Berardelli R, Karamouzis I, Marinazzo E, Prats E, Picu A, Giordano R et al. Effect of acute and prolonged mineralocorticoid receptor blockade on spontaneous and stimulated hypothalamic-pituitary-adrenal axis in humans. Eur J Endocrinol 162: 1067-1074

Division of Endocrinology, Diabetology and Metabolism, Department of Internal Medicine, University of Turin, Ospedale S. Giovanni Battista-Molinette, Dogliotti 14, Turin, Italy.
European Journal of Endocrinology (Impact Factor: 4.07). 03/2010; 162(6):1067-74. DOI: 10.1530/EJE-09-1076
Source: PubMed


Mineralocorticoid receptors (MRs) in the hippocampus display an important role in the control of the hypothalamic-pituitary-adrenal (HPA) axis, mediating the proactive feedback of glucocorticoids, which maintains the basal HPA activity. The systemic administration of MR antagonists enhances spontaneous and CRH-stimulated ACTH, cortisol, and DHEA secretion, while the effects of chronic treatment with MR antagonists are scanty. Our study was performed in order to clarify this point.
ACTH, cortisol, and DHEA levels were studied during the infusion of placebo, canrenoate, a MR antagonist (CAN, 200 mg i.v. bolus at 1600 h followed by 200 mg infused over 4 h), and human CRH (hCRH; 2.0 microg/kg i.v. bolus at 1800 h) before and during the last week of 28-day treatment with CAN (200 mg/day p.o.) in eight young women.
Pre-treatment sessions: CAN and hCRH administration increased ACTH, cortisol, and DHEA levels versus placebo (P<0.05). Post-treatment sessions: during placebo infusion, cortisol and DHEA were significantly amplified versus pre-treatment session (P<0.05), while ACTH levels were not modified; CAN infusion, differently from pre-treatment session, was not able to significantly increase ACTH, cortisol, and DHEA levels; ACTH, cortisol, and DHEA responses to hCRH were amplified with respect to pre-treatment session, although statistical significance was obtained for cortisol and DHEA only.
MR blockade by acute CAN administration significantly enhances the HPA activity in the afternoon, during the quiescent phase of the circadian rhythm. At the same period, prolonged treatment with CAN amplifies both spontaneous and CRH-stimulated activities of the HPA axis, while it blunts the HPA responsiveness to a further MR-mediated stimulation.

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    • "Therefore, it has been suggested that the MR may be more influential during the nocturnal nadir of plasma cortisol via tonic inhibitory projection to the paraventricular nucleus (PVN) of the hypothalamus which leads to reduced CRH secretion (Jacobson De Kloet et al., 1998). Several MR challenge studies using antagonists (Dodt et al., 1993; Deuschle et al., 1998; Arvat et al., 2001; Berardelli et al., 2010) and agonist (Otte et al., 2003aOtte et al., , 2003b Buckley et al., 2007; Karamouzis et al., 2013) have demonstrated the importance of the MR in HPA regulation during late afternoon and early night. Data regarding HPA axis during night sleep beyond midnight are rare and conflicting (Steiger et al., 1993; Wiedemann et al., 1994; Groch et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Nocturnal hyperactivity of hypothalamic-pituitary-adrenal axis (HPA) indicates decreased feedback inhibition with stress-related conditions such as major depression and sleep disorders. To characterize the role of mineralocorticoid (MR) in regulation of HPA axis activity during nocturnal sleep and involvement in sleep architecture, we investigated sleep endocrine effects of the MR agonist fludrocortisone in healthy men after pretreatment with metyrapone to minimize the impact of endogenous cortisol. Subjects (n=8) were treated on three occasions in a single-blinded design in random order with a) metyrapone, b) fludrocortisone after metyrapone, and c) placebo. Polysomnography was recorded and blood samples were drawn for determination of adrenocorticotropic hormone (ACTH) and cortisol during the entire night. After metyrapone administration ACTH was significantly enhanced, while overall nocturnal cortisol secretion remained largely unchanged. Whereas administration of fludrocortisone induced a significant inhibitory effect on basal ACTH and cortisol secretion, no considerable effects on sleep pattern were detectable. While the involvement of MR in sleep regulation needs further study, endocrine findings underline the role of MR in tonic regulation of HPA axis during nocturnal sleep and demonstrate the ability of fludrocortisone to further suppress HPA axis activity overnight. Additional studies would be required to evaluate endocrine and clinical fludrocortisone effects in depressive patients showing HPA hyperactivity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Feb 2015 · Psychiatry Research
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    • "However, biological effects of stress hormones are still not completely elucidated, although their role in complex interrelation of endocrine, metabolic, immune, neurological and cardiovascular system in stress situations is based on assumption [95]. To achieve complex regulatory role, HPA axis interacts with hypothalamo–pituitary–thyroid axis, hypothalamo–pituitary–gonad axis, hypothalamo–pituitary–growth hormone axis [48,60], brain serotonergic, noradrenergic and dopaminergic systems [72] and renin–angiotensin–aldosterone system [9,31] . In addition, putative role of several peptides in these complex regulations and interaction is under investigation. "
    Full-text · Dataset · Oct 2013
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    • "blockade, stress responses, and memory S Cornelisse et al basal cortisol levels after spironolactone administration. Although MR blockade was previously reported to increase cortisol levels during rest at both the peak and the trough of the circadian rhythm (Young et al, 1998) as well as during physical exercise (Wellhoener et al, 2004) and in response to dexamethasone suppression/corticotrophin releasing hormone stimulation (Berardelli et al, 2010; Heuser et al, 2000), its effect on psychosocial stress responses was unknown. We can now report that cortisol responses to psychosocial stress are increased after spironolactone compared with placebo treatment. "
    [Show abstract] [Hide abstract] ABSTRACT: Corticosteroids, released in high amounts after stress, exert their effects via two different receptors in the brain: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). GRs have a role in normalizing stress-induced effects and promoting consolidation, while MRs are thought to be important in determining the threshold for activation of the hypothalamic-pituitary-adrenal (HPA) axis. We investigated the effects of MR blockade on HPA axis responses to stress and stress-induced changes in cognitive function. In a double-blind, placebo-controlled study, 64 healthy young men received 400 mg of the MR antagonist spironolactone or placebo. After 1.5 h, they were exposed to either a Trier Social Stress Test or a non-stressful control task. Responses to stress were evaluated by hormonal, subjective, and physiological measurements. Afterwards, selective attention, working memory, and long-term memory performance were assessed. Spironolactone increased basal salivary cortisol levels as well as cortisol levels in response to stress. Furthermore, spironolactone significantly impaired selective attention, but only in the control group. The stress group receiving spironolactone showed impaired working memory performance. By contrast, long-term memory was enhanced in this group. These data support a role of MRs in the regulation of the HPA axis under basal conditions as well as in response to stress. The increased availability of cortisol after spironolactone treatment implies enhanced GR activation, which, in combination with MR blockade, presumably resulted in a decreased MR/GR activation ratio. This condition influences both selective attention and performance in various memory tasks.
    Full-text · Article · Aug 2011 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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