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Reproductive Sciences Program (K.M.B., A.V.P., E.R.W., E.A.Y., F.J.K.), Department of Molecular and Integrative Physiology (K.M.B., A.V.P., E.R.W., F.J.K.), Mental Health Research Institute (E.A.Y.), University of Michigan, Ann Arbor, Michigan 48109-0404; Department of Physiology, Monash University (C.A.S., A.J.T.), Clayton, Victoria 3800, Australia; and Prince Henry’s Institute of Medical Research (I.J.C.), Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Dr. Fred J. Karsch, Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1101 SW, Ann Arbor, Michigan 48109-0404. E-mail: fjkarsch{at}umich.edu.
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Introduction |
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Although it is clear that glucocorticoids inhibit gonadotropin secretion, the types of cells involved, the receptors, and the mechanisms for this suppression are not known. The present study sought to determine which receptor mediates the suppressive effect of glucocorticoids on pituitary responsiveness to GnRH. At least three types of receptors have been implicated in mediating neuroendocrine responses to corticosteroids. One is the mineralocorticoid receptor (MR; type I), which primarily mediates tonic feedback actions of basal levels of corticosteroids (10, 11). The second is the glucocorticoid receptor (GR; type II), which is involved not only in feedback actions of basal corticosteroids, but also in feedback actions of elevated levels of glucocorticoids after stress (10, 11, 12, 13). The third is a membrane-bound receptor that appears to mediate rapid, nongenomic actions of glucocorticoids in neuroendocrine cells (14). In the course of conducting a recent study to examine the neuroendocrine site of action of cortisol in suppressing pulsatile LH secretion in sheep (9), we obtained preliminary evidence that the inhibitory action of cortisol was reduced by an antagonist of GR, but not MR. In this report we describe those preliminary findings and the results of two follow-up studies to test the hypothesis that the type II GR mediates the suppressive effect of cortisol on pituitary responsiveness to GnRH in the ovariectomized ewe.
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Materials and Methods |
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Cortisol
Cortisol was administered by one of two routes. In the preliminary experiment, cortisol (hydrocortisone sodium succinate, aqueous solution, 50 mg/ml; Solu-Cortef, Pharmacia & Upjohn, Kalamazoo, MI) was dissolved in heparinized saline and continuously infused iv at a dose of 0.375 mg/kg·h. Pilot studies indicated that this rate of infusion elevated serum cortisol to approximately 125–150 ng/ml, similar to the maximum value observed during an immune/inflammatory stress induced by endotoxin (15, 16, 17). In the main experiments (experiments 1 and 2), cortisol (hydrocortisone sodium succinate, aqueous solution, 250 mg/2 ml Act-O-Vial; Solu-Cortef, Pharmacia & Upjohn was suspended in sesame oil and injected sc (note that cortisol was injected sc rather than infused iv because both jugular veins had been cannulated for blood sampling and infusing GnRH). In experiment 1, the cortisol dose was 0.2 mg/kg administered every 30 min, based on our prior finding (9) that this would elevate plasma cortisol levels to approximately 125 ng/ml. The results indicated that this treatment elevated circulating cortisol levels to twice the target value (note that our prior study used a different cortisol preparation, which had become unavailable). In experiment 2, therefore, the cortisol dose was lowered to 0.125 mg/kg·30 min, sc, to achieve a plasma cortisol concentration of about 125 ng/ml.
