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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 4 1380-1383
Copyright © 1998 by The Endocrine Society

Original Articles

Age-Related Changes in Glucocorticoid Fast Feedback Inhibition of Adrenocorticotropin in Man1

Marco Boscaro, Agostino Paoletta, Elena Scarpa, Luisa Barzon, Paolo Fusaro, Francesco Fallo and Nicoletta Sonino

Division of Endocrinology, Institute of Semeiotica Medica, University of Padova (M.B., A.P., E.S., L.B., F.F., N.S.), and Geriatric and Gerontology Hospital (P.F.), Padova, Italy

Address all correspondence and requests for reprints to: M. Boscaro, M.D., Division of Endocrinology, Institute of Semeiotica Medica, University of Padova, Via Ospedale 105, 35100 Padova, Italy.

Abstract

A decrease in hypothalamic-pituitary-adrenal axis sensitivity to glucocorticoid feedback suppression seems to occur with aging. To investigate possible abnormalities in the inhibitory effect of glucocorticoids on ACTH secretion in the elderly, we evaluated the endogenous ACTH response to hydrocortisone (25 mg as an iv bolus) in 15 healthy aged (65–88 yr) and 15 healthy young (18–26 yr) men. Blood samples for ACTH and cortisol determinations were collected at -15, 0, 2, 5, 10, 15, 30, 45, 60, 90, 120, and 180 min. Hydrocortisone injection produced a rapid increase in plasma cortisol levels within the first 2 min in both groups. In old men, in concomitance with the cortisol increase, ACTH levels showed only a slight and nonsignificant decrease within the first 15 min, followed by a pronounced and significant decline thereafter. In young subjects, in concomitance with the plasma cortisol increase, a marked decrease in ACTH levels was observed within the first 15 min, followed by a less pronounced decline thereafter. The response curve of ACTH inhibition could be arbitrarily divided in two parts. The first part (from 0–60 min) showed a significant difference between old and young men, whereas the remaining part of the curve (from 60–180 min) showed no differences between the two groups. The slower response in glucocorticoid feedback inhibition of ACTH in old men supports the concept of some alteration in the central regulation by steroids in aging. Age-related vascular factors affecting cortisol penetration through the blood-brain barrier more than hippocampus-hypothalamus receptor abnormalities could be involved in the fast component of hypothalamic-pituitary-adrenal axis feedback regulation.

IT IS STILL unclear whether the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis undergoes significant changes during aging (1). Unaltered circadian patterns of cortisol (2, 3, 4, 5, 6) and normal cortisol responsiveness to dynamic tests (7, 8, 9, 10, 11, 12, 13) have been reported in the elderly. However, a number of studies demonstrated age-related abnormalities of the HPA axis (14, 15, 16). A slight adrenal hyperfunction in old subjects might be a consequence of decreased HPA axis sensitivity to corticosteroid feedback suppression. This hypothesis, previously suggested by Dilman et al. (15), is supported by the recent work of Wilkinson et al. (17).

The inhibitory effect of glucocorticoids on the HPA is exerted at multiple target sites and appears to operate in at least three time domains: fast (within seconds to minutes), intermediate (within 2–10 h), and slow (within hours to days) (18). The sites of fast feedback regulation are thought to be predominantly the hypothalamus and the hippocampus (19). In aged animals, the decrease in both type I and type II corticosteroid receptors in specific brain regions (i.e. hippocampus) is thought to underlie at least some of the effects of age on HPA axis (20, 21, 22, 23, 24, 25). A reduction of both types of receptors has also been described in aged humans (26). A lesser activation of central and peripheral catecholaminergic system has been recently found in old compared to young rats (27).

The HPA axis response to glucocorticoid feedback inhibition in normal human aging has usually been tested by dexamethasone (1, 10), which differs from endogenous glucocorticoids in affinity for corticosteroid receptor subtypes (28, 29, 30, 31). Wilkinson et al. (17) overcame this problem by using hydrocortisone infusion. Some of these findings are consistent with an age-related decrease in glucocorticoid feedback inhibition of ACTH secretion. To investigate the hypothesis that HPA feedback is reduced in aging, we tested ACTH suppressibility after hydrocortisone injection in aged men compared to young men. We focussed on the first phase of the inhibitory process, which is regulated by areas of the brain presumably altered in old age.

Subjects and Methods

Fifteen aged (mean age, 76 ± 12 yr; range, 65–88 yr) and 15 young (mean age, 22 ± 8 yr; range, 18–26 yr) men were studied. Before entering the study, they were evaluated by physical examination and routine laboratory analyses. None had diabetes, hypertension, or other systemic disorders. Use of medications able to influence endocrine function, abuse of alcohol or other substances, and depression were all excluded.

Body mass indexes were similar in young and old subjects (23.7 ± 3.2 and 24.6 ± 2.7, respectively; P = NS).

The study was approved by the local research ethical committee. Informed consent was obtained from all subjects.

