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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58:B900-B905 (2003)
© 2003 The Gerontological Society of America

Mineralocorticoid Receptor-Mediated Inhibition of the Hypothalamic-Pituitary-Adrenal Axis in Aged Humans

Christian Otte1, Alexander Yassouridis2, Holger Jahn1, Philipp Maass1, Nina Stober1, Klaus Wiedemann1 and Michael Kellner1

1 Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
2 Max-Planck-Institute of Psychiatry, Munich, Germany.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
In aged humans, diminished mineralocorticoid receptor (MR)-mediated feedback in the brain could contribute to impaired feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis, but no study specifically compared young and old individuals with regard to MR function. We examined 10 healthy young (mean age ± SD [standard deviation] 26.1 ± 2.9 years) and 10 elderly men (68.3 ± 4.7 years) at the nadir of cortisol levels (2:00 pm–9:00 pm) when HPA activity is mainly controlled by the MR. After pretreatment with 3 g metyrapone to minimize the impact of basal endogenous cortisol secretion, participants received orally, in randomized order on two separate occasions, either 0.5 mg of the MR agonist fludrocortisone or placebo. Fludrocortisone significantly decreased maximum adrenocorticotropic hormone (ACTH) and cortisol concentrations in both groups. ACTH and cortisol values after fludrocortisone were significantly higher in older men compared with young men. Our results implicate that a decrease in MR-mediated negative feedback contributes to the diminished feedback activity in older humans.

THERE is evidence for an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis during aging. Elevated glucocorticoid concentrations are associated with an increased risk for many age-related diseases such as diabetes, hypertension, and cardiovascular disease (1,2). Furthermore, elevated glucocorticoid concentrations have been shown to deteriorate cognitive functioning (3–6) and sleep (7–9), and might also lead to an increased risk for major depression (4).

Studies examining age-related alterations in HPA activity have not only found higher unstimulated plasma cortisol (10–12) but also increased adrenocorticotropic hormone (ACTH) concentrations after cortisol administration, indicating decreased feedback inhibition in older individuals (12–16). However, the dexamethasone-suppression test revealed equivocal results concerning the effect of aging on feedback sensitivity to dexamethasone (2,9).

The activity of the HPA axis is controlled by glucocorticoid feedback mechanisms, which act at pituitary, hypothalamic, and hippocampal levels via two different receptor systems. Mineralocorticoid receptors (MR) are restricted in anatomical localization, with the hippocampus being the major target site. They bind glucocorticoids with a higher affinity than glucocorticoid receptors (GR) and are already partially saturated at lower basal glucocorticoid levels (9,17). In contrast, the GR has a low affinity for glucocorticoids and is widely distributed in the brain and periphery. As brain glucocorticoid levels increase, e.g., during stress, an increasing number of GR will be activated (9). Also, it has recently become apparent that the prereceptor metabolism of glucocorticoids by enzymes such as 11ß-hydroxysteroid dehydrogenase (11ß-HSD) also contributes to feedback regulation, thereby adding another level of regulation in specific tissues (18,19). 11ß-HSD catalyzes the conversion of active 11ß-hydroxy-glucocorticoids such as cortisol in humans and their inert keto forms. There are two isoenzymes of 11ß-HSD, which differ considerably in tissue distribution and function. 11ß-HSD1 is widely expressed in the hippocampus, cerebellum, and neocortex, suggesting a role in modulating the effects of glucocorticoids on mood, learning, and memory (18,19). 11ß-HSD1 regenerates active glucocorticoids in target cells from the circulating inert 11-keto steroids, and is also found in the hypothalamus and anterior pituitary indicating a role in neuroendocrine control (18,19).