Antagonists
This study employed three antagonists: spironolactone, RU486, and Organon 31710. Spironolactone, an antagonist of the type I MR (13, 18), was obtained from Sigma-Aldrich Corp. (St. Louis, MO), dissolved in propylene glycol, and delivered by sc injection at a dose of 50 mg/kg. This dose was based on that used previously in rodents (13, 19). RU486 is a nonspecific antagonist of both the type II GR and the progesterone receptor (PR) (18, 20, 21). We used this nonspecific antagonist because a specific GR antagonist was unavailable. RU486 was obtained from Sigma-Aldrich Corp., suspended in vehicle (sesame oil containing equal part of 75% ethanol), and delivered by im injection at a dose of 10 mg/kg (2.5 mg/kg in the preliminary experiment). Organon 31710 (a gift from N.V. Organon, Oss, The Netherlands) is a highly specific antagonist of PR (22, 23). Its affinity for PR is similar to that of RU486, whereas its affinity for GR is less than 5% of that for RU486 (22). Organon 31710 was suspended in the same vehicle as RU486 and delivered by im injection at a dose of 2.5 mg/kg. Pilot studies were conducted to determine effective doses and time courses of both RU486 and Organon 31710 based on their efficacy in blocking the inhibitory effect of progesterone on pulsatile LH secretion in ovariectomized ewes. For RU486, we initially confirmed prior findings that a dose of 2 mg/kg, im, was effective in this regard; this dose was similar to that used in the preliminary experiment. In the main experiments (experiments 1 and 2), this dose was increased 5-fold (10 mg/kg), because RU486 is reported to be 5-fold less effective in blocking GR- than PR-mediated responses (20, 21). Further, the preliminary experiment suggested the lower dose reversed cortisol-induced suppression of LH secretion in only two of three ewes (see Results).
Preliminary experiment: effects of RU486 and spironolactone on cortisol-induced suppression of reproductive neuroendocrine activity
This initial assessment of the effects of these antagonists was part of a larger study that determined the influence of cortisol on pulsatile GnRH and LH secretion in ovariectomized ewes (9). Ovariectomized ewes that had not been treated with ovarian steroids for 3 months were surgically prepared for pituitary portal blood sampling using the procedure described by Caraty et al. (24). This procedure permits sampling from fully conscious animals that do not exhibit overt signs of anxiety or distress. After 2 wk recovery, the ewes were penned individually and equipped with two indwelling jugular catheters, one for collecting peripheral blood and one for infusing heparin saline (250 U/min) with or without cortisol. Jugular blood was withdrawn continuously and separated into 10-min fractions for analysis of LH and cortisol. Pituitary portal blood was withdrawn continuously, dispensed into tubes containing ice-cold bacitracin to minimize GnRH degradation, and separated into 10-min fractions. These fractions were extracted within 1.5 h of sampling and stored at –80 C until GnRH analysis. The first 6 h of the 13-h collection period represented the pretreatment period, after which ewes received either RU486 (n = 3), spironolactone (n = 3), or no antagonist (n = 9). One hour later, a 6-h cortisol infusion was begun. After sample collection, the ewes were killed with a barbiturate overdose (Fatal Plus, Vortech Pharmaceuticals, Dearborn, MI), and the pituitary was inspected to confirm appropriate placement of the cut in the portal vasculature for monitoring GnRH secretion.
Experiment 1: does RU486 reverse cortisol-induced suppression in pituitary responsiveness to exogenous GnRH pulses?
Animal model.
This study was performed using a pituitary clamp model, the same as that used previously to demonstrate that cortisol inhibits pituitary responsiveness to GnRH (9). During the anestrous season, ovariectomized ewes were treated sc with a 3-cm estradiol-filled SILASTIC brand implant (Dow Corning Corp., Midland, MI) that produces a midluteal phase serum level of estradiol (
2 pg/ml) (25). The hypothalamus is exquisitely sensitive to estradiol negative feedback during anestrus (26), and this estradiol treatment essentially eliminates pulsatile secretion of GnRH (27). Blockade of endogenous GnRH pulses was confirmed in each ewe by determining that the plasma LH concentration was reduced to an undetectable level, and the pituitary remained responsive to exogenous GnRH. After 3 wk of estradiol treatment, the ewes were penned individually and equipped with an indwelling jugular catheter for GnRH delivery. Hourly boluses of GnRH (5 ng/kg, iv, over 6 min) were provided for a 6-d period to reactivate the gonadotropes and stabilize pituitary responsiveness to GnRH. We previously determined that this GnRH treatment creates artificial GnRH pulses that have amplitudes within the range of endogenous GnRH pulses in pituitary portal blood of ovariectomized ewes (27, 28). For delivery, a 250 ng/ml solution of GnRH (Sigma-Aldrich Corp.) was prepared by diluting a stock solution (100 µg/ml) with sterile saline containing 0.1% BSA. This solution was infused intermittently via a peristaltic pump activated hourly by an electric timer.
