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

Abstract

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.

Effect of acute and prolonged mineralocorticoid receptor blockade on spontaneous and stimulated hypothalamic–pituitary–adrenal axis in humans

“…The results of our study demonstrate that mineralocorticoid antagonism by CAN significantly enhances the activity of HPA axis in the afternoon, during the quiescent phase of the circadian rhythm, similarly to what was observed previously in the early night hours, at the nadir of the HPA activity (5,6,28,32). They also show that prolonged treatment with CAN is able to clearly amplify both spontaneous and CRH-stimulated activities of the HPA axis during the same phase of the circadian rhythm, while it significantly blunts the HPA Different studies have clearly reported that MRs located at the hippocampal level play an important role in the regulation of the glucocorticoid feedback control of the HPA axis (3,4,7).…”

“…This could simply reflect the chronic MR occupation during CAN treatment before acute infusion, but the occurrence of an intrinsic modification can also be hypothesized, including the downregulation of these hippocampal receptors after prolonged MR binding, similar to that observed during prolonged glucocorticoid binding (14,34). These findings are similar to observations in aging, where, as a consequence of an impairment of hippocampal MR activity, HPA function is hyperactivated and MR antagonists show a reduced stimulatory effect (4,28).…”

“…On the other hand, the data about the systemic administration of MR antagonists in humans showed controversial results. Specifically, previous studies have demonstrated that MR occupation by spironolactone and CAN has a stimulatory effect on HPA activity (5,6,(24)(25)(26)28), while others have reported only an increase in cortisol levels without an enhanced corticotroph secretion both basally and after CRH administration (23,29). These contradictory results may be due to the use of different doses, routes of administration, and phases of the circadian rhythm in which the studies have been performed.…”

“…In humans, the administration of spironolactone, a MR antagonist, increased cortisol secretion both during the peak and during the trough of the circadian rhythm of the HPA axis (23,24). Moreover, the systemic administration of another and more selective MR antagonist, canrenoate (CAN), which easily penetrates the blood-brain barrier, induced a significant increase in ACTH, cortisol, and DHEA levels during the nadir of the HPA rhythm in normal young subjects, suggesting that hippocampal MRs are widely involved in the regulation of the basal activity of the HPA axis in humans (5,6,(25)(26)(27)(28)(29)(30). There is also evidence that MR antagonists enhance the ACTH, cortisol, and DHEA responses to both CRH and AVP stimulations, thus indicating that the stimulatory effect of MR blockade is probably mediated by concomitant modulation of both CRH and AVP (5,23,29).…”

Aging and Subclinical Thyroid Dysfunction

“…In contrast the glucocorticoids produced in the adrenal cortex fasciculate layer tend to be more responsive to stimuli, have a slightly delayed clearance rate, and are less entrained to the circadian phase in aged subjects than in young ones. Although not all authors agree [6], most report that healthy elder subjects have higher cortisol levels presumably in response to increased corticotrophin (ACTH) secretion [7,8]. It is difficult to evaluate -in humans -if this discordance is gender-related.…”