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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0105
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 10 5656-5662
Copyright © 2005 by The Endocrine Society

Hypothalamus-Pituitary-Adrenal Hyperactivity in Human Aging Is Partially Refractory to Stimulation by Mineralocorticoid Receptor Blockade

Roberta Giordano, Mario Bo, Micaela Pellegrino, Marco Vezzari, Matteo Baldi, Andreea Picu, Marcella Balbo, Lorenza Bonelli, Giuseppe Migliaretti, Ezio Ghigo and Emanuela Arvat

Division of Endocrinology and Metabolism (R.G., M.P., M.Bald., A.P., M.Balb., L.B., E.G., E.A.), Department of Internal Medicine, Department of Medical and Surgical Disciplines (M.Bo, M.V.), Section of Geriatrics, and Department of Public Health and Microbiology (G.M.), University of Turin, 10126 Turin, Italy

Address all correspondence and requests for reprints to: Emanuela Arvat, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, Ospedale Molinette, C.so Dogliotti 14, 10126 Turin, Italy. E-mail: emanuela.arvat{at}unito.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by CRH, arginine vasopressin, and glucocorticoid feedback. Hippocampal mineralocorticoid receptors mediate proactive glucocorticoid feedback and mineralocorticoid antagonists, accordingly, stimulate HPA axis. Age-related HPA hyperactivity reflects impaired glucocorticoid feedback at the suprapituitary level.

Design: ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion were studied in eight healthy elderly (75.1 ± 3.2 yr) and eight young (25.0 ± 4.6 yr) subjects during placebo or canrenoate (CAN) administration (200 mg iv bolus followed by 200 mg infused over 4 h).

Results: During placebo administration, ACTH and cortisol areas under the curve (AUCs) in elderly subjects were higher than in young subjects (P ≤ 0.01); conversely, DHEA AUCs in elderly subjects were lower than in young subjects (P = 0.002). CAN increased ACTH, cortisol, and DHEA levels in both groups. In young subjects, ACTH, cortisol, and DHEA levels at the end of CAN infusion were higher (P ≤ 0.05) than after placebo. In elderly subjects, at the end of CAN infusion, ACTH, cortisol, and DHEA levels were higher (P = 0.01) than after placebo. Under CAN, ACTH and cortisol AUCs were persistently higher (P ≤ 0.01) and DHEA AUCs lower (P = 0.006) in elderly than in young subjects. Cortisol AUCs after CAN in young subjects did not become significantly different from those in elderly subjects after placebo.

Conclusions: 1) Evening-time ACTH and cortisol secretion in elderly subjects is higher than in young subjects; 2) ACTH and cortisol secretion in elderly subjects is enhanced by CAN but less than that in young subjects; and 3) DHEA hyposecretion in elderly subjects is partially restored by mineralocorticoid antagonism. Age-related variations of HPA activity may be determined by some derangement in mineralocorticoid receptors function at the hippocampal level.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ACTIVITY OF the hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by the CRH and arginine vasopressin (AVP) neurohormones (1, 2) and by the glucocorticoid feedback that modulates circadian activity of the HPA axis, as well as its stress response by acting at the pituitary, hypothalamic, and hippocampal levels (3).

Glucocorticoid action is mediated by both glucocorticoid (GRs) and mineralocorticoid (MRs) receptors, with GRs being distributed throughout the brain but mostly in hypothalamic neurons and corticotroph cells (3, 4, 5), whereas MRs are present in the hypothalamus, with their highest expression being detected in the hippocampus (3). At this level, MRs lose aldosterone selectivity and bind glucocorticoids more than 10-fold higher than GRs, as demonstrated by animal in vitro studies (3, 4, 5). Hippocampal MRs play a major role in the control of the proactive glucocorticoid feedback, aimed at maintaining basal HPA activity (4). The stimulatory effect of MRs blockade by spironolactone or canrenoate (CAN), MRs antagonists, on the HPA axis has been demonstrated in both animals and humans. The systemic administration of CAN enhances spontaneous and CRH- or AVP-stimulated ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion, as well as cortisol response to physical exercise, in normal young subjects (6, 7, 8, 9, 10). Thus, the study of mineralocorticoid antagonist effects on corticotroph and adrenal secretion represents a new approach to investigating the glucocorticoid feedback effect at a suprapituitary level, i.e. likely at the hippocampal level (11).

HPA axis hyperactivity has been clearly demonstrated in aged animals and humans (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23), and, moreover, it could be involved in the structural, metabolic, and cognitive alterations of aging (12, 13, 14). In aged animals, HPA hyperactivity is likely to reflect loss of resiliency and reduced sensitivity to the negative glucocorticoid feedback, which mainly reflects hippocampal receptor damage (4, 12, 13, 14).