Experimental design.
The experimental design is illustrated in Fig. 1
. On the fifth day of hourly exogenous GnRH pulses to stabilize pituitary responsiveness, RU486 (n = 3) or vehicle (n = 4) was injected im, and each ewe was equipped with a second indwelling jugular catheter for blood collection. A second injection of RU486 or vehicle was administered 12 h after the initial injection. Beginning 18 h after the initial injection, jugular blood was sampled at 12-min intervals for 12 h to assess LH pulse amplitude as an index of pituitary responsiveness to the exogenous GnRH pulses. For the first 6 h, no further treatment was applied. During the next 6 h, cortisol was injected sc every 30 min (cortisol treatment began 24 h after initial RU486 injection).
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). After 5 d of hourly exogenous GnRH pulses and 24 h before cortisol treatment, ewes (n = 7/treatment) received an im injection of vehicle, RU486, or Organon 31710. RU486 was injected again 12 h later; vehicle in place of Organon 31710 was injected at this time because pilot experiments indicated that this antagonist blocked PR for at least 48 h. Beginning 18 h after the initial antagonist injection, jugular blood was sampled at 12-min intervals for 12 h for LH pulse analysis. During the first 6 h, no further treatment was applied. During the next 6 h, cortisol was injected sc every 30 min.
Hormone assays
LH concentrations were determined in duplicate aliquots (25–100 µl) of plasma using a modification (29) of a previously described RIA (30, 31). Values are expressed in terms of NIH LH-S12. The mean intra- and interassay coefficients of variation were 4.8% and 8.0%, respectively, and assay sensitivity averaged 0.9 ng/ml (22 assays). In the preliminary experiment, GnRH was measured in duplicate in methanol extracts of portal plasma (250 µl plasma extract/assay tube) using a previously described RIA (32, 33). Intra- and interassay coefficients of variation were 9.6% and 14.2%, respectively, and assay sensitivity averaged 0.16 pg/ml (nine assays). Total plasma cortisol concentrations were determined in duplicate 50-µl aliquots of unextracted plasma using the Coat-A-Count cortisol assay kit (Diagnostic Products Corp., Los Angeles, CA), validated for use in sheep (16). Mean intra- and interassay coefficients of variation were 4.2% and 5.0%, respectively (14 assays). Assay sensitivity averaged 0.8 ng/ml.
Data analysis
In the preliminary experiment, GnRH in pituitary portal blood was calculated as a collection rate (picograms per minute) rather than concentration. This minimizes errors due to contamination of portal samples with peripheral blood or cerebrospinal fluid (judged to be minimal) or due to changes in the rate of portal blood collection resulting from changes in the ewe’s posture. Formal statistical analysis was not performed because this was a preliminary experiment included as part of a larger study conducted for another purpose (9).
