Hypocortisolemic clamp unmasks jointly feedforward- and feedback-dependent control of overnight ACTH secretion.
BACKGROUND
ACTH secretion is under hypothalamic stimulatory (feedforward) and adrenal inhibitory (feedback) control.


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


METHODS
Seven healthy men.


METHODS
An oral dose of placebo (PLAC), 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).


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


RESULTS
Compared with PLAC, administration of METY and KTCZ reduced morning cortisol concentrations by >or=77 and 54% respectively (P<0.001). Hypocortisolemia elevated pulsatile ACTH secretion by 8.2- (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 the drug (P=0.001), denoting enhanced feedforward coordination.


CONCLUSIONS
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.
Iranmanesh
Ali
A
Department of Medicine, Salem Veterans Affairs Medical Center, Salem, Virginia 24153, USA.
Veldhuis
Johannes D
JD
D000324:Adrenocorticotropic Hormone / Q000097:blood* / Q000378:metabolism; D000328:Adult; D002940:Circadian Rhythm / Q000502:physiology; D019277:Entropy; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D025461:Feedback, Physiological / Q000187:drug effects* / Q000502:physiology; D005938:Glucocorticoids / Q000097:blood / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000097:blood* / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008797:Metyrapone / Q000008:administration & dosage*; D008875:Middle Aged; D010919:Placebos
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D010919:Placebos; D000324:Adrenocorticotropic Hormone; D007654:Ketoconazole; D006854:Hydrocortisone; D008797:Metyrapone