One possible explanation for increased HPA activity during aging could be decreased MR function in the hippocampus, which has been shown to exert an inhibitory effect on HPA activity (9,20,21). Within the brain the highest density of glucocorticoid and mineralocorticoid receptors are found in the hippocampus, and there is some evidence that the hippocampus exerts its inhibitory effect on the HPA axis via MR (22–26). Importantly, age differences of HPA activity are mostly apparent in the evening and early part of the night with an elevation of cortisol during the circadian nadir (10–12), when MR are responsible for controlling HPA activity due to their high affinity for cortisol (27). Therefore, it is reasonable to assume that a diminished MR capacity in the hippocampus leads to an increase of cortisol concentrations during that time. Accordingly, hippocampal MR, but not GR, levels were decreased in aged dogs (28,29). Furthermore, blockade of MR with spironolactone for 8 days has been shown to exert an enhanced increase in HPA activity in elderly controls compared with young controls (30). However, spironolactone was given in different dosages and route of application to young and old participants, which makes a direct comparison difficult.

Fludrocortisone, a mineralocorticoid receptor agonist, exerts a strong inhibitory effect on both ACTH and cortisol after pretreatment with metyrapone during the circadian nadir (22). Metyrapone crosses the blood–brain barrier (31) and blocks, not only at the adrenal glands but also within the brain, the conversion of the endogenous precursor 11-deoxycortisol to cortisol by inhibiting the action of 11-ß-hydroxylase. Furthermore, it selectively blocks the activity of the 11ß-HSD1, which is present in the hippocampus, thereby preventing the regeneration of active cortisol (32,33). Thus, by blocking these two enzymes, metyrapone further decreases cortisol concentrations in the brain during the nadir of glucocorticoid secretion. As a result, MR are thought to become largely depleted, and the effect of MR agonists in the regulation of the HPA axis can be studied during minimized endogenous cortisol inhibition.

To further characterize the role of MR in age-related changes in HPA activity, we studied the effect of fludrocortisone during the circadian nadir of HPA activity in young and elderly healthy men after pretreatment with metyrapone. Fludrocortisone has also been shown to pass the blood–brain barrier (34). We hypothesized that fludrocortisone would exert an inhibitory effect on HPA activity in both groups, and that the inhibition would be diminished in the group of elderly controls due to their putative loss of MR in the hippocampus.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Participants
Ten healthy young men (aged 20–31 years, mean ± SD [standard deviation] 26.1 ± 2.9) and 10 elderly men (aged 63–80 years, mean 68.3 ± 4.7) were studied. Participants were community volunteers in excellent physical general health as determined by an interview, a physical examination, routine laboratory tests, and a urine drug screening. All participants were within 20% of their ideal body weight. Diagnosis of a psychiatric axis I illness was excluded by the Mini-International-Neuropsychiatric Interview (35). The Ethics Committee of the General Medical Council of Hamburg approved the study, and written informed consent was obtained from all participants.

Experimental Design
Participants were studied on two occasions with 1 week between the respective study days in a randomized order. An intravenous catheter was inserted at 2:00 pm and volunteers were restricted from smoking, eating, and ad libitum drinking and remained sedentary in bed without sleeping. All participants spent their time reading or listening to music. Between sampling, the tubing system was kept patent by using a 0.9% saline infusion at a rate of 50 ml/h.

On both occasions, participants received 3 g metyrapone (Novartis, London, UK) p.o. at 2:00 pm. In random order at 3:00 pm they received placebo p.o. or 0.5 mg fludrocortisone (Merck, Darmstadt, Germany) p.o. Blood samples were obtained at 2:00 pm, 3:00 pm, 4:00 pm, and then every 30 minutes until 9:00 pm. These samples were placed on ice, plasma was separated, and aliquots stored at –80°C until analysis. Blood pressure and heart rate were registered at blood sampling time points with an automatic device.

Plasma concentrations of ACTH, cortisol, and 11-deoxycortisol were determined using commercial immunoradiometric and radioimmunoassays (ICN Biomedicals, Carson, CA; Nichols Institute, San Juan Capistrano, CA). Interassay and intrassay coefficients of variation for all determinations were below 8%. Detection limits were 0.5 µg/dl for cortisol, 0.5 µg/ml for 11-deoxycortisol, and 2 pg/ml for ACTH.

Statistical Analyses
All 20 participants were included for statistical analysis. Postmetyrapone hormonal plasma concentrations at 3:00 pm, before fludrocortisone or placebo administration, were taken as baseline data.