In experiments 1 and 2, each exogenous GnRH pulse induced an increase in circulating LH levels, and no extraneous LH pulses were observed, indicating that endogenous GnRH pulses were effectively abolished by the estradiol treatment. Amplitudes of these LH responses (peak minus preceding nadir) were averaged across the pre- and postcortisol periods in each ewe, as an index of pituitary responsiveness. Before statistical analysis, hormonal values were log-transformed because we observed that SDs were directly proportional to the mean plasma LH concentration, a relationship typical of studies involving measurement of circulating hormones. The ratio of the post- to precortisol mean was calculated in each ewe as an index of the change in pituitary response to GnRH. To determine whether responsiveness to GnRH after treatment with cortisol differed among ewes that had been pretreated with vehicle or the antagonists, these ratios were analyzed by ANOVA. Post hoc analysis in experiment 2, which involved three groups (vehicle, RU486, and Organon 31710), consisted of successively excluding data from one group and repeating the ANOVA on the remaining two. To determine the time course of cortisol-induced suppression of responsiveness to GnRH, the ratio of the amplitude of LH pulses for each hourly postcortisol response to the precortisol mean was calculated and analyzed by repeated measures ANOVA (treatment x time). When a significant treatment x time interaction was observed, post hoc analysis was conducted to identify specific treatment effects. In experiment 1, this consisted of conducting a one-treatment variance test across the postcortisol ratios within the vehicle and RU486 groups. In experiment 2, which involved three groups, this consisted of successively excluding data from one group and conducting the repeated measures ANOVA on the remaining two groups before conducting a one-treatment variance test across the postcortisol ratios within individual groups.
Plasma cortisol concentrations were log-transformed before statistical analysis to normalize the distribution across a range of values. Mean values for the pre- and postcortisol periods were then obtained in every ewe, and treatment effects were identified by repeated measures ANOVA. Post hoc analysis in experiment 2, which involved three groups, consisted of successively excluding data from one group and conducting the repeated measures ANOVA on the remaining two. The significance level was set at P < 0.05.
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Results |
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illustrates GnRH and LH pulse profiles in ewes receiving cortisol alone (A), or RU486 (B) or spironolactone (C) before receiving cortisol. Cortisol in the absence of either antagonist induced a marked inhibition of pulsatile LH secretion without suppressing GnRH secretion in each of nine ewes, suggesting cortisol inhibits pituitary responsiveness to endogenous GnRH pulses (Fig. 2A; full dataset previously reported in Ref.9). Pretreatment with RU486 prevented cortisol-induced suppression of pulsatile LH secretion in two of three ewes (Fig. 2B). In contrast, spironolactone failed to reverse the inhibitory effects of cortisol in all three ewes (Fig. 2C). The pulsatile release of GnRH did not appear to change in ewes treated with cortisol alone or in combination with either antagonist.
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for two ewes receiving vehicle plus cortisol and for two ewes receiving RU486 plus cortisol. Figure 4 presents composite results describing the overall effect of cortisol in vehicle- and antagonist-treated ewes and the time course of cortisol-induced suppression in pituitary responsiveness to GnRH. In each vehicle-treated ewe, cortisol reduced LH pulse amplitude in response to the exogenous GnRH pulses (Fig. 3, A and B), but this was not evident in ewes pretreated with RU486 (Fig. 3, C and D). The reduction in LH pulse amplitude in control ewes was to about 50% of the precortisol mean (Fig. 4A), with the maximal effect evident within 2 h (Fig. 4B). RU486 completely blocked the effect of cortisol (RU486 vs. vehicle, P < 0.005; Fig. 4, A and B). Before cortisol treatment, LH pulse amplitude was not different between ewes that had been pretreated with vehicle or RU486 (7.4 ± 1.5 vs. 7.0 ± 1.4 ng/ml, respectively), indicating that this dose of RU486 alone does not alter pituitary responsiveness to GnRH.
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displays LH profiles in two representative ewes receiving vehicle plus cortisol, RU486 plus cortisol, or Organon 31710 (selective PR antagonist) plus cortisol. Figure 6 depicts composite results comparing overall percent suppression of LH pulse amplitude and time course of the response in all seven ewes from each treatment.