Experimental protocol

Subjects were studied at the Division of Endocrinology of Padova University (Padova, Italy). To test ACTH feedback inhibition, hydrocortisone (Solucortef, Upjohn, Italy) was administered to both groups of young and old subjects. Tests were performed in the morning at 0800 h, with subjects maintaining a supine position after overnight fasting. Hydrocortisone (25 mg) was administered as an iv bolus over 30 s through a cannula placed in the forearm 1 h before testing. Blood samples for ACTH and cortisol determinations were drawn from the opposite forearm at -15, 0, 2, 5, 10, 15, 30, 45, 60, 90, 120, and 180 min. As control, 2–4 days earlier, saline instead of hydrocortisone was injected with the same protocol. The baseline value was the mean between -15 and 0 min values.

No side-effects were observed, and none of the subjects was excluded from the protocol.

Hormone assays

Plasma ACTH was measured by a two-site immunoradiometric assay supplied by Nichols Institute (San Juan Capistrano, CA). Normal values at 0800 h were up to 22 pmol/L. Intra- and interassay coefficients of variation were 5% (n = 10) and 9% (n = 20), respectively. Plasma cortisol was measured by a RIA kit from Diagnostic Products Corp. (Los Angeles, CA). Normal values at 0800 h were 138–550 nmol/L. Intra- and interassay coefficients of variation were 4% (n = 10) and 5% (n = 20), respectively. Normal limits for ACTH and plasma cortisol were established in our laboratory. As no significant age-related differences were found, normal values refer to the age range from 18–88 yr. All hormone samples were assayed in duplicate.

Statistical analysis

Results are reported as the mean ± SD. The intragroup response of each hormone at subsequent time points with respect to the baseline level was made by paired Student’s t test. The intergroup response of ACTH to hydrocortisone injection at each time point was evaluated by one-way ANOVA, followed by Fisher’s protected least significant difference test. Global and partial responses between groups were compared by two-way ANOVA with repeated measures. P < 0.05 was considered significant.

Results

After placebo administration, ACTH and cortisol did not differ between old and young men at any time point (data not shown). There was a tendency toward a slight decrease in cortisol in both groups, probably due to normal circadian decline.

Old subjects

Both basal ACTH and cortisol levels were in the normal range in all subjects. Hydrocortisone (25 mg as an iv bolus) produced a maximal increase in circulating cortisol levels within the first 2 min (from 507.5 ± 311.8 to a peak of 1558 ± 298.8 nmol/L; P < 0.0001). Cortisol levels showed a progressively slow decrease thereafter, but remained still higher than baseline at 120 min (700.2 ± 334.7 nmol/L; P < 0.05; Fig. 1Go). In concomitance with plasma cortisol increase, ACTH levels showed only a slight and not significant decrease within the first 15 min (from 8.4 ± 3.0 to 8.1 ± 2.7 pmol/L; P = NS), followed by a pronounced and significant decline thereafter (from 8.1 ± 0.7 pmol/L at 15 min to 3.9 ± 2.0 pmol/L at 90 min; P < 0.001; Fig. 1Go).



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  		Figure 1. Mean (±SD) plasma cortisol (upper panel) and ACTH (lower panel) concentrations in 15 old (•) and 15 young ({circ}) normal men after an iv bolus injection of hydrocortisone (25 mg). *, P < 0.05 (old vs. young men at each time point).

 
Young subjects

Both plasma ACTH and cortisol levels were in the normal range and were not significantly different from those observed in the group of old subjects. Hydrocortisone (25 mg as an iv bolus) led to a maximal increase in cortisol levels within the first 2 min (from 476.8 ± 126.4 to a peak of 1593 ± 332.7 nmol/L; P < 0.0001). Cortisol levels showed a progressive decrease thereafter, but remained still higher than baseline at 120 min (680.4 ± 231.5 nmol/L; P < 0.05; Fig. 1Go). In concomitance with the plasma cortisol increase, a marked decrease in ACTH was observed within the first 15 min (from 9.2 ± 2.9 at 0 min to 5.8 ± 2.1 pmol/L at 15 min; P < 0.0001) followed by a less pronounced decline thereafter (from 5.8 ± 2.1 pmol/L at 15 min to 3.8 ± 1.2 pmol/L at 90 min; P < 0.001; Fig. 1Go).

After hydrocortisone injection, no significant differences in circulating cortisol levels were observed between old and young subjects (by ANOVA, F1,10 = 0.6; P = NS; Fig. 1Go). ACTH response curves were significantly different between old and young groups (by ANOVA, F1,10 = 9.8; P < 0.0001; Figs. 1Go and 2Go). Based on the pattern of ACTH response observed in both groups, the ACTH curve could be arbitrarily divided in two parts: the part corresponding to the first 60 min showed a significant difference between groups (by ANOVA, F1,7 = 8.4; P < 0.0001), whereas the remaining part of the curve showed no differences between groups (by ANOVA, F1,3 = 0.1; P = NS; Figs. 1Go and 2Go).



