Jj. Puder et al., Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women, J CLIN END, 86(6), 2001, pp. 2403-2408
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.