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, A and B). As in experiment 1, prior treatment with RU486 eliminated this effect (Fig. 5, C and D). Importantly, Organon 31710 did not reverse cortisol-induced suppression of pituitary responsiveness to GnRH (Fig. 5, E and F). The overall average reduction in LH pulse amplitude during the 6-h cortisol treatment period in vehicle-treated ewes was to 54 ± 7% of the precortisol value (Fig. 6A), and maximal suppression was evident within 2 h (Fig. 6B). The degree and time course of suppression were similar in ewes treated with Organon 31710 (64 ± 5%; P > 0.05; Fig. 6). Again, RU486 prevented the inhibitory effect of cortisol (P < 0.0001 vs. vehicle; Fig. 6). Finally, LH pulse amplitude did not differ among the three groups before cortisol (vehicle, 6.9 ± 1.2 ng/ml; RU486, 8.6 ± 1.7 ng/ml; Organon 31710, 9.2 ± 1.0 ng/ml; P > 0.05), indicating that the antagonists per se had no effect.
Plasma cortisol concentrations
In the preliminary experiment continuous infusion of cortisol elevated plasma cortisol concentrations to approximately 150–175 ng/ml (data not shown; previously reported in Ref.9). Figure 7 illustrates mean (±SEM) plasma cortisol concentrations for the ewes in experiments 1 and 2. Before cortisol treatment, values remained at a stable baseline in ewes that had been pretreated with vehicle for the antagonists (6.6 ± 1.5 and 7.1 ± 0.8 ng/ml in experiments 1 and 2, respectively). Twice hourly injections of cortisol elevated plasma cortisol concentrations within 1–1.5 h to 231 ± 7 ng/ml in experiment 1 and 119 ± 4 ng/ml in experiment 2. The cortisol values in experiment 1 were approximately 2-fold greater than those we previously observed in response to endotoxin (solid vertical bar in Fig. 7), whereas those in experiment 2 were comparable to cortisol concentrations induced by this immune/inflammatory stressor (15, 16, 17).
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, because cortisol values in vehicle and antagonist groups were pooled for graphic presentation.) This rise in basal cortisol levels confirms that our dose of RU486 was biologically effective in blocking GR-mediated negative feedback actions of endogenous cortisol on the hypothalamic-pituitary-adrenal axis. The elevated baseline was not evident in ewes treated with Organon 31710. |
Discussion |
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In making the foregoing conclusion, three issues must be considered. One pertains to a potential role for the type I MR, a receptor that has been identified in the anterior pituitary gland of rats (10). The failure of spironolactone to reverse the suppressive effect of cortisol is consistent with the idea that MR does not mediate the cortisol-induced suppression of pituitary responsiveness to GnRH. Nevertheless, there is no direct evidence that the dose of spironolactone used here, which was derived from studies in rodents, effectively antagonizes MR in sheep. Thus, our study does not exclude the possibility that MR might contribute to cortisol-induced suppression of pituitary responsiveness to GnRH.
The second issue in relation to the present work pertains to antagonist specificity. Because a selective GR antagonist was not available for this study, we used RU486, a nonspecific antagonist of both GR and PR. We do not consider this lack of specificity to weaken the present conclusions, because the PR antagonist, Organon 31710, delivered at a dose that prevented neuroendocrine feedback actions of progesterone, did not block the inhibitory action of cortisol on the response to GnRH. In addition to PR antagonism, preliminary evidence suggests RU486 may elicit weak estrogenic antagonism (38). In the present study, however, RU486 neither affected the LH response to GnRH in the precortisol period, nor lessened the ability of estradiol to suppress endogenous GnRH secretion, suggesting that RU486 did not elicit an antiestrogenic effect in our model system. Thus, the most probable interpretation of our findings is that the effect of RU486 is due to blockade of GR and that this receptor is essential for mediating the suppressive effect of cortisol on pituitary responsiveness to GnRH.
A third qualification of the present study is that our conclusion regarding the mediatory role of GR applies only to the inhibitory effect of cortisol on pituitary responsiveness to GnRH. Although this is the principle action of cortisol in suppressing reproductive neuroendocrine activity in the ovariectomized ewe (9), this may not be the sole mode of cortisol action under all physiological conditions. In this regard, we recently observed that stress-like increments in plasma cortisol inhibit LH pulse frequency in ovary-intact ewes during the follicular phase of the cycle (39). Suppression of LH pulse frequency is generally taken as evidence for reduced GnRH pulse frequency, implying an additional inhibitory action of cortisol at the hypothalamic level in follicular phase ewes. If this proves true, future work would be necessary to determine whether GR also mediates the central actions of cortisol in suppressing reproductive neuroendocrine function.