So far, human studies have generally been performed by studying HPA sensitivity to the negative feedback action of dexamethasone, which has difficulty crossing the blood-brain barrier (24, 25), and/or of pharmacological hydrocortisone doses (26, 27). Therefore, these experimental models might not conceptually represent the most reliable way to evaluate age-dependent variations in feedback control of HPA axis, which is mainly under central modulation.

Reduction in both basal and stimulated levels of DHEA and its sulfate is another intriguing aspect in age-related variations of HPA axis, despite hyperactivity of ACTH and cortisol secretion (22, 23, 28, 29, 30, 31, 32). Reduction in DHEA synthesis and secretion probably reflects particular atrophy of the reticularis zone of the aged adrenal gland, where specific defects in the steroidogenic pathway, namely in the activity of the 17,20-lyase, have been demonstrated (29, 33), and it could contribute to age-related changes in structure functions and metabolism (30, 34).

To clarify the role of MRs on HPA activity in normal aging, the effect of CAN on the spontaneous ACTH, cortisol, and DHEA secretion in the evening (during the nadir of the circadian HPA rhythm) was studied in a group of normal elderly subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Drugs

Vials containing 200 mg of potassium CAN were purchased from Knoll Farmaceutici Spa (Milan, Italy).

Study protocol

Eight elderly subjects (four women and four men; age, 75.1 ± 3.2 yr; body mass index, 22.9 ± 2.4 kg/m2) and eight young subjects (five women studied in their early follicular phase, and three men; age 25.0 ± 4.6 yr; body mass index, 22.1 ± 1.2 kg/m2) were studied. The study was approved by the Ethical Committee of the University of Turin, and informed consent to participation was obtained from all subjects.

All subjects received the following treatments in random order at least 5 d apart: 1) placebo (1.0 ml of saline as an iv bolus at 2000 h, followed by 250 ml infused over 4 h up to 2400 h); and 2) CAN (200 mg as an iv bolus at 2000 h, followed by 200 mg infused in 250 ml of saline over 4 h up to 2400 h).

The tests started at 2000 h after at least 4 h fasting and 30 min after venous cannulation, kept patent by slow infusion of isotonic saline; all subjects remained awake during both testing sessions.

Blood samples from individual subjects were taken basally at 2000 h and every 15 min from 2000–2400 h and analyzed together; at each time point in every testing session, ACTH, cortisol, and DHEA levels were assayed.

Plasma ACTH levels (picograms per milliliter; 0.22 pg/ml = 1 pmol/liter) were measured in duplicate by immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). Assay sensitivity was 1 pg/ml; the inter- and intraassay coefficients of variation ranges were 2.4–8.5% and 3.9–9.9%, respectively.

Serum cortisol levels (micrograms per liter; 2.7 µg/liter = 1 nmol/liter) were measured in duplicate by RIA (CORT-CTK 125; DIASORIN Biomedica, Saluggia, Italy). Assay sensitivity was 4 µg/liter; inter- and intraassay coefficients of variation were 6.7–14.6% and 5.67–9.95%, respectively.

Serum DHEA levels (micrograms per liter; 3.4 µg/liter = 1 nmol/liter) were measured in duplicate by RIA [DEA-DRG (Pantec) Germany]. Assay sensitivity was 0.02 µg/liter; inter- and intraassay coefficients of variation ranged from 10.68–13.72% and 5.2–6.4%, respectively.

Statistical analysis

Hormonal responses are expressed as mean, SD, and relative 95% confidence interval (CI) of absolute values and areas under the curve (AUC2000–2400).

For each subject, the differences between placebo and CAN were computed at each time point, and ANOVA for repeated-measure model (Greenhouse-Geisser estimation) was used to analyze the variation of the differences among young subjects and elderly subjects in the period 2000–2400 h. Variations between placebo and CAN effects at each time point and differences between young and elderly subjects (separately for placebo and CAN) were compared by means of nonparametric Wilcoxon and Mann-Whitney U tests, respectively. Differences of P < 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal hormonal levels at 2000 h in different testing sessions showed no significant differences in either group.

Analysis of differences between placebo and CAN at each time point showed a significant variation during 2000–2400 h, for both young (P < 0.05) and elderly (P < 0.05) subjects. Differences measured changed variably between young and elderly subjects, particularly for cortisol and DHEA (P = 0.03).

During the placebo session, in both elderly and young subjects, spontaneous ACTH and cortisol secretion showed a progressive decrease between 2000 and 2400 h (P = 0.01 in young and P ≤ 0.05 in elderly subjects), whereas DHEA levels did not change in either group. At each time point, both ACTH and cortisol levels in the elderly subjects were higher, whereas DHEA levels were lower, than those in the young subjects (P ≤ 0.05). Besides, ACTH and cortisol AUCs during placebo in the elderly subjects were higher (P ≤ 0.01), whereas the DHEA AUCs were lower, than in the young (P = 0.002) (Tables 1–3GoGoGo and Figs. 1Go and 2Go).


