Moderate obesity is known to be associated with multiple endocrine abnormalities. Less information is available on the hormonal status of patients with morbid obesity and on the effects of major weight loss. We studied 16 severely obese (BMI 40.6-69.9 kg/m(2)) nondiabetic patients and 7 nonobese (BMI range 24.6-27.7 kg/m(2)), sex- and age-matched healthy volunteers. During 24 h in a metabolic ward, four meals were administered and hourly blood samples were drawn from a central venous catheter for the measurement of glucose, insulin, leptin, thyrotropic hormone (TSH), growth hormone (GH) and prolactin. Insulin sensitivity was measured by a euglycaemic hyperinsulinaemic clamp. Studies were repeated 6 months after biliopancreatic diversion, a mainly malabsorptive surgical approach, which caused an average weight loss of 35+/-4 kg (or 26+/-2% of initial weight). Compared with controls, patients were hyperinsulinaemic (290+/-31 vs 88+/-4 pmol l(-1), P=0.0002), insulin resistant (23.5+/-2.8 vs 52.9+/-4.9 micromol min(-1) kg(FFM)(-1), P=0.0006) and hyperleptinaemic (52.5+/-5.8 vs 10.9+/-3 ng ml(-1), P=0.0002). Plasma TSH levels were increased throughout the day-night cycle (averaging 2.02+/-0.18 vs 1.09+/-0.19 muU ml(-1) of controls, P=0.01), whereas serum GH levels were suppressed (0.46+/-0.10 vs 3.01+/-1.15, P=0.002). Following surgery, the hyperinsulinaemia and insulin resistance were fully normalized; in concomitance with a major drop in leptin levels (to 14.4+/-2.7 ng ml(-1), P=0.02), TSH decreased and GH increased to near-normal levels. In the whole dataset, mean 24-h leptin levels were directly related to mean 24-h TSH levels after controlling for confounders this relationship was lost only after adjusting for fat mass. We conclude that in morbid obesity leptin is a determinant of changes in pituitary function.