Although our findings clearly demonstrate GR is obligatory for cortisol to reduce pituitary responsiveness to GnRH, the exact locus of this effect remains unclear. The possibility that cortisol acts via GR located within the pituitary is supported by findings that cortisol inhibits GnRH-induced LH release from bovine and porcine pituitary cells in culture (40, 41). Further, GR has been identified in gonadotropes in the rat, indicating potential for a direct action of cortisol on this cell type (42). Alternatively, cortisol may act within the pituitary through a paracrine mechanism via GR located in nongonadotrope cells. For example, folliculostellate cells within the anterior pituitary contain GR (43), and these cells respond to glucocorticoids by synthesizing annexin-1, an inhibitory paracrine agent (44). The receptor for annexin-1 has been identified on gonadotrope cells (45). Thus, the inhibitory effects of cortisol on responsiveness to GnRH might be mediated indirectly via annexin-1 from folliculostellate cells. Another indirect means of cortisol-induced suppression in pituitary responsiveness is via GR located at extrapituitary sites. We are intrigued by this possibility because recent work in sheep demonstrates that cortisol fails to reduce pituitary responsiveness to GnRH when the pituitary is surgically disconnected from the hypothalamus (46). This is consistent with the view that a factor of central origin mediates the inhibition of pituitary responsiveness. A precedent for such a factor is the putative gonadotropin inhibitory hormone recently discovered in birds, which acts at the pituitary level to suppress responsiveness to GnRH (47, 48). Clearly, further work is needed to identify the exact locus of action of cortisol in suppressing pituitary responsiveness to GnRH.
With regard to cellular mechanisms of action, cortisol could act at either a genomic or a nongenomic level. Recent evidence in a human pituitary cell line suggests that glucocorticoids activate the MAPK pathway via a nongenomic mechanism involving GR (49). In addition, a membrane-bound corticosteroid receptor has been identified in neuronal tissue of amphibians and is speculated to mediate rapid, nongenomic actions (14). Given our finding that the influence of cortisol became evident as early as the first hourly GnRH pulse after the onset of cortisol treatment, it seems reasonable to consider the possibility that cortisol acts via a membrane-bound GR. Nevertheless, a membrane-bound GR has not yet been identified in mammals. Further, strong evidence suggests that glucocorticoids can act genomically to suppress pituitary responsiveness by regulating the transcription and translation of the GnRH receptor. For example, glucocorticoids regulate GnRH receptor gene transcription via the response element, activating protein-1 (50), and cortisol has been shown to suppress estrogen-dependent accumulation of GnRH receptor mRNA and protein in pituitary tissue (51). Further work is needed to determine whether such genomic effects occur with sufficient rapidity to account for the acute suppression of pituitary responsiveness observed in this study.
Finally, it is of interest to consider our findings in light of evidence that RU486 attenuated the suppression of LH secretion in rats subjected to immobilization stress (52). Not only does that observation provide evidence that glucocorticoids are physiologically relevant to the suppression of gonadotropin secretion in response to this type of stress, it also implicates GR as the receptor mediating this response. Our present work embraces this understanding by demonstrating that the type II GR is necessary for the suppressive influence of glucocorticoids on pituitary function, namely the responsiveness of the gonadotrope to GnRH. This provides impetus for further work to identify sites, cell types, and cellular mechanisms for suppressive effects of the corticosteroids on reproductive neuroendocrine activity.
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Acknowledgments |
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Footnotes |
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Abbreviations: GR, Glucocorticoid receptor; MR, mineralocorticoid receptor; PR, progesterone receptor.
Received February 2, 2004.
Accepted for publication March 8, 2004.
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