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  		TABLE 1. ACTH levels (mean, SD, 95% CI) at 2000, 2200, and 2400 h and AUCs2000–2400 (picograms per liter; 0.22 pg/ml = 1 pmol/liter) during placebo or CAN in young and elderly subjects

 

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  		TABLE 2. Cortisol levels (mean, SD, 95% CI) at 2000, 2200, and 2400 h and AUCs2000–2400 (micrograms per liter; 2.7 µg/liter = 1 nmol/liter) during placebo or CAN in young and elderly subjects

 

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  		TABLE 3. DHEA levels (mean, SD, 95% CI) at 2000, 2200, and 2400 h and AUCs2000–2400 (micrograms per liter; 3.4 µg/liter = 1 nmol/liter) during placebo or CAN in young and elderly subjects

 


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  		FIG. 1. Mean (±95% CI) ACTH (picograms per milliliter; 0.22 pg/ml = 1 pmol/liter), cortisol (micrograms per liter; 2.7 µg/liter = 1 nmol/liter), and DHEA (micrograms per liter; 3.4 µg/liter = 1 nmol/liter) levels after placebo or CAN in young and elderly subjects.

 


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  		FIG. 2. ACTH (picograms per milliliter; 0.22 pg/ml = 1 pmol/liter), cortisol (micrograms per liter; 2.7 µg/liter = 1 nmol/liter), and DHEA (micrograms per liter; 3.4 µg/liter = 1 nmol/liter) AUCs2000–2400 (mean ± 95% CI) after placebo or CAN in young and elderly subjects.

 
During CAN administration, in young subjects, spontaneous ACTH, cortisol, and DHEA levels showed progressive rises, with peaks between 2300 and 2400 h. Variation analysis during 2300–2400 h showed a significant difference between placebo and CAN for each hormone (P < 0.05). ACTH, cortisol, and DHEA levels at the end of CAN infusion were significantly higher than those recorded at baseline, as well as the same time point during placebo (P ≤ 0.05) (Tables 1–3GoGoGo and Fig. 1Go).

In elderly subjects, CAN infusion slightly increased ACTH levels, with a significant difference obtained at 2400 h only (P = 0.01 vs. the same time point during placebo). In contrast to young subjects, CAN increased cortisol secretion in elderly subjects, with a significant difference starting from 2045 h (P = 0.03 vs. the same time point during placebo). Hormonal levels at the end of CAN infusion were similar to those at baseline but higher (P = 0.01) than those recorded at the same time point during placebo. Conversely, even in the elderly subjects, CAN significantly increased DHEA levels which, at the end of the infusion, resulted in higher levels (P = 0.01) than those at the same time point during placebo (Tables 2Go and 3Go and Fig. 1Go).

Under CAN infusion, ACTH and cortisol AUCs were persistently higher (P ≤ 0.01) and DHEA AUCs lower (P = 0.006) in the elderly subjects than in the young subjects. Interestingly, cortisol AUCs after CAN in the young subjects did not become significantly different from those in the elderly subjects after placebo (Tables 1–3GoGoGo and Fig. 2Go).

Side effects

CAN administration induced no significant side effects. Testing sessions never had to be stopped and/or medication withdrawn.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this study demonstrate that: 1) evening-time ACTH and cortisol secretion in elderly subjects is clearly higher than in young subjects; 2) ACTH and cortisol secretion in elderly subjects is enhanced by mineralocorticoid antagonism by CAN but less than in young subjects; and 3) DHEA hyposecretion in elderly subjects is partially restored by mineralocorticoid antagonism.

Spontaneous hypersecretion of ACTH and glucocorticoids has been more clearly demonstrated in aged animals (13, 14), whereas spontaneous ACTH and cortisol hypersecretion in aged humans has not been definitely proven. Some authors have found age-associated increases in basal ACTH and cortisol concentrations in terms of basal evening levels and nadirs (16, 17, 19, 35), plasma levels of free cortisol (36), whereas others have reported an elevated cortisol nadir uncoupled with ACTH nadir changes (37). Moreover, an anticipated nocturnal cortisol rise and acrophase have also been shown in aged subjects, without gender-related differences (16, 17, 38). Some studies have observed decreased basal cortisol concentrations with aging (15), whereas others have failed to observe any significant effect of age on ACTH or cortisol levels at different times of the day (25, 37, 38, 39).

Conversely, in both aged humans and animals, circulating levels of DHEA and its sulfate form, which are generally considered good ACTH secretion markers in young adulthood (40, 41), are generally reduced (22, 23, 28, 29, 30, 31, 32) as a consequence of particular age-related atrophy in the reticularis adrenal zone (29, 33).

