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Differential Effects of Estradiol on the Adrenocorticotropin Responses to Interleukin-6 and Interleukin-1 in the Monkey¹

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.