Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women

Endotoxin stimulates the release of the inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha, which are potent activ ators of the hypothalamic-pituitary-adrenal (HPA) axis. Recent studies in t he rodent and in the primate have shown that the HPA responses to endotoxin and IL-1 were enhanced by gonadectomy and attenuated by estradiol (E2) rep lacement. In addition, there is some evidence, in the rodent, that estrogen modulates inflammatory cytokine responses to endotoxin. To determine wheth er estrogen has similar effects in humans, we studied the cytokine and HPA responses to a low dose of endotoxin (2-3 ng/kg) in six postmenopausal wome n with and without transdermal E2 (0.1 mg) replacement. Mean E2 levels were 7.3 +/- 0.8 pg/mL in the unreplaced subjects and increased to 102 +/- 13 p g/mL after estrogen replacement. Blood was sampled every 20 min for 1-2 h b efore, and for 7 h after, iv endotoxin administration. Endotoxin stimulated ACTH, cortisol, and cytokine release in women with and without E2 replacem ent. E2 significantly attenuated the release of ACTH (P < 0.0001) and of co rtisol (P = 0.02). Mean ACTH levels peaked at 190 <plus/minus> 91 pg/mL in the E2-replaced group vs. 411 +/- 144 pg/mL in the unreplaced women, wherea s the corresponding mean cortisol levels peaked at 27 +/- 2.9 mug/dL with E 2 us. 31 +/- 3.2 mug/dL, without E2. Estrogen also attenuated the endotoxin -induced release of IL-6 (P = 0.02), IL-1 receptor antagonist (P = 0.003), and TNF-alpha (P = 0.04). Mean cytokine levels with and without E2 replacem ent peaked at 341 +/- 94 pg/ml, vs. 936 +/- 620 pg/mL, for IL-6, 82 +/- 14 ng/ml vs. 133 +/- 24 ng/mL for IL-1 receptor antagonist, and 77 +/- 46 pg/m L vs. 214 +/- 87 pg/mL for TNF-alpha, respectively. We conclude that inflam matory cytokine and HPA responses to a low dose of endotoxin are attenuated in postmenopausal women receiving E2 replacement. These data show, for the first time in the human, that a physiological dose of estrogen can restrai n cytokine and neuroendocrine responses to an inflammatory challenge.