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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 545-550
Copyright © 2001 by The Endocrine Society

From the Clinical Research Centers

Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study1

CHARLES W. WILKINSON, ERIC C. PETRIE, SHARON R. MURRAY, ELIZABETH A. COLASURDO, MURRAY A. RASKIND and ELAINE R. PESKIND

Geriatric Research, Education, and Clinical Center (C.W.W., E.A.C.); Mental Illness Research, Education, and Clinical Center (M.A.R., E.R.P.); Mental Health (E.C.P., S.R.M., M.A.R.), VA Puget Sound Health Care System, Seattle, Washington 98108; and Department of Psychiatry and Behavioral Sciences (C.W.W., E.C.P., M.A.R., E.R.P.), University of Washington, Seattle, Washington 98195

Address correspondence and requests for reprints to: Dr. Charles W. Wilkinson, GRECC (182B), VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, Washington 98108. E-mail: wilkinso{at}u.washington.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We have previously shown that when tested in the morning, older men and women, pretreated with metyrapone to block endogenous cortisol synthesis, exhibit delayed suppression of plasma ACTH in response to cortisol infusion. To confirm this finding and to determine whether aging-related changes in feedback responsiveness are exaggerated near the time of the circadian nadir in adrenocortical secretion, we performed a similar study in the evening. Healthy young (20–35 yr, n = 22) and old (>65 yr, n = 21) men and women were administered metyrapone orally (750 mg) at 1600 and 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Blood samples were taken at 15-min intervals for 4 h following infusion onset for measurement of plasma ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin. When corrections were made for differences in circulating cortisol concentrations achieved among age and gender subgroups, feedback inhibition of ACTH was found to be significantly greater in young than in old subjects of both genders. Our studies support the hypothesis that glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus increasing the total exposure to glucocorticoids.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AGING IN RODENTS has been found to result in prolonged glucocorticoid responses to stress and impaired feedback inhibition of ACTH secretion by glucocorticoids (1, 2, 3). These age-related modifications of hypothalamic-pituitary-adrenal (HPA) function have been linked to deficits in learning and memory (4, 5, 6). Until recently, it has not been clear whether similar changes occur in the human HPA axis during aging. Several groups have reported age-associated increases in resting cortisol levels, especially near the nadir of the cortisol circadian rhythm (7, 8, 9, 10, 11, 12, 13, 14, 15, 16). The magnitude of pituitary-adrenal responses to ovine corticotropin-releasing factor (CRF) has generally not been found to change with aging in humans (17, 18). However, when human CRF has been used to provoke the HPA axis, greater ACTH and cortisol responses have been found in older individuals (19, 20), both with and without concurrent administration of arginine vasopressin (19).

Impairment of glucocorticoid feedback inhibition of ACTH secretion, one of the primary age-related changes in HPA function reported in animal studies, has been supported by some, but not all, human studies. Pavlov et al. (17) concluded that the finding of a trend toward increased ovine CRF-stimulated levels of plasma ACTH and cortisol in older subjects in the face of age-related increases in resting cortisol was "consistent with the hypothesis that aging is associated with decreased pituitary sensitivity to negative feedback regulation by glucocorticoids."

Studies of age-related changes in feedback inhibition using dexamethasone have reported age-related impairments (11, 20, 21, 22, 23, 24, 25, 26) or no change (18, 27, 28, 29). In these studies, dexamethasone was administered orally, cortisol was generally measured 9 or more hours after dexamethasone administration, and ACTH responses were measured only by Waltman et al. (18). These studies do not provide information regarding the time course of the rapid effects of glucocorticoid feedback inhibition involved in the regulation of ACTH secretion (30). Furthermore, the use of dexamethasone to evaluate relative differences in feedback sensitivity is complicated by the fact that the effects of dexamethasone, unlike the endogenous glucocorticoids, are mediated primarily at the pituitary rather than the central nervous system (30, 31, 32, 33), and the affinities of corticosteroid receptors for dexamethasone differ considerably from those for cortisol (34).

