Adrenocorticotropin Inhibition by Restoration of Normal Evening Cortisol Levels: A Measure of Putative Hippocampus-Mediated Glucocorticoid Feedback in Humans

Abstract

Hippocampus-mediated glucocorticoid negative feedback is thought to be relevant to the pathophysiology of neuropsychiatric disorders, but no reliable method of measuring it in humans has been developed. Converging lines of evidence indicate that basal hypothalamic-pituitary-adrenal axis activity during the unstressed circadian trough is primarily regulated by this feedback process. To assess whether negative feedback can be demonstrated under these circumstances, we studied normal controls (n = 5) who were pretreated with metyrapone to lower their basal evening cortisol levels. On two separate occasions, in double-blind randomized order, subjects received an infusion of cortisol or of saline. Restoration of normal evening plasma cortisol by the cortisol infusion produced a drop in plasma adrenocorticotropin (ACTH) apparent in the last sample obtained at +200 min (p < 0.05). The ACTH response in schizophrenic patients (n = 4), whose mental illness may arise from hippocampal dysfunction, was relatively blunted compared to that seen in normals (p < 0.02). 11-Desoxycortisol levels paralleled the ACTH responses across conditions and subject groups. These preliminary data suggest that hippocampus-mediated glucocorticoid feedback can be measured in normal subjects and may provide an index of hippocampal dysfunction in neuropsychiatric patients.