Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) have immunomodulatory effects in vitro and in vivo. Additionally, their plasma levels are altered during chronic infection and inflammation. However, it remains unknown whether these steroids are involved in early host responses to infection in humans. We examined DHEA and DHEA-S levels during experimental endotoxinemia, a well established pathophysiological model of bacterial infections in humans. Purified Salmonella abortus equi endotoxin (0.2, 0.4, or 0.8 ng/kg body weight) was injected in a single-blind, placebo-controlled experiment to 17 healthy male volunteers. During the following 12 h, rectal temperature and the plasma levels of ACTH, cortisol, DHEA, DHEA-S, interleukin 6, and tumor necrosis factor alpha were determined. Confirming earlier studies, temperature and cytokine levels showed monophasic, dose-dependent increases in response to endotoxin. In contrast, endocrinological effects of endotoxin showed a complex, biphasic pattern: cortisol levels were not affected by 0. 2 ng/kg but significantly increased during the first 6 h following 0. 4 and 0.8 ng/kg endotoxin, whereas ACTH and DHEA levels were significantly enhanced during the first 6 h following 0.8 ng/kg only. ACTH, DHEA, and cortisol secretion was blunted 6-12 h following 0.8 ng/kg. DHEA-S levels were unaffected during the first 6 h following all dosages, but between 6-12 h after injection they were significantly increased following 0.2 ng/kg, unaffected by 0.4 ng/kg, and significantly decreased following 0.8 ng/kg endotoxin. The present results suggest that similarly to glucocorticoids, the adrenal androgens DHEA and DHEA-S play an important role during early host responses to bacterial infections in humans.