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

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.

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.