CONTINUOUS ADMINISTRATION OF HUMAN CORTICOTROPIN-RELEASING HORMONE INTHE ABSENCE OF GLUCOCORTICOID FEEDBACK IN MAN

Continuous 24-hour infusions of a maximally stimulating dose (1 mu g/k g/h) of corticotropin-releasing hormone (CRH) have been shown to cause elevations of plasma cortisol and ACTH, but the pattern of results we re confounded by serum cortisol causing feedback changes. We have look ed at ACTH responses to saline or CRH infusions over 24 h in 6 normal subjects who, in addition, received either placebo or metyrapone, an 1 1 beta-hydroxylase inhibitor which blocks the formation of cortisol an d thus abolishes glucocorticoid feedback. Cortisol and ACTH levels wer e measured by radioimmunoassay. Before metyrapone, CRH infusion result ed in exaggerated ACTH peaks throughout the day, as compared with norm al saline: there was no influence on the noctural rise in ACTH. Follow ing metyrapone alone, absolute cortisol levels were lower but circadia n rhythmicity was preserved. Circadian rhythm of ACTH was maintained, with a fall in the evening to 14.5 +/- 4 pg/ml (mean +/- SE) at midnig ht 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 s imilar pattern of responses, but with further enhanced ACTH levels. Th e evening fall reached a nadir of 30 +/- 6 pg/ml at 01:00 h. With dimi nished glucocorticoid feedback the nocturnal rise in ACTH was augmente d 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 l eads to a retention of the circadian rhythmicity in ACTH secretion, re set at a higher absolute level. As this pattern is similar to that see n in certain patients with depressive illness, the data are compatible with our previous data which suggest that such patients have an incre ase in endogenous hypothalamic CRH release.