to that of RU486, as detected in in vitro systems, is generally not reflected by corresponding differences in in vivo biopotency. Comparable biopotencies of the two drugs can be demonstrated in inhibition of nidation (19), stimulation of LH secretion (29), blockade of uterine intraluminal fluid release and suppression of the preovulatory gonadotropin surges (present study), and suppression of FSH secretion in primary cultures of rat anterior pituitary cells in vitro (Kilen et al., abstract submitted to the 79th Annual Meeting of The Endocrine Society). One notable exception to this generalization is the much more potent stimulation of PRL secretion by RU486 than by ZK98299, leading to differential increases in pituitary and ovarian weight and ovarian steroidogenesis reported by Uilenbroek (29). This in vivo study, however, involved prolonged (21-day) treatment with large daily doses of the antiprogestins; the results, therefore, are not comparable to the acute effects observed in the present study. Finally, the underphosphorylated state of the ZK98299-occupied PR cannot account for the differential effects of the drug on estrus compared to those on proestrus.

Although the present in vivo data do not allow precise definition of the differences between the actions of the two drugs at the molecular level, they clearly indicate that the functional state of the PR, including its association with the transcriptional activation complex, in the gonadotrope is different on estrus than on proestrus, such that it is no longer susceptible to blockade by ZK98299. Estrous cycle stage-dependent differences in the relative expression of the A and B isoforms of PR, which can function as transcriptional repressors and activators, respectively (23, 30), in the extent of phosphorylation (25, 31), or in the expression of transcriptional coactivators/corepressors (32, 33, 34, 35) could all contribute to the observed differences. Because much of the large body of data on regulation of PR indicates cell- and promoter-specific mechanisms, and neither the site(s) nor the target gene(s) involved in regulation of FSH secretion by PR has been identified with certainty, interpretation of the present results is not possible. More direct examination of the mechanisms underlying the regulatory role of the PR will have to rely on in vitro systems (e.g. a FSH-secreting cell line).

Finally, because the preovulatory gonadotropin surges are GnRH mediated, but the secondary FSH surge is independent of GnRH (1), it is likely that E-inducible PR in both the hypothalamus (36, 37) and the anterior pituitary (37) is relevant in the generation of primary gonadotropin surges, but only those in the pituitary participate in the generation of the secondary FSH surge. It is tempting to speculate that only hypothalamic, not pituitary, PR are blocked by ZK98299, whereas both are blocked by RU486. Studies monitoring the estrous cycle stage-dependent expression of PR overall and of the A and B isoforms selectively in rat pituitary and hypothalamus could prove fruitful in furthering our understanding of these complex regulatory processes.

In summary, we demonstrated that RU486 and ZK98299, which are thought to represent two different types of antiprogestins, have similar effects on serum gonadotropins and FSHß mRNA on proestrus, but differentially affect serum FSH on estrus. The data support our earlier conclusion that PR in the gonadotrope participate in the generation of both the preovulatory gonadotropin surges and the secondary FSH surge and indicate further that the functional state of the receptor/transcriptional activation complex is different on estrus than on proestrus.

	Acknowledgments

 
We are grateful to Roussel-UCLAF (Romainville, France) and to Dr. K. Stoeckemann of Schering (Berlin, Germany) for the supply of RU486 and ZK98299 used in this study. We thank Dr. William Chin for the gonadotropin subunit probes, Dr. Kelly Mayo for the Chinese hamster ovary-B probe, and Brigitte Mann and Stephanie Kluge for expert technical assistance.

	Footnotes

 
¹ This work was supported in part by NIH Grants R01-HD-07504, P01-HD-21921, and P30-HD-28048 (to N.B.S.) and T32-HD-07068 (to K.L.K.). Presented in part at the 29th Annual Meeting of the Society for the Study of Reproduction, London, Ontario, Canada (Abstract 194).

² Present address: Womens and Childrens Health Care Research Center, State University of New York Health Science Center, Syracuse, New York 13202.

Received November 7, 1996.

	References

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				F. Gaytán, C. Bellido, C. Morales, and J.E. Sánchez-Criado Both Prolactin and Progesterone in Proestrus Are Necessary for the Induction of Apoptosis in the Regressing Corpus Luteum of the Rat Biol Reprod, November 1, 1998; 59(5): 1200 - 1206. [Abstract] [Full Text]

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