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  		Figure 2. Plasma ACTH after an iv injection of hydrocortisone, expressed as the percent change from baseline ACTH values in old (•) and young ({circ}) subjects. *, P < 0.005; **, P < 0.0001 (old vs. young men at each time point).

 
Discussion

The fast feedback in man has been clearly shown to occur within 2 min of administration of an iv bolus of hydrocortisone (100 mg) (32). In our study, hydrocortisone injection elicited a rapid increase in circulating cortisol, reaching supraphysiological levels despite the lower dose administered. The frequent measurements of cortisol allowed a continuous monitoring of blood levels, which achieved the same peak concentrations in young and old men. In concomitance with cortisol rise, an immediate decline in ACTH levels (rate-sensitive inhibition) occurred within the first 15 min in young, but not in old, men. In the second part of the curve, the subsequent decrease was similar in both groups. The slower suppression of plasma ACTH in old compared to young men provides evidence for a reduced responsiveness to feedback inhibition in aging. Similar results have been recently obtained by Wilkinson et al. (17). In their study, subjects were pretreated with metyrapone to avoid endogenous cortisol interference. However, the enzyme inhibitory activity of metyrapone is only partial; the resulting ACTH hypersecretion might overcome enzyme blockade (33), and the extent of inhibition of steroid pathways may be individually different (34, 35). Interestingly, we obtained very similar results, i.e. a significant difference in the inhibitory response between old and young men, using the same hydrocortisone dose as an iv bolus rather than an infusion and for unstimulated ACTH levels. In particular, we focussed on the immediate response (i.e. more frequent sampling in the first 15 min).

The majority of studies in humans considered only the delayed feedback inhibition, and no age differences in cortisol suppression in this phase have been reported (12, 13, 36, 37), except by Weiner et al. (38, 39). Fehm et al. (40), using cortisol (25 mg as an iv bolus), failed to obtain any fast feedback ACTH inhibition in Addisonian adults and suggested that a bolus injection may be too brief to produce a strong rate signal and an immediate inhibition of ACTH. In the light of our data and as the fast feedback mechanism primarily acts via the inhibition of ACTH release (18), it is conceivable that a brief inhibitory signal, such as that produced by an iv bolus, may obtain a fast feedback effect in normal, but not hyperstimulated, ACTH release (40, 41). Also, in adrenalectomized or stressed dogs, an inhibitory effect was evident only 20 min after cortisol administration (42, 43).

Although the hypothalamus has generally been considered the major site of fast feedback (44, 45, 46), the hippocampus seems to be of considerable interest as well. In animal brains, hippocampus has the highest concentration of corticosteroid receptors (47). Their most pronounced decrease with age (22, 23, 48) might play a role in the decline in HPA sensitivity to negative feedback regulation (21, 22, 23, 24, 48, 49, 50). On the other hand, age-related differences in steroid concentrations in cerebrospinal fluid (CSF) have been reported (51), probably due to disturbances in the cortisol clearance rate in CSF and/or the blood-brain barrier in aging (52, 53). Accordingly, the rapid increase in circulating cortisol levels after an iv bolus might have produced a concomitant increase in CSF hormone concentrations in young, but not in old, subjects in our study. An age-related decrease in the MCR of cortisol (54, 55) might influence the feedback inhibition in the elderly. However, plasma cortisol concentrations throughout the test were the same in young and old subjects.

In conclusion, our data, although confirming previous findings, clearly demonstrate that differences between young and old age in ACTH inhibition pertain only to the fast feedback component of the curve. The patterns of response favor the hypothesis that age-related vascular factors may be involved in conveying a slower feedback message to central structures.

Footnotes

1 This work was supported in part by grants from MURST (60%) and Regione Veneto (Ricerca Sanitaria Finalizzata 545/01/94), Italy. Back

Received August 19, 1997.

Revised January 5, 1997.

Accepted January 8, 1997.

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Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study
J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 545 - 550.
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D. A. Gust, M. E. Wilson, T. Stocker, S. Conrad, P. M. Plotsky, and T. P. Gordon
Activity of the Hypothalamic-Pituitary-Adrenal Axis Is Altered by Aging and Exposure to Social Stress in Female Rhesus Monkeys
J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2556 - 2563.
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M. Bergendahl, A. Iranmanesh, T. Mulligan, and J. D. Veldhuis
Impact of Age on Cortisol Secretory Dynamics Basally and as Driven by Nutrient-Withdrawal Stress
J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2203 - 2214.
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C. R. Parker Jr., S. M. Slayden, R. Azziz, S. L. Crabbe, G. A. Hines, L. R. Boots, and S. Bae
Effects of Aging on Adrenal Function in the Human: Responsiveness and Sensitivity of Adrenal Androgens and Cortisol to Adrenocorticotropin in Premenopausal and Postmenopausal Women
J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 48 - 54.
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