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Reproductive Sciences Program and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Fred J. Karsch, Reproductive Sciences Program, University of Michigan, 300 N. 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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Materials and Methods |
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Experiment 1: acute effect of cortisol on pulsatile GnRH and LH secretion
Twenty ovariectomized ewes that had not been treated with ovarian steroids for 3 months were surgically prepared for pituitary portal blood collection using the procedure described by Caraty et al. (14). This procedure permits sampling from fully conscious animals that do not exhibit overt signs of anxiety or distress. After a 2-wk recovery period, 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) to prevent coagulation. Jugular blood was withdrawn continuously and separated into 10-min fractions for analysis of LH and cortisol. Pituitary portal blood was withdrawn continuously, dispensed into tubes containing ice-cold bacitracin to minimize GnRH degradation, and separated into 10-min fractions. Plasma was extracted within 1.5 h of sampling and stored at -80 C until GnRH analysis. After a 6-h pretreatment period, the ewes received either a constant infusion of vehicle (heparin saline) or cortisol (0.375 mg/kg/h dissolved in vehicle; Solu-Cortef, hydrocortisone sodium succinate, aqueous solution, 50 mg/ml; Pharmacia & Upjohn, Kalamazoo, MI) for 6 h (n = 10/group). Pilot studies indicated this infusion dose elevates serum cortisol to approximately 150 ng/ml. This is within the upper range of values we have observed during immune/inflammatory challenge with endotoxin (6, 15, 16). 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. One ewe was excluded from each group due to technical problems encountered during portal blood collection: extensive leaking of cerebrospinal fluid into portal sampling site or the animal exhibiting physiological and behavioral signs of distress (high basal cortisol during pretreatment period, no interest in food, agitation, and labored breathing).
Experiment 2: does cortisol acutely inhibit pituitary responsiveness to exogenous GnRH pulses?
This experiment was conducted on ovariectomized ewes in which endogenous GnRH pulses were blocked by a 3-cm, sc, estradiol-filled SILASTIC brand implant (Dow Corning Corp., Midland, MI) that produces a midluteal phase serum level of estradiol (
2 pg/ml) (17). During the anestrous season, when this experiment was performed, the hypothalamus is exquisitely sensitive to estradiol negative feedback (18), and this estradiol treatment essentially eliminates endogenous GnRH pulsatility (19). To ensure the animals had entered anestrus in February, when the experiment was conducted, the ewes were housed indoors and exposed to long-day photoperiod (75 long days, 16 h light and 8 h dark, beginning December 2001). The blockade of endogenous GnRH pulses was confirmed in each ewe by an undetectable plasma LH concentration together with maintenance of pituitary responsiveness to exogenous GnRH.
The design of the study is illustrated in Fig. 1
. To stabilize pituitary responsiveness, ewes individually restrained in small pens received hourly boluses of GnRH (5 ng/kg, iv, over 6 min) for a 6-d period via an infusion pump activated by an electronic timer. Prior studies indicate this GnRH treatment creates artificial GnRH pulses that have amplitudes within the range of endogenous GnRH pulses in pituitary portal blood of ovariectomized ewes (19, 20). For delivery, a 250 ng/ml solution of GnRH (Sigma Chemical Co., St. Louis, MO) was prepared by diluting a stock solution (100 µg/ml) with sterile saline containing 0.1% BSA. After the 6-d stabilization period, jugular blood was sampled at 12-min intervals by catheter 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 additional treatment was applied. During the next 6 h, vehicle (1 ml sesame oil) or cortisol (0.2 mg/kg suspended in vehicle) was injected sc every 30 min in an area of loose skin on the back. This route of cortisol administration was chosen instead of iv infusion (as in experiment 1), because ewes were already equipped with two jugular catheters, one for GnRH treatment and one for blood collection. Pilot studies determined this dose of cortisol elevates serum cortisol concentrations to maximal values observed in ewes treated with endotoxin (150 ng/ml) (6, 15, 16). This experiment was conducted according to a crossover design, such that each of the eight ewes received both vehicle and cortisol in a random sequence separated by 72 h.
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250 µl of plasma extract per assay tube) using a previously described RIA (24, 25). Intra- and interassay coefficients of variation were 9.4 and 14.0%, respectively, and assay sensitivity averaged 0.14 pg/ml (16 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 (15). Mean intra- and interassay coefficients of variation were 3.8 and 5.2%, respectively (12 assays). Assay sensitivity averaged 0.7 ng/ml.
