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Effects of Ovine Corticotropin-Releasing Hormone on Adrenocorticotropin Secretion in the Absence of Glucocorticoid Feedback Inhibition in Man^*

C. ROWAN DEBOLD, RICHARD V. JACKSON, THEMIS C. KAMILARIS, WILLIAM R. SHELDON, JR.^||, G. STEPHEN DECHERNEY^**, DONALD P. ISLAND and DAVID N. ORTH

Department of Medicine, Vanderbilt University Medical Center Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Dr. C. Rowan DeBold, Division of Endocrinology, Room AA4206 Vanderbilt Medical Center North, Nashville, Tennessee 37232.

We studied 1) the nature of the plasma ACTH response to ovine CRH (oCRH) in the absence of normal glucocorticoid negative feedback inhibition and 2) the cause of the diminished circadian peak in plasma ACTH in normal men the morning after 3–30 µg/kg BW doses of oCRH. Placebo or oCRH (3 µg/kg BW, iv) was administered as iv injections to five normal men given metyrapone to produce acute glucocorticoid deficiency. Four studies were performed: 1) placebo oCRH plus placebo hydrocortisone (HC), 2) oCRH plus placebo HC, 3) placebo oCRH plus HC, and 4) oCRH plus HC. HC was given as a variable rate iv infusion to mimic the plasma cortisol response to the same dose of oCRH in normal men.

Plasma cortisol levels rose only slightly after oCRH, indicating nearly complete blockade of cortisol biosynthesis. Plasma cortisol levels during the HC infusion were similar to those in normal men given 3 µg/kg oCRH. There was an exaggerated rise in both the first and second peaks of the plasma ACTH response to oCRH in the metyrapone-treated men. HC infusion did not alter the plasma ACTH response during the first 60 min after oCRH, but markedly attenuated the response thereafter; however, it did not affect the timing of the second peak. This inhibitory effect continued for up to 11 h, which was 2–3 h longer than the period that plasma cortisol levels were increased. Thus, cortisol secreted in response to ACTH released by oCRH modulates, after about a 60-min delay, the continuing release of ACTH.

Despite the greater oCRH-induced release of pituitary ACTH in the metyrapone-treated men, the magnitude of their next morning’s circadian plasma ACTH peak was similar to that after they received placebo oCRH. Thus, depletion of pituitary ACTH did not appear to explain the diminished circadian peak. Its magnitude was reduced by the combination of oCRH and HC, but not by HC alone. Administration of oCRH, alone or in combination with HC, delayed the onset of the circadian rise, while oCRH, HC, or the combination thereof delayed the time of the circadian peak. Thus, it appears that both the glucocorticoid response to oCRH and direct or indirect effect(s) of oCRH are required to produce these two phenomena.

^* Presented in part at the 63rd Annual Meeting of The Endocrine Society, San Antonio, TX, June 1983. This work was supported in part by Research Grants 1-R01-DK-33334, 5-M01-RR-00095 and 5-R01-CA-11685 from the NIH, USPHS.

Recipient of National Research Fellowship Award 1-F32-CA06939 from the NCI. Clinical Associate Physican of the Vanderbilt General Clinical Research Center (RR00095) and John A. and George L. Hartford Foundation Fellow during these studies.

Applied Health Sciences Fellow, National Health and Medical Research Council of Australia. Present address: Department of Medicine, University of Queensland, Greenslopes Hospital, Brisbane, Australia 4120.

Present address: Building 10, Room 10B09, National Institutes of Health, Bethesda, Maryland 20892.

^|| Recipient of a Fellowship Award from Research and Training Diabetes and Endocrinology Grant 5-T32-DK07601. Present address: Madigan Army Medical Center, Box 878, Tacoma, Washington 98431.

^** Recipient of National Research Fellowship Award 1-F32-DK06758. Present address: Department of Medicine, Uniformed Services Medical University, Bethesda, Maryland 20814.

Received June 6, 1988.

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