To differentiate between early and late effects of treatment, two time intervals were calculated separately, i.e., an early interval immediately after substance administration from 3:00 pm to 6:00 pm and a late interval from 6:00 pm to 9:00 pm. Treatment and time effects on ACTH, cortisol, and 11-deoxycortisol secretion were statistically evaluated using the time course curve indicators area under the curve (AUC) values after subtraction of the linear background and maximal change of hormone concentrations (delta).

We used a multivariate analysis of variance (MANOVA) with repeated measures design in which "age" (old vs young) was the between-participant factor whereas "treatment" (placebo vs fludrocortisone) and "time" were within-participant factors. When significant factor effects were found, univariate F tests followed to identify the indicators or variables, which contribute to the significant effects. Differences between the two treatments or between the time intervals were tested using contrasts. As a nominal level of significance, {alpha} = 0.05 was accepted. All post hoc tests (univariate F tests and tests with contrasts) were performed at a reduced level of significance (Bonferroni procedure) to keep the type I error less than or equal to 0.05.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Placebo Versus Fludrocortisone
In both age groups, fludrocortisone significantly decreased the concentrations of all three hormones compared with placebo. Specifically, analysis of variance revealed a significant main effect of "treatment" and a significant "treatment x time" interaction for delta values of ACTH, cortisol, and 11-deoxycortisol [Wilks' multivariate tests of significance; "treatment": F(3,16) = 3.68, p =.034, "treatment x time": F(3,16) = 9.22, p =.001]. Tests with contrasts revealed that fludrocortisone significantly decreased delta values of all three hormones during the second interval between 6:00 pm and 9:00 pm compared with placebo (tests with contrasts, p <.05). In the first interval only, delta ACTH values were decreased after fludrocortisone compared with placebo (tests with contrasts, p <.05).

With regard to AUC values, no significant "treatment" or "treatment x time" effect emerged [Wilks' multivariate tests of significance; "treatment": F(3,16) = 0.70, p =.565, "treatment x time": F(3,16) = 0.86, p =.496)].

Elderly Versus Young Participants
The inhibitory effect of fludrocortisone on hormone concentrations was stronger in young men compared with elderly men. MANOVA revealed a significant "treatment x time x age" interaction on delta values of ACTH, cortisol, and 11-deoxycortisol values [Wilks' multivariate test of significance; F(3,16) = 4.08, p =.025]. ACTH values were significantly higher (see Figure 1) in the group of older participants compared with young men in both conditions during the first interval (tests with contrasts, p <.05)(see figures 2 and 3).



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  		Figure 1. Mean adrenocorticotropic hormone (ACTH) concentrations ± SEM (standard error of mean) in healthy young and old men after pretreatment with 3 g metyrapone at 2:00 pm and additional placebo or 0.5 mg fludrocortisone p.o. at 3:00 pm. Met = metyrapone; Flu = fludrocortisone; Pla = placebo

 
Furthermore, age differences were also seen for delta cortisol and 11-deoxycortisol values within both time intervals for the placebo condition, indicating higher concentrations in elderly participants after metyrapone (tests with contrasts, p <.05). In the fludrocortisone condition, the differences for delta cortisol and 11-deoxycortisol between young and old participants with higher concentrations in elderly participants were significant only within the first time interval.

AUC values showed a significant "time x age" interaction in MANOVA [Wilks' multivariate tests of significance; F(3,16) = 3.34, p =.046] attributable to cortisol and 11-deoxycortisol (univariate F tests, p <.05). The AUC values of cortisol and 11-deoxycortisol were significantly higher in the older group during the first interval between 3:00 pm and 6:00 pm (tests with contrasts, p <.05).

Blood Pressure, Heart Rate, and Side Effects
In neither group did fludrocortisone change blood pressure or heart rate during the time course of the study. In MANOVA, there was neither an effect of treatment nor a treatment x group interaction for maximal or AUC values of blood pressure or heart rate. All participants tolerated the procedure well, and none reported significant discomfort or nausea from ingestion of metyrapone. Four young and 6 old participants felt a slight dizziness and light-headedness for approximately 1 hour after metyrapone administration.


