In this study of 23 hypopituitary patients and 26 healthy controls, we have addressed whether the obese state of substituted hypopituitary patients is facilitated by abnormal sympathoadrenal activity or energy expenditure (EE). All patients received adequate substitution therapy including GH therapy. The investigation program included assessment of sympathoadrenal activity (urinary catecholamines), body composition (dual-energy x-ray absorptiometry), appetite sensations (visual analog scale), and EE (indirect calorimetry in respiration chamber). Twenty-four-hour urinary epinephrine adjusted for lean body mass and fat mass was significantly lower in patients compared with controls. GH and hydrocortisone were single negative predictors of urinary epinephrine. The major determinants of EE in patients were lean body mass and fat mass, explaining 96, 95, and 80% of the variance in 24-h EE, sleeping EE, and basal metabolic rate, respectively. Addition of urinary catecholamines explained another 1-4% of the variance in 24-h EE and basal metabolic rate, respectively. Lean patients exhibited significantly more hunger than obese patients and lean controls. In conclusion, hypopituitary patients have lower sympathoadrenal activity but normal EE, compared with healthy controls. This may reflect a central defect in hypopituitarism, however the possible impact of long-term GH and hydrocortisone treatment requires further attention.