Fast Feedback Inhibition of Adrenocorticotropic Hormone Secretion by Endogenous Cortisol in Humans

Abstract

Background: Using high-frequency blood sampling, we demonstrate glucocorticoid fast feedback (FF) mediated by endogenous cortisol in 6 normal humans. Methods: We stimulated adrenocorticotropic hormone (ACTH) secretion by ovine corticotropin-releasing hormone (oCRH) with the experimental paradigm in which a high-frequency blood sampling was designed for plasma ACTH and cortisol determinations. Results: We saw previously unrecognized variability in the timing of key events such as onsets of ACTH and cortisol secretion, onset and offset of FF, and in FF duration. This variability mandated analyses referenced to case-wise event times rather than referenced simply to time since oCRH administration. The mean time of FF onset was 4.0 min (range 0–9; median 3) after cortisol secretion began, and the mean FF duration was 7.5 min (range 3–18; median 6.0). The FF effect was rate-sensitive and does not reflect level-sensitive cortisol feedback. In agreement with previous estimates using hydrocortisone infusions, the rate of rise of cortisol that triggered FF was approximately 44 nmol/L/min or 1.6 µg/dL/min. FF onset followed the trigger cortisol slope with an average lag of 1 min (range 0–3; median 0). Unexpectedly, this trigger cortisol slope quickly declined within the FF period. Conclusions: This experimental design may enable new physiological studies of human FF that is mediated by endogenous cortisol, including mechanisms, reproducibility, and generalizability to other activating stimuli.