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Estrogens and the Hypothalamo-Pituitary-Adrenal Axis in Man: Evidence for Normal Feedback Regulation by Corticosteroids^*

Center for Endocrinology, Metabolism, and Nutrition, Department of Medicine, Northwestern University Medical School Chicago, Illinois 60611, Maryland 20205
the Reproduction Research Branch, National Insitute of Child Health and Human Development, National Insitutes of Health Bethesda, Maryland 20205

Address requests for reprints to: Dr. G. Baumann, 303 East Chicago Avenue, Chicago, Illinois 60611.

Estrogen treatment and pregnancy are associated with higher than normal plasma free (nonprotein-bound) cortisol levels. In spite of this, clinical manifestations of steroid excess are not seen in these conditions. To explain this seeming discrepancy, it has been postulated that estrogens may induce tissue resistance to the actions of cortisol, and that one aspect of this resistance may be a higher set-point for ACTH suppression by corticosteroids. This possibility was studied in seven normal women. Plasma total and free cortisol levels as well as urinary cortisol excretion were measured during a control period and during treatment with ethinyl estradiol (100 µg/day). During both periods, graded doses of dexamethasone (0.2-mg increments; 0–1.4 mg/day) were administered. Estrogen treatment resulted in elevated plasma total and free cortisol levels, but urinary cortisol excretion was not affected. Dexamethasone administration resulted in a dose-dependent reduction of plasma total and free cortisol as well as urinary cortisol. The doseresponse curve for suppression by dexamethasone of urinary cortisol during estrogen treatment was indistinguishable from that during the control period. The dose-response curve for plasma free cortisol suppression suggested that during estrogen treatment, slightly more dexamethasone was required to suppress free cortisol. However, this effect was small. In view of the overall data, we conclude that 1) estrogen does not increase integrated free cortisol prevailing in vivo; 2) estrogen does not significantly alter the hypothalamic or pituitary set-point for ACTH suppression by corticosteroid; 3) the elevation of plasma free cortisol is relatively minor and possibly an in vitro phenomenon; and 4) the present findings are compatible with the absence of clinical hypercorticism in hyperestrogenized states.

^* Presented in part at the 61st Annual Meeting of The Endocrine Society, Anaheim, CA, 1979, and reported in abstract form (Program of the 61st Meeting of the Endocrine Society, No. 638). This work was supported in part by NIH Grant AM-27047.

Received April 11, 1983.

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