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Estrogen Modulates the Hypothalamic-Pituitary-Adrenal and Inflammatory Cytokine Responses to Endotoxin in Women1
Ist Teil von
The journal of clinical endocrinology and metabolism, 2001-06, Vol.86 (6), p.2403-2408
Ort / Verlag
Endocrine Society
Erscheinungsjahr
2001
Quelle
Oxford Journals 2020 Medicine
Beschreibungen/Notizen
Endotoxin stimulates the release of the inflammatory cytokines
interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, which
are potent activators of the hypothalamic-pituitary-adrenal (HPA) axis.
Recent studies in the 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) replacement. In addition, there is some
evidence, in the rodent, that estrogen modulates inflammatory cytokine
responses to endotoxin. To determine whether 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 women 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 pg/mL after estrogen replacement. Blood was sampled
every 20 min for 1–2 h before, and for 7 h after, iv endotoxin
administration. Endotoxin stimulated ACTH, cortisol, and cytokine
release in women with and without E2 replacement. E2 significantly
attenuated the release of ACTH (P < 0.0001) and of
cortisol (P = 0.02). Mean ACTH levels peaked at
190 ± 91 pg/mL in the E2-replaced group vs.
411 ± 144 pg/mL in the unreplaced women, whereas the
corresponding mean cortisol levels peaked at 27 ± 2.9 μg/dL
with E2 vs. 31 ± 3.2 μg/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-α (P =
0.04). Mean cytokine levels with and without E2 replacement 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/mL vs.
214 ± 87 pg/mL for TNF-α, respectively. We conclude that
inflammatory 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 restrain cytokine and neuroendocrine responses to an
inflammatory challenge.