Hypothalamus-pituitary-adrenal hyperactivity in human aging is partially refractory to stimulation by mineralocorticoid receptor blockade.
BACKGROUND
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.


METHODS
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 i.v. 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 < or = 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 < or = 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 < or = 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.
Giordano
Roberta
R
Division of Endocrinology and Metabolism, Department of Internal Medicine, Ospedale Molinette, University of Turin, Italy.
Bo
Mario
M
Pellegrino
Micaela
M
Vezzari
Marco
M
Baldi
Matteo
M
Picu
Andreea
A
Balbo
Marcella
M
Bonelli
Lorenza
L
Migliaretti
Giuseppe
G
Ghigo
Ezio
E
Arvat
Emanuela
E
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D002191:Canrenoic Acid / Q000009:adverse effects / Q000494:pharmacology; D002940:Circadian Rhythm / Q000502:physiology; D003687:Dehydroepiandrosterone / Q000097:blood; D004351:Drug Resistance; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000254:growth & development*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000254:growth & development*; D013148:Spironolactone / Q000009:adverse effects / Q000494:pharmacology; D013268:Stimulation, Chemical
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D003687:Dehydroepiandrosterone; D002191:Canrenoic Acid; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone