Continuous Administration of Human Corticotropin-Releasing Hormone in the Absence of Glucocorticoid Feedback in Man

Abstract

Continuous 24-hour infusions of a maximally stimulating dose (1 µg/kg/h) of corticotropin-releasing hormone (CRH) have been shown to cause elevations of plasma cortisol and ACTH, but the pattern of results were confounded by serum cortisol causing feedback changes. We have looked at ACTH responses to saline or CRH infusions over 24 h in 6 normal subjects who, in addition, received either placebo or metyrapone, an 11β-hydroxylase inhibitor which blocks the formation of cortisol and thus abolishes glucocorticoid feedback. Cortisol and ACTH levels were measured by radioimmunoassay. Before metyrapone, CRH infusion resulted in exaggerated ACTH peaks throughout the day, as compared with normal saline: there was no influence on the noctu-ral rise in ACTH. Following metyrapone alone, absolute cortisol levels were lower but circadian rhythmicity was preserved. Circadian rhythm of ACTH was maintained, with a fall in the evening to 14.5 ± 4 pg/ml (mean ± SE) at midnight and an exaggerated rise overnight, reaching a peak level of 90 ± 33 pg/ml at 07:00 h. Subjects receiving CRH with metyrapone showed a similar pattern of responses, but with further enhanced ACTH levels. The evening fall reached a nadir of 30 ± 6 pg/ml at 01:00 h. With diminished glucocorticoid feedback the nocturnal rise in ACTH was augmented by CRH infusion, with a morning peak of 193 ± 21 pg/ml at 07:00 h. Thus, continuous infusion of CRH in the absence of steroid feedback leads to a retention of the circadian rhythmicity in ACTH secretion, reset at a higher absolute level. As this pattern is similar to that seen in certain patients with depressive illness, the data are compatible with our previous data which suggest that such patients have an increase in endogenous hypothalamic CRH release.

The Pulsatility of ACTH Secretion in the Rat Anterior Pituitary Cell Perifusion System

“…Further study on single neuronal activity in the SCN revealed that the dorsomedial part of the SCN is an intrinsic oscillating pacemaker [37], Additionally, the dorsomedial part of SCN is also the main location of AVP neurons [12]. Moreover, the circadian rhythm persists despite a continuous infusion of CRH [38] or AVP, suggesting that CRH or AVP alone is not the mediator of ACTH pulses. Actually, a study discovered a circadian rhythm in AVP RNA expression and the loss of the circadian rhythm of AVP RNA expression was shown in the transgenic CLOCK knockout mice [13].…”

The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids

“…A role for vasopressin release from the PVN in the control of rhythmic ACTH release has been suggested by human experiments where negative feedback regulation by GCs was eliminated by metyrapone treatment and CRH was infused iv at a constant rate. Under these conditions, a clear 24-hour rhythm of ACTH was observed, but it was set at a higher mean level due to the absence of negative feedback ( 130 ). High-affinity MRs in limbic structures, such as the hippocampus, mediate the effect of GCs on the maintenance of basal activity in the HPA axis at that nadir time (late evening in humans, early morning in nocturnal rodents).…”

ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study

“…Our findings open perspectives for novel strategies to protect long-stay ICU patients against the risk of developing adrenal insufficiency. If the lack of priming of the corticotropes by CRH would be responsible for reduced ACTH expression and secretion, providing CRH could potentially allow (re)activation of ACTH synthesis and release in response to any fall in cortisol and could hereby prevent adrenal atrophy in the prolonged phase of illness [ 45 ]. It has been shown that continuous infusion of CRH can reactivate ACTH secretion with preservation of circadian rhythmicity and pulsatility [ 46 ].…”