The mineralocorticoid receptor agonist, fludrocortisone, inhibits pituitary-adrenal activity in humans after pre-treatment with metyrapone

Otte, Christian; Jahn, Holger; Yassouridis, Alexander; Arlt, Josef; Stober, Nina; Maass, P.; Wiedemann, Klaus; Kellner, Michael

doi:10.1016/s0024-3205(03)00513-7

Cited by 50 publications

(36 citation statements)

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“…It has been demonstrated that the hippocampal MRs display an important role in the glucocorticoid-mediated feedback control of HPA axis (3,11), and it is assumed that they mediate the 'proactive' feedback, which maintains the basal HPA activity, mainly at the nadir of the circadian rhythm (4,12). These findings are supported by studies indicating significant occupations of hippocampal MRs (50-70%) during the nadir of glucocorticoid secretion, while GRs are less occupied during the nocturnal nadir (13)(14)(15)(16). The functional role of MRs is proposed to proceed through tonic inhibitory projections to the paraventricular nucleus (PVN) of the hypothalamus (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 88%

“…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). On the other hand, the administration of a strong MR agonist, fludrocortisone, exerted a significant inhibitory effect on spontaneous cortisol levels during the nadir of the circadian rhythm (31), and abolished the stimulatory effect of metyrapone on ACTH and 11-deoxycorticosterone in humans (15,16).…”

Section: Introductionmentioning

confidence: 98%

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

Berardelli¹,

Karamouzis²,

Marinazzo³

et al. 2010

European Journal of Endocrinology

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Context: 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. Design: 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 mg/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. Results: 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. Conclusions: 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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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 98%

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

Berardelli¹,

Karamouzis²,

Marinazzo³

et al. 2010

European Journal of Endocrinology

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“…In healthy humans, blockade of the MR impaired memory and executive function in young healthy men and increased cortisol secretion (Cornelisse et al, 2011;Otte et al, 2007;Rimmele et al, 2013). Furthermore, MR stimulation with the agonist fludrocortisone inhibits cortisol secretion in humans (Buckley et al, 2007;Otte et al, 2003Otte et al, , 2010a. However, this inhibition is attenuated in patients with psychotic depression suggesting impaired MR function in these patients (Lembke et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid Receptor Stimulation Improves Cognitive Function and Decreases Cortisol Secretion in Depressed Patients and Healthy Individuals

Otte

Wingenfeld

Kuehl

et al. 2014

Neuropsychopharmacol

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Memory and executive function are often impaired in patients with major depression, while cortisol secretion is increased. Mineralocorticoid receptors (MR) are abundantly expressed in the hippocampus and in the prefrontal cortex, brain areas critical for memory, executive function, and cortisol inhibition. Here, we investigated whether MR stimulation with fludrocortisone (1) improves memory and executive function and (2) decreases cortisol secretion in depressed patients and healthy individuals. Twenty-four depressed patients without medication and 24 age-, sex-, and education-matched healthy participants received fludrocortisone (0.4 mg) or placebo in a randomized, double-blind, within-subject cross-over design. We measured verbal memory, visuospatial memory, executive function, psychomotor speed, and salivary cortisol secretion during cognitive testing between 1400 and 1700 hours. For verbal memory and executive function, we found better performance after fludrocortisone compared with placebo across groups. No treatment effect on other cognitive domains emerged. Depressed patients performed worse than healthy individuals in psychomotor speed and executive function. No group effect or group Â treatment interaction emerged on other cognitive domains. Fludrocortisone decreased cortisol secretion across groups and there was a significant correlation between cortisol inhibition and verbal memory performance. Our data suggest a crucial role of MR in verbal memory and executive function and demonstrate the possibility to improve cognition in depressed patients and healthy individuals through MR stimulation.

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“…For instance, HPA axis activity is in large part controlled by the balance between mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) (Young et al, 2003;Otte et al, 2003;Spencer et al, 1998;Trapp and Holsboer, 1996;Kalman and Spencer, 2002). An imbalance between the two receptors has been postulated to play a major role in untoward responses to stress and the development of major depression (Young et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…An imbalance between the two receptors has been postulated to play a major role in untoward responses to stress and the development of major depression (Young et al, 2003). MR binds with high affinity to cortisol and has been shown to be involved in the regulation of both the peak and nadir of the circadian rhythm, respectively, the morning and evening in humans (Young et al, 2003;Otte et al, 2003;Kalman and Spencer, 2002). Decreased MR sensitivity has been hypothesized as occurring in major depression (Oitzl et al, 1995;Gesing et al, 2001;Young et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Clinical and Biological Effects of Mifepristone Treatment for Psychotic Depression

Flores

Kenna

Keller

et al. 2005

Neuropsychopharmacol

186

106

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Psychotic major depression (PMD) is found to be a relatively common psychiatric condition that affects up to nearly 20% of patients with major depression. Previous studies by our group have shown rapid reversal of psychotic symptoms in some PMD patients treated with mifepristone, in addition to restoring a more normal afternoon cortisol release. The rationale for treating patients with PMD with a glucocorticosteroid receptor antagonist is further discussed. In total, 30 patients with PMD were treated with either 600 mg/day mifepristone or placebo for 8 days in a randomized double-blind manner. The Hamilton Depression Rating Scale (HDRS) and the Brief Psychiatric Rating Scale (BPRS) were administered at baseline and again after 8 days of treatment. Cortisol and ACTH were measured hourly from 1800 to 0900 at baseline and after 8 days of treatment. Significantly, more patients in the mifepristone group (seven of 15) showed a 50% or greater decline on the BPRS positive symptom subscale, an index of psychotic symptoms, as compared to the placebo group (two of 15). Patients who received mifepristone had lower HDRS and BPRS scores at study completion compared to those who received placebo, but these differences were not statistically significant. In addition, mifepristone significantly elevated cortisol and ACTH levels and steepened ascending slopes from 1800 to 0100 and from 0100 to 0900 as compared to placebo. Clinical and biological effects of mifepristone were comparable among males and females. Age was found to significantly and positively correlate with changes in cortisol and ACTH. These results suggest that short-term use of mifepristone may be effective in the treatment of PMD and may reregulate the HPA axis. Additional blinded studies are warranted.

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The mineralocorticoid receptor agonist, fludrocortisone, inhibits pituitary-adrenal activity in humans after pre-treatment with metyrapone

Cited by 50 publications

References 38 publications

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

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

Mineralocorticoid Receptor Stimulation Improves Cognitive Function and Decreases Cortisol Secretion in Depressed Patients and Healthy Individuals

Clinical and Biological Effects of Mifepristone Treatment for Psychotic Depression

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