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The Role of Mineralocorticoid Receptors in Hypothalamic-Pituitary-Adrenal Axis Regulation in Humans¹

Mental Health Research Institute and Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Elizabeth A. Young, Mental Health Research Institute and Department of Psychiatry, 205 Zina Pitcher Place, University of Michigan, Ann Arbor, Michigan 48109. E-mail: eayoung{at}umich.edu

	Abstract

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In rodents, two types of glucocorticoid receptors, the mineralocorticoid (MR; type I) and the glucocorticoid (type II) receptors, have been demonstrated to play a role in hypothalamic-pituitary-adrenal (HPA) axis regulation. Because MR shows a very high affinity for cortisol, it has been suggested that MR plays an important role in restraint of CRH and ACTH secretion during the nadir of the circadian rhythm. Although a number of studies have established the importance of MR in rodents, the functional role of MR in humans has not been determined. These studies evaluated whether spironolactone, an MR antagonist, had a detectable effect on HPA axis regulation in humans, and whether the effect was greatest during the evening, when plasma cortisol concentrations are in the MR range. Compared to the placebo day, after a single dose of spironolactone at either 0800 or 1600 h, there is a significant increase in plasma cortisol, which is preceded by a rise in ACTH and ß-endorphin. A significant effect of spironolactone on cortisol secretion was demonstrated with no differences between the morning and evening. Because the effect of spironolactone on cortisol was short lived, a second experiment was conducted using two doses of spironolactone, again sampling in the morning and evening. After two doses of spironolactone, plasma cortisol levels showed a significant and sustained spironolactone-induced elevation for the entire sampling period. However, neither plasma ß-endorphin nor ACTH was increased compared to levels on the placebo day. These data suggest that MR appear to play a clear role in HPA axis regulation during the time of the circadian peak as well as the trough. Furthermore, MR blockade may affect the sensitivity of the adrenal to ACTH.

	Introduction

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GLUCOCORTICOIDS exert negative feedback effects on the hypothalamic-pituitary-adrenal (HPA) axis by binding to their receptors, which then bind to glucocorticoid response elements on a number of different genes. The demonstration of the existence of two different glucocorticoid receptors with differing affinities for glucocorticoids was an important conceptual advance in understanding the regulation of the HPA axis (1). The type II glucocorticoid receptor, or GR, has been shown to be widely distributed in brain and periphery, and it has been hypothesized to play a major role in stress responsiveness, because even at high levels of glucocorticoids there are significant numbers of "available" unoccupied receptors (2, 3, 4). In contrast, type I or mineralocorticoid receptors (MR) are more restricted in anatomical localization, with the hippocampus predominating as the major site in brain (1, 2, 5). Mineralocorticoid receptors have an extremely high affinity for glucocorticoids, so that they are saturated at low glucocorticoid concentrations (2, 3, 4). It has been proposed that occupation of MR is important in maintaining inhibition of ACTH during the cortisol nadir. Studies by Dallman and colleagues have demonstrated that at the nadir of the circadian corticosterone rhythm, corticosterone levels are low enough and ACTH levels are inversely high enough to suggest that MR occupation could play a critical role in regulating circadian driven CRH and ACTH secretion (6). This proposed functional role of MR is further supported by the findings of significant occupation of MR (69%) in the hippocampus during the nadir of the cortisol rhythm, whereas hippocampal GR is little occupied (10%) during the same period (4). Stress-induced corticosterone secretion in both the morning (AM) and the evening (PM) produces further occupation of the GR (3, 4, 7).

Another approach in studying the relative roles of GR and MR in restraining circadian-induced and stress-induced HPA secretion involves the use of selective receptor antagonists at different times of the circadian rhythm. The studies of Ratka et al. (8), using the MR antagonist RU 28381 injected intracerebroventricularly, demonstrated a role for MR in both basal HPA axis secretion and feedback inhibition after stress in the AM (the circadian nadir for rodents). Studies in rats by Bradbury et al. (9) using spironolactone, an MR antagonist, found that spironolactone antagonized the negative feedback effects of corticosterone on circadian-induced ACTH secretion in both the AM and the PM. This led to the conclusion that both MR and GR participate in the regulation of ACTH secretion during the peak and the nadir of the circadian rhythm. All of these studies were performed in rodents, in which corticosterone, the main secreted glucocorticoid, is a more potent MR agonist but a weaker GR agonist than is cortisol, the main glucocorticoid in humans. Thus, it is possible that in humans, in whom the predominant glucocorticoid is cortisol, that MR would be less involved in active restraint of the HPA axis, with GR playing the major role in the restraint of circadian-driven ACTH secretion.

