Context: TNF-α generates inflammatory responses and insulin resistance, lipolysis and protein breakdown. It is unclear whether these changes depend on intact hypothalamo-pituitary stress hormone responses triggering release of cortisol and growth hormone. Objective: To define differential effects of TNF-α on glucose, protein and lipid metabolism in hypopituitary patients (without intact hypothalamo-pituitary axis) and healthy controls. Design: Randomized, placebo controlled, single-blinded. Setting, participants and intervention: We studied eight hypopituitary patients(HP) and eight matched control subjects(CTR) twice during 4-h basal and 2-h hyperinsulinemic clamp conditions with isotope dilution during infusion of saline or TNF-α(12 ng/kg/h) for 6 h. Main outcome measures: Phenylalanine, urea, palmitate and glucose fluxes and fat biopsies in basal and clamp periods. Results: TNF-α infusion significantly increased cortisol and GH levels in CTR but not in HP. TNF-α increased phenylalanine fluxes in both groups, the increase being significantly greater in CTR, and raised urea flux by 40 % in CTR without any alteration in HP. Endogenous glucose production(EGP) was elevated in CTR compared to HP after TNF-α administration, whereas insulin sensitivity remained similarly unaffected in both groups. TNF-α increased whole body palmitate fluxes and decreased palmitate specific activity in CTR, but not in HP without statistical difference between groups. We did not detect significant effects TNF-α on lipase expression or regulation in fat. Conclusions: TNF-α increased both urea and amino acid fluxes and EGP significantly more in CTR compared to HP, suggesting that increases in endogenous cortisol and GH release are significant components of the metabolic response to TNF-α.