Corticotropin-releasing hormone and copeptin as acute stress markers in serial cerebrospinal fluid – first evidence for non-response during insulin hypoglycemia test

Abstract

Background: During stress, arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH) can act as potent hypothalamic stimulators of the hypothalamic pituitary adrenocortical (HPA) axis. Recently, plasma CT-proAVP, also termed copeptin, was found to be a stable and sensitive surrogate marker for AVP release. A valid assessment of both CRH and copeptin in cerebrospinal fluid (CSF) might directly quantify an individual’s current stress level. Here we investigated how concentrations of CRH and copeptin in CSF alter during insulin-induced hypoglycemia test (IHT) - which has been shown to activate both hypothalamic AVP and CRH - and hypothesized an increase of both.Methods: Five healthy young men were studied from 08:00 until 14:00 after over-night fasting. They received an i.v. injection of human insulin (0.1 IE/kg body weight) at 11:02. CSF samples were drawn from a subarachnoidal catheter every 20 minutes from 10:40 to 14:00 for the measurement of CSF CRH and CSF copeptin. Plasma adrenocorticotropic hormone (ACTH) and cortisol were analyzed in parallel.Results: Data could be assessed in three of five subjects, of which two responded to IHT by showing glucose levels of < 40 mg/dl and clinical symptoms (sweating). Despite a 17-fold, respectively 11-fold increase of plasma ACTH, neither our hypothesized increase of CSF CRH nor of CSF copeptin was seen in these two responders.Conclusions: This is the first study investigating CSF CRH and CSF copeptin in man during acute stress. Copeptin had not been measured in CSF before. Our results support recent speculations that CSF CRH is not a measure of hypothalamic but rather extrahypothalamic CRH (non-HPA CRH). Further research on copeptin in CSF is needed.