We have previously demonstrated directly that responsiveness to glucocorticoid negative feedback is decreased in the elderly by showing that older men and women, pretreated with metyrapone, exhibit delayed and blunted suppression of plasma ACTH in response to infusion of cortisol in the morning (35). These findings have been supported by another group using a different experimental approach (36). In light of findings that alterations of glucocorticoid circadian rhythms and stress responsiveness in depression, chronic stress, and aging seem to be particularly affected during the evening hours near the nadir of the glucocorticoid rhythm (11, 12, 16, 37, 38, 39, 40), we have now used our protocol of oral metyrapone administration, followed by cortisol infusion, to investigate the hypothesis that age-related changes in glucocorticoid feedback inhibition are further accentuated in the evening.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Experimental subjects

The study was approved by the Human Subjects Review Committee of the University of Washington, and written informed consent was obtained from all subjects. A total of 22 young (28 ± 1 yr old) and 21 older (74 ± 1 yr old) subjects of both genders underwent two study conditions in random order. All young women were studied within days 5–12 of the start of their menstrual cycle. All older women were postmenopausal. No subjects were taking oral contraceptives or hormone replacement at the time of the study. Subjects were nonsmoking community volunteers in excellent general health. Exclusionary criteria included history of psychiatric disorders, alcoholism, or drug abuse, presence of current major depressive episode or neurological diagnoses likely to affect cognitive function, and unstable medical problems including unstable heart disease, uncontrolled hypertension, diabetes in poor control, respiratory disease complicated by hypoxia or hypercapnia, infectious illness, or unstable thyroid dysfunction. Subjects who had undergone a major life event such as a change in residence within the past month or death of a close family member within the past 6 months were excluded. All subjects were free of medications known to affect the HPA axis or cognitive function. Complete blood counts and blood chemistries were performed on samples from all subjects. All were within 25% of ideal body weight (1983 Metropolitan Life Insurance tables). Studies were conducted in a clinical research unit at the VA Puget Sound Health Care System in Seattle.

Materials and methods

Each subject was studied in an active drug condition and a placebo condition in random order. Subjects were blind with respect to study condition. In the experimental condition, subjects were administered 750 mg metyrapone (Metopirone, Ciba-Geigy & Co., Whitehouse Station, NJ) p.o. at 1600 h and again at 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Metyrapone suppresses endogenous cortisol by inhibiting the conversion of 11-deoxycortisol to cortisol by 11ß-hydroxylase. In the control condition, subjects received placebo tablets at 1600 and 1900 h, followed by measurement of baseline hormone levels. Details of the protocols were: subjects fasted from 1000 h on each study day and were maintained at bed rest throughout the study. At 1830 h, an iv catheter was placed in an antecubital vein of each arm and kept patent with a slow infusion of normal saline. One iv catheter was used for blood sampling and the other for infusion. At 1855 and 1900 h, baseline blood samples were drawn for measurement of ACTH, cortisol, and 11-deoxycortisol. Measurement of 11-deoxycortisol was used to affirm the efficacy of the metyrapone in blocking cortisol synthesis. The placebo condition was ended after the withdrawal of the second baseline blood sample, and no infusion was made.

In the metyrapone condition beginning at 1900 h, cortisol (hydrocortisone phosphate injection; Merck, Summit, NJ) was infused at 0.06 mg/kg/h (166 nmol/kg/h) in 300 mL normal saline over 150 min. This was followed by slow infusion (50 mL/h) of normal saline for 90 min. Blood sampling (10 mL/sample) occurred every 15 min for 240 min following baseline.

Plasma ACTH was measured by immunoradiometric assay kits from Nichols Institute Diagnostics (San Juan Capistrano, CA). The detection limit of the assay is 3 pg/mL (0.7 pmol/L), and the intra- and interassay coefficients of variation are 7.2 and 12.3%, respectively.

Cortisol was measured by RIA in unextracted plasma. Samples were diluted with phosphate buffer and heated for 20 min at 80 C to denature binding globulins. Cortisol antiserum was obtained from ICN Biomedicals, Inc. (Costa Mesa, CA). Cross-reactivity of the antiserum with 11-deoxycortisol is 10%. Assay values for cortisol were corrected by subtracting 10% of the 11-deoxycortisol values for each sample. The detection limit for cortisol is 10 pg/mL (28 pmol/L); the intra- and interassay coefficients of variation are 8.1 and 13.8%, respectively.