The hypothesis of this study was that antagonism of MR would lead to HPA axis secretion, and the effect would be greatest at the nadir of the circadian rhythm. The goal of these studies was to determine whether spironolactone had a detectable effect on HPA axis hormone secretion in humans and whether this effect was observed during the peak of the HPA axis rhythm (the AM) or during the trough of the circadian rhythm (the PM).

	Subjects and Methods

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Subjects

All studies were approved by the University of Michigan institutional review board. Subjects consisted of normal healthy adult males and females free of medical illness as established by history, physical exam, and screening blood chemistry, who were taking no other medications as confirmed by a urine drug screen and were free of psychiatric disease as established by a Structured Clinical Interview for DSMIV-Non Patient Version (SCID-NP). Women were studied at random phases of the menstrual cycle. A total of eight subjects were studied in the AM version (five women and three men), and eight subjects were studied in the PM version (four women and four men) of Exp 1. A total of six subjects, three women and three men, were studied in the AM protocol, and six subjects, three women and three men, were studied in the PM protocol of Exp 2.

Experimental design

The initial experimental protocol (Exp 1; Fig. 1) consisted of insertion of an iv catheter for blood drawing and administration of placebo on day 1 and spironolactone (400 mg) on day 2 at the onset of the study. Treatments were not randomized because spironolactone could exert carryover effects on the HPA axis of the placebo day. Subjects were fed 30–45 min before iv catheter insertion, but were fasted during the 6-h blood-drawing protocol to avoid feeding-induced ACTH and cortisol secretion during the blood-drawing period. Blood was drawn every 30 min for 6 h for measurement of ACTH, ß-endorphin, and cortisol. To test the hypothesis that the effect of spironolactone was greatest during the circadian nadir, subjects were tested at two different times of the day. In the AM studies, iv catheter insertion and blood drawing began at 0800 h. In the PM studies, iv catheter insertion and blood drawing began at 1600 h (Fig. 1). These study times were based upon studies with AM and PM administration of metyrapone, a glucocorticoid synthesis inhibitor, where clear circadian differences in ACTH and ß-endorphin response to metyrapone were observed in normal subjects at these times (10, 11).

View larger version (20K): [in this window] [in a new window]   Figure 1. Diagram of the AM and PM versions of Exp 1. A single dose of spironolactone was administered at either 0800 h (AM version) or 1600 h (PM version). Blood was drawn every 30 min for 6 h. Placebo was administered the first day, and spironolactone the second day.

View larger version (24K): [in this window] [in a new window]   Figure 2. Diagram of the AM and PM versions of Exp 2. In the AM version, two doses of spironolactone were administered, one at 0030 h and a repeat dose at 0530 h. Blood was drawn every 20 min between 0630–1000 h. The PM version was similar, but offset by 12 h. Placebo was administered the first day, and spironolactone the second day.

Plasma samples for ß-endorphin were assayed after Sep-Pak extraction using the RIA procedure previously described (12). The antibody used demonstrates 100% cross-reactivity with ß-lipotropin, and thus the measure of immunoreactivity includes both ß-endorphin and ß-lipotropin, the two products of POMC cosecreted with ACTH. This assay can detect 0.5–1 fmol ß-endorphin-like immunoreactivity/assay tube, with an IC₅₀ of 12 fmol. The equivalent of 2 mL extracted plasma is added per assay tube, allowing detection of values betweem 0.25–0.5 fmol/mL plasma. Each sample is run in triplicate, yielding less than 8% variability. Interassay variability within a given tracer is less than 10%. The cortisol assay was a competitive protein binding assay, with confirmation of the cortisol measures by high performance liquid chromatography (HPLC) in some selected samples, as subsequently described. The intraassay coefficient of variation is 2%, and the interassay coefficient of variation is 7%. The method is not completely specific for cortisol, as it also measures other glucocorticoids and gonadal steroids in plasma to a small extent. In terms of their contribution to total plasma corticosteroids measured in this assay, the most significant of these noncortisol steroids are corticosterone, cortisone, and 11-deoxycortisol. An additional cortisol assay was performed on selected samples using a HPLC procedure, which was previously described and validated (11). The ACTH assay used the highly sensitive Allegro HS ACTH immunoradiometric assay kit (Nichols Institute, San Juan Capistrano, CA), which uses 200 µL unextracted plasma. The intraassay coefficient of variation is 3.5%, and the interassay coefficient of variation is 7%. Data were analyzed by two- and three-way repeated measure ANOVA.

