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

Abstract

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 micrograms/kg BW doses of oCRH. Placebo or oCRH (3 micrograms/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 micrograms/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.