Plasma 11-deoxycortisol was measured by RIA in unextracted plasma, to which steroid binding globulin inhibitor was added. Antiserum, standards, and 125I-labeled 11-deoxycortisol were obtained from ICN Biomedicals, Inc., and a modification of the commercial protocol was used. Cross-reactivity of the antiserum with cortisol is 0.14%. Minimum sensitivity of the assay is 0.5 ng/mL (1.4 nmol/L). The intra- and interassay coefficients of variation were 9.1 and 14.4%, respectively.

Plasma corticosteroid binding globulin (CBG) was measured by radial immunodiffusion (The Binding Site, San Diego, CA) as described previously (35). Minimum sensitivity of the assay is 8 mg/L (154 nmol/L). The intra- and interassay coefficients of variation were 3.1 and 5.0%, respectively.

Metyrapone treatment was judged to be effective for a given subject if the treatment resulted in at least a 2-fold increase in the plasma 11-deoxycortisol to cortisol ratio and an increase in plasma ACTH concentration. A total of 35 of 43 subjects (8–9 in each age-gender combination) met these criteria and were included in the data analysis.

Postmetyrapone (or postplacebo) baseline values for ACTH, cortisol, and 11-deoxycortisol were calculated as the means of the concentrations in the two plasma samples collected just prior to starting the cortisol infusion (or in the placebo condition, just prior to terminating the session).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Plasma ACTH concentration was significantly suppressed in both young and old subjects by 60 min after the beginning of the cortisol infusion (as determined by the difference in ACTH concentration between postmetyrapone baseline and each subsequent time point by single group t test; Fig. 1Go). When each gender group was analyzed separately, young men showed a more rapid suppression than old men (significant difference from ACTH baseline at 75 min vs. 90 min), but older women exhibited a more rapid decline in ACTH than young women (45 vs. 90 min; Fig. 2Go). The postmetyrapone baseline levels of ACTH and the rate of decrease of ACTH concentration were higher in the young women, but the variability was also high in this group. The same relationships occurred if percentage change in ACTH concentration rather than absolute concentration change was analyzed, except that differences between young and older women were reduced. The percentage change in plasma ACTH differed significantly from zero at 45 min for the older women and at 60 min for the young women (single group t test).



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  		Figure 1. Plasma ACTH concentration in young (n = 18) and old (n = 17) metyrapone-treated subjects during and after cortisol infusion. *, Time for each age group at which the fall in ACTH concentration below the postmetyrapone baseline first differs significantly from zero by one group t test.

 


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  		Figure 2. Plasma ACTH concentration in metyrapone-treated young and old women (top) and young and old men (bottom) during and after cortisol infusion [0.06 mg/kg/h (166 nmol/kg/h)]. *, Time for each age group at which the fall in ACTH concentration below the postmetyrapone baseline first differs significantly from zero by one group t test. Young women, n = 9; old women, n = 9; young men, n = 9; old men, n = 8. Flags indicate SEM.

 
Comparison of peak plasma cortisol concentrations achieved as a result of the cortisol infusion with cortisol responses elicited in clinical test procedures shows that the cortisol levels reached in this study were below the range of peak values normally observed in response to the standard short Synacthen test or insulin tolerance test, and the rate of increase in circulating cortisol was markedly slower (2–3 nmol/L/min compared with 7–10 nmol/L/min for short Synacthen test and insulin tolerance test; Refs. 41, 42, 43). Comparison of plasma cortisol levels between young and old subjects showed that greater plasma cortisol levels were achieved as a result of the cortisol infusion in old subjects than in young subjects and that women achieved consistently higher plasma cortisol levels than men (Fig. 3Go). Two-way ANOVA for repeated measures revealed significant main effects of age and gender, but no significant age-gender interaction (age: F = 6.20, P < 0.02; gender: F = 10.03, P < 0.005; age-gender interaction: F = 0.00, P = 0.99). Baseline cortisol concentrations did not differ among the age-gender groups in either the placebo or metyrapone pretreatment condition.



