Regulation of pulsatile and entropic ACTH secretion under fixed exogenous secretagogue clamps

Background: Adrenocorticotropic hormone (ACTH) secretion is controlled by unobservable hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) pulses. Clamping exogenous CRH or AVP input could allow indirect quantification of the impact of the endogenous heterotypic hormone. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men). Volunteers underwent a sex-steroid clamp and a cortisol clamp. ACTH was measured over 10 hours by 10-minute sampling during each of four randomized intravenous (IV) secretagogue clamps (i.e., continuous IV CRH, AVP, both peptides, or saline). Desensitization was tested by bolus injection of the noninfused peptide. Results: Mean 6 standard error of the mean 10-hour ACTH concentrations (ng/L) in the sexcombined analysis were: saline, 32 6 4.6; AVP, 29 6 4.6; CRH, 67 6 6.2; and CRH-AVP, 67 6 8.8 (any CRH vs AVP or saline, P , 0.0001). CRH and AVP increased approximate entropy (relative randomness) of ACTH release (P , 0.0001). Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 4664.3, exceeding that seen after bolus CRH or saline injection (2663.3 and 24 6 3.6, respectively; P = 0.002 and 0.001). Sex hormone clamps did not influence ACTH levels. Conclusions: A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness. After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH. Similar interactions mightunderlie chronic stress states.