Data analysis
In experiment 1, GnRH and LH pulses were identified using the Cluster pulse-detection algorithm (26). As explained elsewhere (6), cluster sizes for peaks and nadirs were set at 1 and 2 for LH and 1 and 1 for GnRH. The t statistic used to identify a significant increase and decrease was 2.6 and 2.6 for LH and 3.8 and 3.8 for GnRH. GnRH and LH pulse amplitudes were defined as the difference between the peak and its preceding nadir. Total pulsatile LH and GnRH outputs were calculated as the product of pulse frequency x mean pulse amplitude. GnRH in pituitary portal blood was calculated as a collection rate (picograms per minute) rather than concentration. This minimizes error 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. Before statistical analysis, plasma hormone values were log transformed and pulse frequencies were square root transformed to normalize variability across a range of values. To identify treatment effects, values for pre- and posttreatment periods were obtained in every ewe for each parameter (e.g. frequency, average amplitude, total output, and mean value). Next, a two-way repeated-measures ANOVA (treatment x time) was used to identify significant interactions (i.e. treatment effects) for all parameters between control and experimental groups.
In experiment 2, each exogenous GnRH pulse induced an increase in circulating LH, and no extraneous LH pulses were observed, indicating endogenous GnRH pulses were effectively abolished. Amplitudes of these LH responses (peak minus preceding nadir) were averaged across the pre- and posttreatment periods in each ewe, as an index of pituitary responsiveness. The ratio of these post- to pretreatment means was calculated in each ewe for both the vehicle and cortisol runs (crossover study) and expressed as percent change. To determine whether vehicle or cortisol altered pituitary responsiveness to exogenous GnRH pulses, the percent change in LH pulse amplitude between pre- and posttreatment periods was compared by paired t test. To determine the time course of treatment effects, the percent change in mean amplitude of the LH response between the pretreatment period and each hourly posttreatment response was calculated and analyzed by repeated-measures ANOVA.
In both experiments, hormonal concentrations below assay sensitivity were assigned a value equal to assay sensitivity for the purpose of data analysis. Significance level was set at P < 0.05.
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Results |
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illustrates circulating plasma cortisol concentrations in each experiment. During the pretreatment period and after vehicle, values remained at a stable basal level (<10 ng/ml). The mean plasma cortisol concentration before treatment with cortisol was similar between experiments: 8.0 ± 1.8 ng/ml in experiment 1 (portal sampling) vs. 7.1 ± 0.5 in experiment 2 (no portal blood collection). These observations suggest that neither the procedure for sampling pituitary portal blood, nor that for administering vehicle or cortisol, was sufficiently stressful to activate the hypothalamic-pituitary-adrenal axis. Regardless of whether cortisol was continuously infused (experiment 1) or injected twice each hour (experiment 2), plasma cortisol concentrations increased within 1–1.5 h to approximately 150–175 ng/ml and remained elevated throughout the 6-h treatment. These values were similar to maximal concentrations induced by endotoxin in previous experiments (6, 15, 16), as denoted by solid vertical bars in Fig. 2.
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) and three cortisol-treated ewes (Fig. 4). Composite results for all nine vehicle- and nine cortisol-treated ewes are presented in Table 1. Vehicle did not alter any parameter of pulsatile GnRH or LH secretion, i.e. frequency, amplitude, total output, or mean value (Fig. 3 and Table 1). In contrast, cortisol induced a rapid and robust inhibition in pulsatile LH secretion (Fig. 4 and Table 1). Importantly, this occurred without a suppression in GnRH secretion. Statistical analysis revealed a significant reduction in LH pulse amplitude (P < 0.005), total LH output (P < 0.05), and LH mean concentration (P < 0.005). None of the corresponding GnRH parameters were suppressed, and there was no significant reduction in either GnRH or LH pulse frequency (P > 0.05 in all cases). The overall reduction in LH pulse amplitude during the 6-h cortisol treatment averaged approximately 50%, and significant suppression (P < 0.05) was observed within 1 h (6.7 ± 1.2 ng/ml vs. 3.9 ± 0.7, pre- vs. posttreatment; P < 0.05).