   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
To our knowledge, this is the first study that directly compared young and old humans with regard to mineralocorticoid-mediated negative HPA feedback activity, showing that MR feedback inhibition is diminished in older men compared with a young control group. This attenuated inhibition of HPA activity after fludrocortisone in old men was observed both in ACTH and cortisol values consistent with an inhibitory effect of fludrocortisone at suprapituitary mineralocorticoid receptor sites.

Our results confirm earlier studies that found decreased feedback inhibition in older participants after cortisol administration (13–16). However, it had been unclear whether GR or MR are mainly responsible for this effect since supraphysiological doses of cortisol, as used in these studies, activate both MR and GR. Our study extends earlier findings, and implies that a decrease in hippocampal MR capacity is responsible for the diminished feedback activity in older humans as has been shown in animals earlier (28,29). Our results could also explain why increased cortisol concentrations in older humans were found specifically during the circadian nadir when MR are mainly responsible for controlling HPA activity (10–12), and would also be consistent with equivocal results regarding age effects on cortisol suppression after dexamethasone. Importantly, dexamethasone exerts its effect mainly at GR at the pituitary gland (9,36). This suggests that a decline of central MR is mainly responsible for age-related changes of HPA activity rather than diminished GR function at the pituitary. Therefore, specifically examining MR in aging might be more sensitive than the dexamethasone suppression test in detecting age-related changes of HPA feedback inhibition.

The differences between old and young participants predominantly emerged during the first time interval within the first 4 hours after metyrapone administration. Metyrapone, which has a half-life of between 1–2.5 hours (37), decreased cortisol drastically within the first hour after administration in both old and young participants (Figure 2). Further, fludrocortisone is absorbed within 20 minutes after oral administration and reaches peak plasma concentration after 1.7 hours (34). Therefore, the effects of both substances were presumably most pronounced during the first time interval, which might explain why group differences were most apparent during this time. However, we cannot definitively exclude that differences in drug absorption or metabolism contributed to these results. Further studies using mineralocorticoid antagonists, e.g., spironolactone, and glucocorticoid antagonists, e.g. mifepristone, are clearly indicated to disentangle the role of both receptors in age-related changes of HPA activity. This is all the more important since we do not know exactly to which extent MR are depleted from endogenous cortisol after metyrapone, due to uncertainties concerning the exact concentration of metyrapone, fludrocortisone, and cortisol in the cerebrospinal fluid, the intrabrain metabolism of cortisol by the 11ß-hydroxysteroid dehydrogenase, which is blocked by metyrapone (32,33), and the exact affinity of MR for cortisol in humans. Importantly, recent findings suggest that earlier studies overestimated the proportion of MR that is occupied by low basal cortisol levels (17). While earlier studies suggested that approximately 90% of the MR are occupied during the nadir of cortisol concentration, these newer results seem to indicate that only approximately 50% of all MR are occupied during low physiological concentrations. This implies that the MR may play a more important and dynamic role than previously believed in mediating the negative feedback effects of cortisol on HPA axis activity.



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  		Figure 2. Mean cortisol concentrations ± SEM (standard error of mean) in healthy young and old men after pretreatment with 3 g metyrapone at 2:00 pm and additional placebo or 0.5 mg fludrocortisone p.o. at 3:00 pm. Met = metyrapone; Flu = fludrocortisone; Pla = placebo