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  		Figure 3. Total plasma cortisol concentration in metyrapone-treated subjects during and after cortisol infusion [0.06 mg/kg/h (166 nmol/kg/h)]. Flags indicate SEM.

 
In view of the possibility that age differences in total plasma cortisol concentration were due to differences in bound cortisol rather than in biologically active free cortisol, plasma CBG was measured in two samples from each subject in each experimental session. There was no effect of age on plasma CBG concentration, but despite the exclusion of subjects taking oral contraceptives or estrogen replacement therapy, CBG concentrations were higher in women than in men (age x gender ANOVA: age, F = 1.76, P = 0.19; gender, F = 19.24, P < 0.001). This gender difference was also significant within each age group (t tests: young women vs. young men, t = 2.55, P < 0.05; old women vs. old men, t = 3.72, P < 0.005; see Fig. 4Go). Free cortisol concentration for each subject for each time point was estimated by the method of Coolens et al. (44). A nearly significant age-related difference in free cortisol was found, similar to that described above for total cortisol (age x gender ANOVA for repeated measures: age, F = 3.67, P = 0.06; gender, F = 1.16, P = 0.29).



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  		Figure 4. Plasma CBG concentration in metyrapone-treated subjects. CBG was measured in the first (time, -5 min) and last (time, +240 min) sample from each subject, and the mean of the two determinations for each subject was used to calculate group means and SEM.

 
To produce a measure of feedback responsiveness adjusted for differences in free cortisol concentration achieved among groups, we calculated the ratio of the change in ACTH (relative to baseline) to the change in calculated free cortisol concentration at each time point during the period of dynamic ACTH changes (from 75–150 min). To take into account the time lag between the increase in plasma cortisol and the subsequent fall in ACTH levels, the change in ACTH concentration at a given time point was divided by the change in plasma free cortisol concentration 30 min earlier to provide a "feedback responsiveness index" (Fig. 5Go). The ratio of ACTH suppression to increment of free cortisol increase was significantly higher in the young subjects (F = 5.22, P < 0.05, by ANOVA for repeated measures). When compared by t tests at individual time points, this ratio was significantly greater in young than in old subjects at 105, 120, 135, and 150 min (time of ACTH sample in the ratio). The same relationship held for each of the gender groups analyzed separately.



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  		Figure 5. Index of responsiveness of ACTH to feedback inhibition by cortisol. The index is calculated by dividing the change in plasma ACTH concentration from baseline at each time point by the change in plasma free cortisol achieved 30 min earlier. Flags indicate SEM.

 
There was no significant effect of age or gender and no significant interaction of the two on plasma 11-deoxycortisol concentrations (ANOVA for repeated measures). There was a tendency for 11-deoxycortisol levels to be higher in young subjects than in old subjects (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this evening study confirm our earlier results from a morning study, indicating that feedback inhibition of plasma ACTH concentration by cortisol is diminished in older individuals. This age-related reduction in glucocorticoid feedback inhibition was determined by measurement of: 1) the initial time at which plasma ACTH concentration decreased significantly in response to cortisol infusion; and 2) the relative magnitude of the decline in ACTH concentration for a given increment in plasma cortisol concentration. The latency for a significant decrement in ACTH concentration was significantly longer in older men than in young men. Women exhibited an apparent moderate reversal of age relationships in that older women reached significant levels of ACTH inhibition earlier than young women in the evening study. This apparent reversal, however, was at least partially due to the higher plasma cortisol levels (i.e. a greater feedback signal) achieved in older women. When results are expressed as the ratio of the fall in ACTH concentration at each time point to the increase in free plasma cortisol generated 30 min earlier by cortisol infusion, consistent and pronounced decrements in ACTH feedback responsiveness to cortisol in older individuals are found when compared with young subjects in both the morning and the evening (Fig. 6Go).



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  		Figure 6. Comparison of index of responsiveness of ACTH to feedback inhibition by cortisol between morning and evening studies. For the morning study, n = 16 for young subjects and n = 15 for old subjects. Flags indicate SEM.

