Leptin, the protein product of the ob gene, is thought to have a role in signalling satiety through hypothalamic pathways. Glucocorticoids are potent stimulators of both ob gene expression and circulating leptin levels in the rat, yet are powerful appetite stimulants in humans. We have investigated circulating leptin responses to intermediate term and acute administration of dexamethasone. Dexamethasone 2 mg twice daily resulted in a rapid and sustained rise in 08.00 h leptin levels from basal values of 1.36 +/- 0.25 to 3.58 +/- 1.72 microg/l after 24 hours of treatment. Following placebo administration 24 h profiles confirmed a nocturnal rise in leptin levels with an increase of 73 +/- 37% at midnight compared with 0.9.00 h. After dexamethasone mean leptin levels increased by 123 +/- 51% (p = 0.0016), with an accentuation in the diurnal variation and associated hyperinsulinemia. The study confirms a nocturnal rise in leptin in humans, and demonstrates increases in leptin in response to glucocorticoid administration as previously demonstrated in the rodent. The divergence between appetite stimulating effects of glucocorticoids despite induction of a proposed satiety factor suggests that regulation of leptin levels and regulation of appetite is multifactorial, and other neurotransmitter pathways are presumably involved.