Insulin-induced
hypoglycemia causes a sequential stimulation of all three components of the hypothalamic-pituitary-adrenal axis. States of acute
glucocorticoid excess, such as the overnight (1 mg)
dexamethasone suppression test (DST), inhibit both the basal
cortisol level and the response to an
insulin tolerance test (ITT). However, whether this negative feedback effect is exerted primarily at the hypothalamic or the pituitary level is not clear. To explore this question further we have examined the
cortisol response to
insulin-induced
hypoglycemia in three experimental settings, in the following order: 1) a control ITT performed at 0900 h after an overnight
hospital stay (cITT); 2) an ITT at 0900 h after oral
dexamethasone, 1 mg, at 2300 h on the previous evening (DST + ITT); and 3) an ITT at 0900 h after
dexamethasone, 1 mg, at 2300 h and hCRH, 1 microgram/kg iv, at 90 min intervals from 0100-0700 h (DST+hCRH + ITT). The response to ITT was defined as the peak
cortisol increment (peak minus baseline). Since the study objective was to test whether overnight pulsatile hCRH could prevent
dexamethasone-induced suppression of the response to a morning ITT, only subjects that demonstrated a greater than 25% decrease in the
cortisol response to DST + ITT vs. cITT received the full protocol (five of nine normal men). Basal
ACTH and
cortisol secretion remained suppressed throughout the night during both the Dex + ITT and Dex + hCRH + ITT studies when compared to the control study (cITT, P < 0.05). However, the
cortisol response to
hypoglycemia during DST + hCRH + ITT was significantly greater than during DST+ITT (P < 0.05) and was similar to the cITT response. Thus, pulsatile hCRH, administered during the 10 h between
dexamethasone and the subsequent
hypoglycemic stimulus, prevented acute suppression by
dexamethasone of the
cortisol response to
hypoglycemia. We conclude that the
dexamethasone-induced inhibition of the
cortisol response to
hypoglycemia results primarily from suppression by
dexamethasone of basal hypothalamic
corticotropin-releasing factor and the consequent impairment of corticotroph responsiveness to exogenous and endogenous
corticotropin-releasing factor.