Comparison between cortisol’s and dexamethasone’s negative feedback action in humans: evidence for preferential sensitivity to the natural glucocorticoid

Glucocorticoids (GCs) inhibit HPA axis through different mechanisms and target sites mediated by two receptor types (glucocorticoid receptor, GR, and mineralcorticoid receptor, MR). Within the brain, GRs are mostly distributed in the hypothalamus and in the pituitary, and bind both natural and synthetic GCs; MRs are mainly located in the limbic structures where show high affinity for GCs. HPA response to GCs feedback is usually tested by dexamethasone, a synthetic GC that poorly penetrates BBB and preferentially activates pituitaric GRs. Differently from dexamethasone, cortisol could better evaluate the GC feedback action by acting also at supra-pituitary level. We studied the effects of different doses of hydrocortisone (HC, 15, 30 or 60 µg/kg/h, infused for 150 min) or dexamethasone (DEX, 0.4, 0.8 or 1.6 µg/kg/h, infused for 150 min) on ACTH and cortisol levels in 6 normal subjects (NS, age 252.1 yr, BMI 23.01.2 kg/m2). The effects of HC and DEX were compared with those of placebo. Blood samples were taken every 15 min for 240 min. During placebo, ACTH and cortisol levels showed progressive decrease (baseline vs nadir, mean±SEM: 17.6±1.6 vs 13.4±0.7 pg/ml and 157.6±25.6 vs 71.7±10.6 µg/l, p<0.05). The dose of 15 µg/kg/h HC mantained constant cortisol but did not modify ACTH levels at any time. The doses of 30 and 60 µg/kg/h HC induced dose-dependent cortisol increases (peaks, 30 µg/kg/h: 170.5±14.8 µg/l, p<0.05; 60 µg/kg/h: 203.2±26.6 µg/l, p<0.05) associated to dose-dependent ACTH decrease (nadir, 30 µg/kg/h: 8.1±0.9 pg/ml, p<0.05; 60 µg/kg/h: 7.9±0.7 pg/ml, p<0.05). DEX at doses of 0.4, 0.8 and 1.6 µg/kg/h did not modify cortisol levels at any time. Only 1.6 µg/kg/h DEX induced an ACTH decrease (p<0.05) more pronounced than that after placebo (8.0±3.1 pg/ml) while neither 0.4 nor 0.8 µg/kg/h affected ACTH levels at any time. In conclusion, taking into account the potency at the GR level, doses of dexamethasone relatively higher than hydrocortisone are needed to inhibit ACTH secretion in humans. These findings are likely to reflect different sites where natural and synthetic GCs exert their feedback action, i.e. mainly the CNS for cortisol and the pituitary for dexamethasone. It is suggested that the HPA sensitivity to the feedback action of GCs in various pathophysiological conditions would better be evaluated by using natural GCs.