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. Figure 6A depicts composite results comparing overall percent suppression of LH pulse amplitude, and Fig. 6B presents the percent suppression for each hour over the 6-h treatment period in all eight ewes during the cortisol run. In all eight ewes, cortisol, but not vehicle, induced a marked suppression in LH pulse amplitude in response to the exogenous GnRH pulses (Figs. 5 and 6A). The overall average reduction in LH pulse amplitude during the 6-h cortisol treatment was to 49 ± 3% of the pretreatment value (P < 0.001, Fig. 6A). As in experiment 1, significant suppression (P < 0.01, cortisol vs. vehicle run) was observed by the first hourly LH pulse after onset of cortisol treatment (before plasma cortisol was fully elevated; see Fig. 2
); maximal suppression to 29 ± 2% of the pretreatment value was observed after 2 h (P < 0.001; Fig. 6B). LH pulse amplitude during the pretreatment period was not different between runs 1 and 2 of the crossover, and pretreatment values during run 2 were not influenced by treatment with cortisol in run 1 (data not illustrated).
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Discussion |
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The suppressive action of glucocorticoids on pituitary responsiveness to GnRH has been observed previously in species ranging from rodents to primates and domestic animals (7, 8, 9, 10, 11). Complementing those findings, cortisol has been found to reduce GnRH receptor message and protein expression in sheep, although this effect requires the presence of estradiol (27). Our findings here reinforce and extend the earlier observations by demonstrating that a defined, stress-like increment in cortisol inhibits pituitary responsiveness to physiologically relevant GnRH pulses. This was observed regardless of whether the GnRH pulses were endogenous or exogenous in origin and regardless of whether the ewes were exposed to estradiol (experiment 2) or devoid of ovarian steroids (experiment 1). Additional work is required to understand sites and mechanisms by which glucocorticoids inhibit GnRH-induced LH release and to determine whether the suppression in pituitary responsiveness is the sole mechanism of reproductive neuroendocrine disruption under all physiological circumstances.
With regard to sites, a suppressive action directly upon the pituitary is an attractive possibility. Alternatively, cortisol might act indirectly via an extra-pituitary mechanism to suppress pituitary responsiveness to GnRH. Of interest in this regard, recent work in sheep demonstrates cortisol does not suppress pituitary responsiveness to GnRH when the pituitary is surgically disconnected from the hypothalamus (28). This raises the possibility that a factor of central origin may mediate cortisol-induced inhibition in pituitary responsiveness. However, a direct action upon the pituitary is confirmed by the findings that cortisol inhibits GnRH-induced LH release from bovine and porcine pituitary cells in culture (9, 10).
With regard to mechanisms for suppression at the level of the pituitary, it is necessary to assess the cell type, relevant receptor(s), and intracellular signal transduction pathways that mediate the suppressive action of cortisol. In terms of pituitary cell type, cortisol could act directly or indirectly on gonadotrope cells to inhibit their responsiveness to GnRH. Consistent with a direct action, the type II glucocorticoid receptor (GR) has been identified within gonadotropes (29). This receptor, however, has also been localized in folliculostellate cells within the pituitary (30). Folliculostellate cells respond to glucocorticoids by synthesizing annexin 1, an inhibitory paracrine agent whose receptor has been identified within gonadotrope cells (31, 32, 33). It is possible, therefore, that the inhibitory effects of cortisol on responsiveness to GnRH could be mediated indirectly via annexin-1 from folliculostellate cells. Another important mechanistic question is whether the suppressive effect of cortisol on pituitary responsiveness is mediated by genomic or nongenomic actions. Indeed, the rapidity of the response observed in the present study (suppression within 1 h) might be more consistent with a nongenomic action, which emerges in a matter of minutes, in comparison to a genomic action, which is generally thought to require hours (34, 35). In accord with this thinking, recent evidence in a pituitary cell line suggests glucocorticoids activate the MAPK pathway via a nongenomic mechanism involving GR (32). Furthermore, a membrane-bound receptor for corticosteroids has been identified in neuronal tissue of amphibians and may mediate rapid nongenomic glucocorticoid actions (36). The present findings encourage additional study of the cell types, relevant receptor(s), and mechanisms whereby cortisol inhibits the action of GnRH in the sheep pituitary gland.