	Results

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The cortisol data from the AM version of Exp 1 are shown in Fig. 3. On the placebo day there was a gradual decrease in cortisol, followed by a relative plateau in cortisol. In contrast, on the spironolactone day, there was a significant increase in plasma cortisol, which reached a maximum 3.5–4 h after spironolactone administration (by two-way ANOVA, significant interaction between drug and repeated measure: F = 2.8, df = 12, P = 0.002). The increase in cortisol was clearly preceded by rises in ACTH and ß-endorphin (Fig. 4). However, because of the greater variation in peptide levels on the placebo day, neither the ACTH nor the ß-endorphin data demonstrated a significant effect by two-way ANOVA (Fig. 5). Similar findings were seen in the data from the PM study (Fig. 6). On the placebo day, a decrease in cortisol was seen over the course of the study. After spironolactone administration, plasma cortisol declined at a slower rate and was elevated compared to the level on the placebo day (F = 2.5, df = 12, P = 0.004). In Exp 1, there was a significant AM/PM circadian difference in cortisol (F = 3.65, df = 12, P = 0.0001), but no difference in the effectiveness of spironolactone with AM vs. PM administration (no significant interactions). For ACTH, no significant effect of spironolactone or interactions involving spironolactone was found, although there was the expected circadian difference in ACTH (F = 3.98, df = 12, P = 0.0001). For ß-endorphin data, no significant effect of spironolactone or circadian differences was observed. Because the effect of spironolactone appeared to be short lived, it was hypothesized that a more sustained peptide response would be observed by administering an additional dose of spironolactone.

View larger version (22K): [in this window] [in a new window]   Figure 3. Effects of a single dose of spironolactone on plasma cortisol in the AM. A significant increase in cortisol was seen on the spironolactone day.

View larger version (18K): [in this window] [in a new window]   Figure 4. Time course of ACTH and cortisol secretion on the spironolactone day (upper panel) and the parallelism of ACTH and ß-endorphin secretion (lower panel). A rise in ACTH preceded the rise in cortisol. The fall in ACTH coincided with the rise in cortisol, suggesting that cortisol exhibited negative feedback effects on ACTH secretion, leading to a short-lived increase in cortisol. Both ACTH and ß-endorphin showed parallel rises and falls in secretion in response to spironolactone administration.

View larger version (19K): [in this window] [in a new window]   Figure 5. Comparison of ACTH (upper panel) and ß-endorphin (lower panel) secretion on spironolactone and placebo days. ACTH data were not available for two of the eight subjects. Neither peptide showed a significant increase in secretion in response to spironolactone.

View larger version (18K): [in this window] [in a new window]   Figure 6. Cortisol (upper panel) and ACTH (lower panel) responses to a single dose of spironolactone administered at 1600 h. Although the increase in cortisol was significant in both the AM and PM versions, the ACTH increase was not significant.

View larger version (17K): [in this window] [in a new window]   Figure 7. Cortisol (upper panel) and ACTH (lower panel) responses to two doses of spironolactone administered before the onset of sampling during the peak of circadian activation. A significant sustained increase in cortisol secretion was observed. However, ACTH was not elevated.

View larger version (18K): [in this window] [in a new window]   Figure 8. Cortisol (upper panel) and ACTH (lower panel) responses to two doses of spironolactone administered in the afternoon, before the onset of blood drawing. The increase in cortisol was significant in the AM and the PM, but the changes in ACTH secretion were not significant.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The above studies were conducted to determine whether mineralocorticoid receptors play a role in HPA axis regulation in man. The data presented support a role of MR in HPA axis regulation in humans. The data from the single dose study clearly demonstrate an increase in ACTH that precedes an increase in cortisol. The most consistent explanation is that MR antagonism has a small effect on ACTH secretion that is short lived and small in magnitude and that this small effect is amplified by the adrenal and results in significant cortisol changes. The effect of spironolactone could be short lived because the increased cortisol feeds back to higher centers of the HPA axis and, acting upon GR, yields a decrease in pituitary secretion, resulting in the return of ACTH to normal levels. Alternatively, the effectiveness of MR blockade may have been lost after several hours. To address this possibility, Exp 2, using two doses of spironolactone, was conducted. In this experiment, a sustained effect of spironolactone on cortisol secretion was observed, although a significant increase in ACTH secretion was again not seen.