 
It is not clear whether increased plasma cortisol levels achieved in women and in older subjects, in general, as a result of the cortisol infusion are due entirely to the measured differences in CBG concentration or partially to differences in cortisol metabolism or distribution volume among groups. However, the consistent rates of decline in plasma cortisol concentration after the termination of the infusion suggest that metabolic clearance does not differ appreciably with age or gender.

One of the questions to be addressed by this study was that of human nycthemeral differences in feedback sensitivity to cortisol inhibition. The answer is complex. When the latency to significant decreases in ACTH concentration are compared between morning and evening subjects, it is clear that a significant feedback-elicited decline in plasma ACTH occurs more rapidly in the evening than in the morning. This finding holds for every gender-age group, except the young males (see Table 1Go). However, when the magnitude of the decrease in ACTH concentration to a given increase in plasma free cortisol is compared between morning and evening, the effectiveness or potency of feedback inhibition is greater in the morning for young subjects and not different for old subjects (Fig. 6Go). Our interpretation of these data is that the "threshold" change in cortisol concentration necessary to initiate feedback inhibition is lower in the evening than in the morning, but once inhibition is initiated, the magnitude of the inhibition for a given change in level of circulating cortisol is greater in the morning. Although an age-related difference in feedback inhibition was found in both morning and evening studies, the magnitude of the difference was much greater in the morning for both genders (Fig. 7Go).


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  		Table 1. Time (in minutes after the onset of the cortisol infusion) at which the change in plasma ACTH concentration is significantly different from zero (the postmetyrapone baseline) by one group t test, P < 0.05

 


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  		Figure 7. The mean index of responsiveness across all time points between 75 and 150 min was calculated for each subject. Means and SEM for those values are indicated for young and old subjects in the morning and evening studies. ACTH and free cortisol concentrations are expressed in nmol/L.

 
Suppression of plasma cortisol by dexamethasone has also been found to be impaired as a function of increasing age (11, 20, 21, 22, 23, 24, 25, 26), although other studies have failed to find a relationship (18, 27, 28, 29). Dexamethasone differs from the endogenous glucocorticoid cortisol in its affinities for corticosteroid receptor subtypes (34) and the HPA axis level at which feedback inhibition primarily occurs (30, 31, 32, 33). Direct comparisons in human subjects have indicated discordant feedback responses to cortisol and dexamethasone (45, 46), and, thus, use of dexamethasone may not accurately characterize the effects of aging on feedback inhibition by endogenous glucocorticoids.

Gender differences and gender-age interactions in HPA responses to challenge have been found by several groups (e.g. Refs. 47, 48, 49), but relatively few studies have investigated gender differences in human glucocorticoid feedback inhibition directly. Gallucci et al. (50) found that young women showed more sustained elevations of cortisol to released ACTH than young men, "suggesting relatively greater resistance to cortisol feedback" in women. Studies using dexamethasone have found that women exhibit significantly greater (20), slightly greater (26), or no different (29) cortisol suppression than men. In this study, we found neither gender differences nor age-gender interactions in the ratio of ACTH inhibition to circulating free cortisol concentration (Fig. 5Go). However, data from our previous morning study indicate resistance to glucocorticoid feedback inhibition in both young and older women in comparison with same age-group men (35).

In conclusion, this study of age-related responsiveness to glucocorticoid feedback inhibition in the evening confirms our earlier morning study in showing deficits in suppression of ACTH secretion in older subjects. Differences in results between the two studies indicate that not only gender, but time of day, influences the expression of age-related reductions in feedback sensitivity. These studies support the assertion that in humans, as well as in rodents, glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus heightening the probability that integrated levels of glucocorticoid exposure are elevated with increasing age.


   Acknowledgments
 
We thank Molly Wamble, Shannon Boldt, Richard Vertz, Rebekah Rein, Carl Sikkema, and Robert Beckham, III, for excellent technical assistance.


   Footnotes
 
1 Supported by the Department of Veterans Affairs. Back

Received December 16, 1999.

Revised October 2, 2000.

Accepted October 18, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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