With regard to our conclusion that cortisol inhibits pulsatile LH secretion by suppressing pituitary responsiveness to GnRH rather than by inhibiting hypothalamic GnRH release, additional work is necessary to determine whether the suppression in pituitary responsiveness is the sole mechanism of reproductive neuroendocrine suppression under all physiological conditions. Substantial evidence suggests gonadal steroids modulates responsiveness of the reproductive neuroendocrine axis to the suppressive effects of stress and glucocorticoid exposure (4, 5, 37). For example, isolation-restraint stress inhibits LH pulse amplitude in ovariectomized ewes not replaced with gonadal steroids, whereas the same stress preferentially inhibits LH pulse frequency in ovariectomized ewes treated with estradiol (38). Along similar lines, we recently observed that cortisol suppresses LH pulse frequency in ovary-intact ewes during the follicular phase of the estrous cycle (38A ). Frequency suppression suggests a hypothalamic site of cortisol action, affecting the GnRH neurosecretory system and frequency of GnRH pulses. Of considerable interest, a recent study in the ewe indicates GR is colocalized in a majority of hypothalamic neurons containing estradiol and progesterone receptors in regions that regulate GnRH secretion (39). Because these estradiol and progesterone receptor-containing neurons are implicated in GnRH release, they could provide a neural substrate for cortisol to inhibit GnRH secretion as well as an interface for gonadal steroids to modulate this action of cortisol.
Another pertinent question arising from the present study pertains to the physiological relevance of cortisol in mediating stress-induced suppression of reproductive neuroendocrine activity. In this context, it should be noted that the dose of cortisol in the present study produced a plasma cortisol increment within the range we observe in ewes during immune/inflammatory stress. Furthermore, the suppression of pituitary responsiveness developed within the first hour of cortisol administration when plasma cortisol was still rising. One hour is well within the duration of stress-induced stimulation of cortisol secretion (1, 3, 4, 40). Thus, suppression of pituitary responsiveness to GnRH can be achieved with a physiologically relevant exposure to cortisol. Surprisingly, few studies have tested whether stress-induced inhibition of gonadotropin secretion can be attenuated by blocking glucocorticoid synthesis or action. The nonselective GR antagonist, RU486, attenuated LH inhibition during immobilization stress in gonadectomized male rats, suggesting a mediatory role of glucocorticoids in gonadotropin suppression (41). In contrast, blockade of increased cortisol synthesis during immune/inflammatory stress did not reverse the suppression of pulsatile GnRH and LH secretion in ovariectomized sheep (6). Furthermore, isolation-restraint stress acutely suppressed pituitary responsiveness to GnRH in hypothalamic-pituitary disconnected sheep, which lack a cortisol response (42). That suppression, however, lasted for only one LH pulse and thus cannot explain the more prolonged suppression of pulsatile LH secretion during isolation-restraint stress. Based on these considerations, it is apparent that a mediatory role for glucocorticoids in stress-induced suppression of reproductive neuroendocrine function remains an open question and may depend on the nature of the stressor and gonadal steroid status of the animal.
In summary, this study, in conjunction with earlier work, demonstrates that cortisol inhibits reproductive neuroendocrine function at the pituitary level. Specifically, an acute, stress-like elevation in cortisol inhibits pituitary responsiveness to physiologically relevant pulses of GnRH. Furthermore, cortisol does not acutely inhibit GnRH pulsatility in the absence of gonadal steroids. These findings pave the way for additional work to determine 1) sites, cell types, and mechanisms of action of cortisol in suppressing pituitary responsiveness, 2) whether ovarian steroids enable cortisol to suppress pulsatile GnRH secretion, and 3) whether cortisol mediates reproductive neuroendocrine suppression in response to stress. Such studies will be instrumental to understanding not only the basis for stress-induced impairment of fertility but also how reproductive state determines susceptibility to the disruptive effects of stress on the ovarian cycle.
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Acknowledgments |
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Footnotes |
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Preliminary reports of this work have appeared in the 2002 Society for Neuroscience Abstract Viewer Itinerary Planner (Abstract 770.1) and the Program of the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, 2003 (Abstract P2-644).
Abbreviation: GR, Glucocorticoid receptor.
Received August 26, 2003.
Accepted for publication October 16, 2003.
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, and the type II glucocorticoid receptor are coexpressed in the same neurons of the ovine preoptic area and arcuate nucleus: a triple immunolabeling study. Biol Reprod 67:1605–1612This article has been cited by other articles:
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