Context: HPA axis is mainly regulated by CRH, AVP and glucocorticoid feedback. Hippocampal mineralcorticoid receptors (MRs) 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 DHEA secretion were studied in 8 healthy elderly subjects (ES, 75.1 ± 3.2 yr) and 8 young subjects (YS, 25.0 ± 4.6 yr) during placebo or canrenoate (CAN, 200 mg i.v. bolus followed by 200 mg infused over 4 h).

Results: During placebo, ACTH and cortisol AUCs in ES were higher than in YS (P 0.01); conversely, DHEA AUCs in ES were lower than in YS (P = 0.002). CAN increased ACTH, cortisol and DHEA levels in both groups. In YS, both ACTH, cortisol and DHEA levels at the end of CAN infusion were higher (P 0.05) than after placebo. In ES, 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 persisted higher (P 0.01) and DHEA AUCs lower (P = 0.006) in ES than in YS. Cortisol AUCs after CAN in YS did not become significantly different from those in ES after placebo.

Conclusions: i) evening-time ACTH and cortisol secretion in ES is higher than in YS; ii) ACTH and cortisol secretion in ES is enhanced by CAN but less than in YS; iii) DHEA hyposecretion in ES is partially restored by mineralocorticoid antagonism. Age-related variations of HPA activity may be determined by some derangement in MRs function at the hippocampal level.