To investigate the hypothalamic responsiveness in obesity, changes in the levels of plasma cortisol and growth hormone (GH) were studied in 11 obese and six normal-weight subjects after hypothalamic alpha-adrenergic stimulation with methoxamine, 20 mg i.v. To allow for dose/body weight differences, five additional obese subjects received 30 mg methoxamine. Plasma GH, cortisol, insulin, free fatty acid and glucose levels were determined during the 3-h infusion of methoxamine. The responses of cortisol and GH were reduced in the obese subjects as compared with the normal-weight subjects. No significant changes in plasma glucose, free fatty acids or insulin were observed in any of the groups. The reduced responses of plasma cortisol ang GH in the obese subjects are considered to be an expression of hypothalamic underresponsiveness, since the stimuli for the secretion of these hormones are at least partially controlled by an alpha-adrenergic mechanism.