 
While fludrocortisone is known to exert some glucocorticoid activity, its affinity for MR is about 15-fold higher than for GR, with even greater affinity for the mineralocorticoid receptor than the natural hormone aldosterone (38). Also, fludrocortisone did not induce a decrease in cortisol concentrations during treatment of chronic fatigue syndrome over 6 and 9 weeks (39,40). Furthermore, our group studied fludrocortisone (0.5 mg) suppression of the HPA axis overnight in healthy volunteers and found no inhibitory effect on cortisol secretion after fludrocortisone, in spite of the long biological half-life of 18–36 hours (H. Jahn, unpublished observations). In contrast, dexamethasone, a strong GR agonist that exerts most of its inhibitory effect at GR in the pituitary (36), suppresses cortisol overnight. If one would expect fludrocortisone to elicit considerable GR-mediated HPA inhibition, one should see cortisol suppression after fludrocortisone administration as it is caused by dexamethasone. However, this is not the case, and therefore it seems unlikely that the inhibitory effect of fludrocortisone on the HPA axis in our study is glucocorticoid mediated. However, since MR and GR are colocalized in the hippocampus and other brain areas and are able to interact by forming heterodimers that activate specific genes (41), a functional differentiation between MR- and GR-mediated effects might be less conclusive.

Interestingly, group differences in our study already emerged in the placebo condition, after metyrapone administration only, with higher ACTH, cortisol, and 11-deoxycortisol values in the group of elderly participants. This is in contrast to an earlier study (13) in which metyrapone led to an attenuated increase of ACTH in older individuals. However, this could be partially explained by the fact that the former study used a lower dose of metyrapone and was conducted in the morning when cortisol levels were higher and regulated by both MR and GR. In our study, the increased ACTH response, despite higher cortisol concentrations after metyrapone and placebo in older participants in the first time interval, could also be explained by impaired feedback inhibition of ACTH due to loss of MR in the hippocampus. This would also be consistent with similar ACTH levels in both groups during the second interval despite higher cortisol concentrations in elderly participants, also arguing for impaired feedback inhibition.

One shortcoming of our study is that it examined only men. However, it has been shown that, in older populations, women have higher unstimulated cortisol concentrations (10) and show higher HPA responsivity to pharmacological (13,42,43) and psychological challenges (44,45) compared with aged men. This has been related to the decline of estrogen in postmenopausal women (45,46). Thus, it seems unlikely that the impaired MR-mediated feedback inhibition in the older group in this study is caused by a gender effect, but further studies should confirm our results in women.

Summary
This study of MR-mediated feedback inhibition in young and old men showed a decreased feedback inhibition of ACTH, cortisol, and 11-deoxycortisol in old men consistent with diminished MR function in the brain, leading to increased glucocorticoid concentrations. According to the "glucocorticoid cascade hypothesis," increased HPA activity is also associated with hippocampal damage, which can then lead to even further-increasing glucocorticoid concentrations (47). Indeed, cross-sectional and longitudinal studies in humans have reported an association between hippocampal volume reductions, elevated cortisol levels, and impaired cognition during aging (3,6,16).

Furthermore, HPA alterations have been associated with psychiatric disorders such as Alzheimer's disease (48), depression (9,49,50), and posttraumatic stress disorder (51,52), and loss of hippocampal volume has also been described in these disorders (53–56). Therefore, increased HPA activity in elderly individuals could be a risk factor for the development of these disorders (4), and more insight into the complex interrelationship between hippocampal mineralocorticoid and glucocorticoid receptors, increased HPA activity, and psychopathology in aged humans might help to prevent or treat these disorders.



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  		Figure 3. Mean 11-deoxycortisol concentrations ± SEM (standard error of mean) in healthy young and old men after pretreatment with 3 g metyrapone at 2:00 pm and additional placebo or 0.5 mg fludrocortisone p.o. at 3:00 pm. Met = metyrapone; Flu = fludrocortisone; Pla = placebo

 

   Acknowledgments
 
We thank Mrs. Heike Kloss and Mrs. Iris Remmlinger-Marten for their technical assistance. This study is part of the doctoral thesis of N. Stober and P. Maass.

Address correspondence to Dr. Christian Otte, University of California–San Francisco Veterans Administration Medical Center, PTSD Research Program, 4150 Clement Street, San Francisco, CA 94121. E-mail: cott9153{at}itsa.ucsf.edu or otte{at}uke.uni-hamburg.de


   Footnotes
 
Decision Editor: Peter Hornsby, PhD

Received May 14, 2003

Accepted June 25, 2003


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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