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 μg/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.

Objective: We evaluated the safety and efficacy of metyrapone treatment for Cushing's syndrome (CS). Design: International, prospective, single-arm, open-label study. Methods: Fifty adults with endogenous CS (either unsuitable for or uncontrolled after surgery) and 3 urinary free cortisol (UFC) concentrations each ≥1.5-fold the upper limit of normal (ULN) were enrolled. After 12 weeks of metyrapone titration, participants with mean 24 h UFC (mUFC) ≤ 2-fold ULN could enter a 24-week extension phase. Safety was assessed, and doses adjusted at weeks 1-5, 8, 12, and 24. Pre-defined endpoints included normalization of mUFC at weeks 12 (primary), 24, and 36, and proportion of “responders” (normalization or ≥50% decrease of baseline mUFC), time to eucortisolemia, salivary cortisol day-curve, and quality of life (QoL). Results: Of the 49 evaluable participants, 47 completed the 12-week visit; 40 were evaluated at week 24 and 35 at week 36. The primary endpoint was met in 46.9% of participants (95% CI 32.5%-61.7%), with efficacy maintained at week 24 (52.5%; 95% CI 37.5%-67.1%) and week 36 (48.6%; 95% CI 33.0%-64.4%). The responder rates were 80.9%, 77.5%, and 71.4% at weeks 12, 24, and 36, respectively. Forty-seven participants (94%) developed mild-to-moderate adverse events (AEs), mostly during the first 12 weeks and most commonly nausea (38%), fatigue (26%), and headache (22%); 8 experienced severe AEs. Six participants developed reversible adrenal insufficiency during titration. Clinical features and QoL improved. Conclusion: Metyrapone is a safe and effective treatment for endogenous CS.