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Departments of Medicine and Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Dr. Sharon L. Wardlaw, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032.
Endotoxin and the inflammatory cytokines interleukin (IL)-1 and IL-6 are potent activators of the hypothalamic-pituitary-adrenal (HPA) axis. Although estradiol (E2) has been shown to enhance the HPA response to certain types of stress, previous studies in the rodent have shown that HPA responses to endotoxin and to IL-1 were enhanced by ovariectomy and attenuated by E2. The mechanisms underlying these observations are unclear, but there is evidence that E2 may have direct inhibitory effects on IL-6 synthesis and release. Because endotoxin and IL-1 both stimulate IL-6, it is possible that the E2-induced suppression of the HPA response to endotoxin and IL-1 results from decreased IL-6 release. We have therefore examined the ACTH response to IL-6 and IL-1ß in six ovariectomized rhesus monkeys with and without 3 weeks of E2 replacement. In the first study, plasma ACTH levels peaked at 60 min after iv injection of 6 µg recombinant human IL-6. Both the ACTH response, over time, and the area under the ACTH response curve were significantly higher in the E2-treated animals (P < 0.05). The peak ACTH level was 66 ± 16 pg/ml without E2 vs. 161 ± 69 pg/ml with E2. In the second study, iv infusion of recombinant human IL-1ß (400 ng) produced plasma IL-6 levels comparable with those seen after IL-6 injection in the first study. In the IL-1 study, however, there was a significant attenuation of the ACTH response, over time, in the E2-treated animals (P < 0.001); the peak ACTH level was 83 ± 34 pg/ml vs. 13 ± 4.4 pg/ml after E2. The IL-6 response was similarly attenuated (P < 0.001); the peak IL-6 level was 614 ± 168 pg/ml vs. 277 ± 53 pg/ml after E2 treatment. Our results demonstrate that physiological levels of E2 enhance the ACTH response to IL-6 but attenuate the ACTH response to IL-1. The attenuated ACTH response to IL-1 was accompanied by a blunted IL-6 response. Our results suggest that the blunted HPA response to IL-1 can be explained, at least in part, by E2-induced alterations in IL-6 release. It remains to be determined whether E2 affects other inflammatory mediators that also participate in this process.
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