In aged humans, diminished mineralocorticoid receptor (MR)-mediated feedback in the brain could contribute to impaired feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis, but no study specifically compared young and old individuals with regard to MR function. We examined 10 healthy young (mean age +/- SD [standard deviation] 26.1 +/- 2.9 years) and 10 elderly men (68.3 +/- 4.7 years) at the nadir of cortisol levels (2:00 pm-9:00 pm) when HPA activity is mainly controlled by the MR. After pretreatment with 3 g metyrapone to minimize the impact of basal endogenous cortisol secretion, participants received orally, in randomized order on two separate occasions, either 0.5 mg of the MR agonist fludrocortisone or placebo. Fludrocortisone significantly decreased maximum adrenocorticotropic hormone (ACTH) and cortisol concentrations in both groups. ACTH and cortisol values after fludrocortisone were significantly higher in older men compared with young men. Our results implicate that a decrease in MR-mediated negative feedback contributes to the diminished feedback activity in older humans.
