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This Article Accepted manuscript (PDF) All Versions of this Article: EJE-08-0417v1 159/5/561    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Iranmanesh, A. Articles by Veldhuis, J. PubMed PubMed Citation Articles by Iranmanesh, A. Articles by Veldhuis, J.

Hypocortisolemic clamp unmasks jointly feedforward- and feedback-dependent control of overnight ACTH secretion

A Iranmanesh, Research & Development Office, VA Medical Center, Salem, United States
J Veldhuis, Endocrine Research Unit, Mayo Clinic, Rochester, 55905, United States

Correspondence: Johannes Veldhuis, Email: veldhuis.johannes{at}mayo.edu

Abstract

Background. ACTH secretion is under hypothalamic stimulatory (feedforward) and adrenal inhibitory (feedback) control.

Hypothesis. Assessment of overnight ACTH secretion during a hypocortisolemic clamp will permit estimation of changing feedforward and feedback.

Subjects. Seven healthy men.

Interventions. An oral dose of placebo, metyrapone (METY, 3 g) or ketoconazole (KTCZ, 1.2 g) was given at midnight (MN) to block glucocorticoid synthesis. Plasma ACTH was sampled every 10 min (MN to 0800 h).

Analysis. Variable-waveform deconvolution analysis of ACTH secretion, and approximate entropy (ApEn) analysis of pattern regularity.

Results. Compared with placebo, METY and KTCZ reduced morning cortisol concentrations by 77% and 54%, respectively [P < 0.001]. Hypocortisolemia elevated pulsatile ACTH secretion by 8.2-fold (METY) and 5.3-fold (KTCZ) [both P < 0.001]. Basal ACTH secretion rose by 3.4-fold under METY-induced cortisol depletion (P = 0.020). ACTH secretory-burst shape and half-life were stable. ApEn of ACTH release declined overnight (P = 0.021) and with drug (P = 0.001), denoting enhanced feedforward coordination.

Conclusion. The combined data predict overnight amplification and coordination of hypothalamic feedforward drive onto ACTH release. Therefore, disruption of either mechanism might contribute to clinical pathophysiology, such as late-day elevations of cortisol output in fasting, alcoholism, depression or aging.