Leptin, produced by adipocytes, has homeostatic effects on body fat mass through inhibition of appetite and stimulation of the sympathetic nervous system. Several studies have reported that high-dose exogenous glucocorticoids increase circulating leptin concentrations in humans. Conversely, leptin has inhibitory effects on the hypothalamic-pituitary-adrenal (HPA) axis, both at the hypothalamic and adrenal levels. We hypothesized that acute hypercortisolism, in the physiological range, may not alter leptin secretion. Four stimuli of the HPA axis were administered to eight healthy male volunteers in a placebo-controlled study. On separate afternoons, in a randomised order, fasting subjects received i.v. injections of saline, naloxone (125 microg/kg); vasopressin (0.0143 IU/kg); naloxone and vasopressin in combination; or insulin (0.15 U/kg; a dose sufficient to induce hypoglycaemia). Plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol and leptin were measured before and for 120 min after the injection. The cortisol secretory response was greatest after insulin-hypoglycaemia, this response was significantly greater than that following naloxone, naloxone/vasopressin, or vasopressin alone. Despite the cortisol release, leptin concentrations were not increased after any stimulus. Insulin-hypoglycaemia was associated with a decrease in leptin concentration at 60 and 90 min, while naloxone did not alter leptin concentrations. However, basal leptin concentrations were positively correlated with integrated ACTH and cortisol responses to naloxone, but did not correlate with ACTH or cortisol responses to the other stimuli. Thus acute elevations of plasma cortisol, in the physiological range, do not appear to influence plasma leptin concentrations. The fall in plasma leptin concentration after insulin-induced hypoglycaemia may reflect catecholamine secretion after this stimulus.