Our findings clearly show ACTH and cortisol hypersecretion, coupled with reduced DHEA levels, in elderly subjects: whereas DHEA levels were invariably lower in the elderly subjects than in the young, evening-time ACTH and cortisol levels under placebo infusion in the elderly subjects were higher than in the young.

HPA hyperactivity in aging seems to be a consequence of refractoriness to glucocorticoid feedback, as also indicated by reduced resiliency in the ACTH and glucocorticoid response to stimuli (13, 18, 19, 26, 27). As anticipated, the negative glucocorticoid feedback is likely to act at the hippocampal level (3), and impaired hippocampal MRs might underlie the blunted inhibitory effect of glucocorticoid feedback and chronic HPA hyperactivation in aged animals (13, 14).

Reduced HPA sensitivity to the negative glucocorticoid feedback has also been demonstrated in human aging (3, 12, 13, 14, 26, 27). In fact, the inhibitory effect of dexamethasone, in contrast to hydrocortisone, was unchanged in elderly subjects (37, 42); however, dexamethasone has difficulty crossing the blood-brain barrier and is, therefore, unlikely to explore the central sensitivity to glucocorticoids (24, 25).

As anticipated, mineralocorticoid antagonists are likely to represent a new tool to investigate the glucocorticoid feedback action in both humans and animals (6, 7, 8, 9, 10). Our present results show that blockade of MRs by CAN stimulates the enhanced ACTH and, above all, cortisol secretion in normal elderly subjects; these findings, therefore, indicate that MRs still operate in the control of basal HPA function in aging, as also supported by the evidence that even the reduced DHEA levels are augmented by CAN infusion in elderly subjects.

The stimulatory effect of CAN on adrenal function is not coupled with the same strong effect on ACTH release, which is puzzling, taking into account that central stimuli of the HPA axis usually release more ACTH than cortisol (1). Direct stimulatory effect of CAN on adrenal function cannot be ruled out although some in vitro data showed an inhibitory, rather than a stimulatory, effect of spironolactone on adrenal steroidogenesis (43). Decreased cortisol clearance rate is unlikely, as suggested by the fact that cortisol metabolism is not modified by CAN in normal subjects (7). Another potential hypothesis is that CAN-induced cortisol increase might exert its feedback action mainly through GRs, partially counteracting the MRs blockade by CAN, which would blunt ACTH response.

Stimulatory action of MR antagonisms on ACTH and cortisol levels in the elderly subjects was less marked than in the young subjects, suggesting that elderly subjects are partially refractory to the stimulatory effect of MRs blockade by CAN, which would reflect age-related MRs function impairment. The latter hypothesis would explain either the increase of spontaneous nocturnal ACTH and cortisol secretion or its reduced sensitivity to the stimulatory action of MR blockade.

Furthermore, our study demonstrates that, although significantly increased, DHEA levels in the elderly are partially refractory to the stimulatory effect of MR blockade by CAN compared with young adults. As anticipated, clear reduction of both basal and ACTH-stimulated DHEA levels in elderly subjects has been demonstrated in both humans and animals (22, 23, 28, 29, 30, 31, 32), and it would reflect defects in steroidogenic pathways in the aged reticularis zone (29, 33). Because CAN has also been reported to inhibit adrenal steroidogenesis in vitro (43), it is, therefore, surprising that its infusion is able to significantly increase DHEA levels in elderly subjects. The slight DHEA response to CAN in the elderly could reflect the slight CAN-induced ACTH increase. DHEA is even stimulated by an extremely low exogenous ACTH dose (44, 45), although its response is reduced in human aging (21, 22, 23).

In conclusion, the results of this study show that elderly subjects are characterized by HPA hyperactivity that is partially refractory to the stimulatory effect of MRs blockade by CAN. Thus, age-related variations of HPA activity may be determined by some derangement in MRs function at the hippocampal level.


   Acknowledgments
 
We thank Prof. F. Camanni for suggestions and support to the study; Dr. A. Bertagna, Mrs. A. Barberis, and M. Taliano for skillful technical assistance; and L. Massari for English editing.


   Footnotes
 
This work was supported by grants from the University of Turin and the Foundation for the Study of Endocrine and Metabolic Diseases of Turin, Italy.

First Published Online July 12, 2005

Abbreviations: AUC, Area under the curve; AVP, arginine vasopressin; CAN, canrenoate; CI, confidence interval; DHEA, dehydroepiandrosterone; GR, glucocorticoid receptor; HPA, hypothalamus-pituitary-adrenal; MR, mineralocorticoid receptor.

Received January 18, 2005.

Accepted July 6, 2005.


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 Results
 Discussion
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