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Human glucocorticoid feedback inhibition is reduced in older individuals: evening study
C W Wilkinson1, E C Petrie, S R Murray
1Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington 98108, USA. wilkinso@u.washington.edu
Abstract:
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.
Insights
Older adults show impaired negative feedback of the hypothalamic-pituitary-adrenal axis, leading to prolonged exposure to stress hormones like cortisol. This age-related blunting of adrenocorticotropic hormone (ACTH) suppression affects both men and women.
Area of Science:
- Endocrinology
- Neuroscience
- Gerontology
Background:
- Aging is associated with altered stress hormone regulation.
- Previous studies indicated age-related delays in ACTH suppression in the morning.
Purpose of the Study:
- To confirm morning findings in the evening.
- To investigate if aging-related feedback changes are exaggerated near the circadian nadir of cortisol secretion.
Main Methods:
- Healthy young (20-35 yrs) and old (>65 yrs) participants received metyrapone to block cortisol synthesis.
- A cortisol infusion was administered, followed by frequent blood sampling for 4 hours.
- Plasma levels of ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin were measured.
Main Results:
- After correcting for circulating cortisol levels, feedback inhibition of ACTH was significantly blunted in older adults compared to younger adults.
- This age-related difference was observed in both men and women.
Conclusions:
- Aging is associated with impaired negative feedback control of the hypothalamic-pituitary-adrenal axis.
- Blunted and delayed ACTH inhibition in older individuals may lead to prolonged glucocorticoid exposure during stress.