The present study compares the effects of endotoxin, a key factor in gram-negative bacterial infection, and of corticotropin-releasing hormone (CRH) on ACTH and cortisol secretion in healthy male volunteers in a placebo-controlled design. Endotoxin (isolated from Salmonella abortus equi; 0.4 ng/kg body weight) induced a significantly delayed and prolonged increase of ACTH and cortisol secretion as compared to CRH (100 micrograms), supporting the hypothesis that different intermediate mechanisms are involved (baseline/peak: ACTHEndotoxin vs. ACTHCRH: 140 +/- 40 min vs. 44 +/- 17 min (p < 0.001); CortisolEndotoxin vs. CortisolCRH: 113 +/- 51 min vs. 66 +/- 31 min (p < 0.05); peak/baseline: ACTHEndotoxin vs. ACTHCRH: 244 +/- 79 min vs. 200 +/- 25 min (p < 0.05); CortisolEndotoxin vs. CortisolCRH: 278 +/- 76 min vs. 182 +/- 16 min (p < 0.001)). Activation of the hypothalamo-pituitary-adrenocortical (HPA) system by endotoxin in men is associated with increased interleukin-6 (peak value: 124 +/- 109 pg/ml) and tumor necrosis factor-alpha (peak value: 69 +/- 53 pg/ml) plasma levels which, probably together with locally produced interleukin-1, stimulate the HPA system both at the hypothalamic and (to a lesser degree) at the pituitary site. Provided that strictly controlled laboratory conditions are applied, the endotoxin challenge test presented here may serve as an appropriate and safe tool to explore an individual's capacity for neuroendocrine adaptation to a bacterial stressor, thus providing information complementary to the CRH test.