Given the data demonstrating that MR blockade stimulates cortisol secretion, interaction of the MR antagonist with the phase of the circadian rhythm is the second question addressed. In the single dose study, spironolactone resulted in an increase in cortisol secretion, with peak elevation between 2.5–3.5 h after spironolactone administration and some decline thereafter. This did not differ between the AM and the PM. In the two-dose study, there was a clear elevation of cortisol after spironolactone administration, which again did not differ between the AM and the PM. The clear effect of spironolactone in the AM, during the time of active circadian-induced ACTH and cortisol secretion, agrees with Bradbury et al. (8), who reported effects of spironolactone at both the peak and the nadir of the circadian rhythm and concluded that MR is playing a role in HPA axis regulation at all times of the circadian rhythm.

The data from the two-dose study suggest that in addition to stimulating ACTH secretion, MR antagonism appears to increase the sensitivity of the adrenal to ACTH, perhaps via increased ACTH secretion or another mechanism. This results in a sustained increase in cortisol levels even when ACTH secretion has returned to normal. This is seen most clearly in Exp 2, when two doses of spironolactone were administered, and ACTH, ß-endorphin, and cortisol were measured, but an increase in cortisol secretion only was observed. Although it is possible that the peak of ACTH secretion was missed due to the short half-life of ACTH, every 20 min sampling should be frequent enough to detect anything other than a very transient increase in ACTH. Alternatively, as blood sampling did not begin until 1 h after the second dose of spironolactone, there may have been an increase in ACTH that disappeared by the time of our first sample. A similar finding of increased cortisol secretion in the absence of increased ACTH secretion was reported by Dodt et al. (13) using potassium canrenoate, an active metabolite of spironolactone. The researchers also examined the effects of canrenoate on the half-life of cortisol and found no effect. Although they did not observe an effect on ACTH, they assumed that their infrequent sampling (five samples over 9 h) resulted in a missed ACTH peak. In a recent report, Born et al. (14) also demonstrated that canrenoate reversed sleep-induced inhibition of the ACTH and cortisol response to oCRH, again suggesting a role for MR in HPA regulation in man. These data are consistent with the data presented here that MR blockade affects HPA axis secretion and possibly increases the sensitivity of the adrenal to ACTH. Because the dose of spironolactone administered in Exp 2 was quite high, it is possible that the effects observed are indirect and dependent upon other nonmineralocorticoid actions. A study by Michelson et al. (15) using lower doses of spironolactone (50 and 100 mg) showed no effect on baseline plasma cortisol 4–6 h after the administration of a single dose of spironolactone, nor was there any difference in ovine CRH-stimulated ACTH and cortisol release when ovine CRH was administered 6 h after spironolactone. Although differences in doses may account for these discrepancies, it is also clear that the effect of spironolactone on ACTH and cortisol secretion was transient in our studies and disappeared by 4–6 h. In many ways the picture observed after spironolactone administration in normal subjects resembles that of the hypercortisolemia of depression, where despite clear increased baseline cortisol (16, 17, 18, 19, 20), an increase in pituitary ACTH secretion has been an inconsistent observation (19, 20). Thus, the mechanism of action of spironolactone on HPA axis secretion may have relevance for the understanding of depression-induced hypercortisolemia. In conclusion, these studies suggest an active role of MR in HPA axis regulation in man at both the peak and the nadir of the circadian rhythm, even at the times when GR was previously believed to be playing the major role in mediating glucocorticoid negative feedback.

	Footnotes

 
¹ This work was supported by Grant MH-00427 (to E.Y.), Grant MH-01164 (to J.F.L.), Grant MH-42251 (to S.J.W. and H.A.), Grant MO1-RR-00042 (to the General Clinical Research Center) for support services, and Grant P30-HD-18258 (to the Assay and Reagents Core).

Received January 29, 1998.

Revised March 13, 1998.

Revised May 19, 1998.

Accepted May 28, 1998.

	References

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