Effect of Synthetic Ovine Corticotropin-Releasing Factor: Prolonged Duration of Action and Biphasic Response of Plasma Adrenocorticotropin and Cortisol

The duration of the response to synthetic ovine corticotropin-releasing factor (CRF) was studied in 13 healthy male volunteer subjects. Placebo or CRF (0.3, 3, or 30 micrograms/kg BW) was administered as an iv bolus or, in the case of the largest dose, a 30-sec infusion in single blind fashion in the late afternoon. Basal plasma immunoreactive ACTH (IR-ACTH) and IR-cortisol were 10.8 +/- 7.7 pg/ml and 5.0 +/- 1.8 micrograms/dl (mean +/- SD), respectively. IR-ACTH rose rapidly after CRF, reached an initial peak at 15 min, fell rapidly until 1.5 h after CRF, and then either fell more slowly (after the lowest dose) or rose to a second major peak at 2-3 h before falling back to baseline. After 0.3, 3, and 30 micrograms/kg CRF, IR-ACTH remained elevated for 4, 7, and 8 h, respectively. The effect on plasma IR-cortisol was similar, but more prolonged. The magnitude of both peaks of IR-ACTH, the duration of the response, and the area under the curve all appeared dose dependent. The same was true for IR-cortisol, except that the first peak height was similar after all three doses. The duration of CRF's action is probably due to its long circulating half-life. The biphasic response curve may reflect initial secretion of a readily releasable pool of ACTH, followed by later secretion of a second pool of newly synthesized and/or matured peptide. The next morning's normal circadian rise in both IR-ACTH and IR-cortisol was delayed and diminished after 3 micrograms/kg CRF; there was no increase in IR-ACTH after 30 micrograms/kg CRF, and the IR-cortisol level was diminished. Inhibition of the normal circadian rise may reflect inhibition of ACTH secretion by the sustained high plasma cortisol levels.