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The Antiglucocorticoid and Antiprogestin Steroid RU 486: Its Glucocorticoid Agonist Effect Is Inadequate to Prevent Adrenal Insufficiency in Primates

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (L.L., W.G., D.L.L., G.P.C.) Bethesda, Maryland 20892
the Department of Surgery, Johns Hopkins Medical Center (R. U.) Baltimore, Maryland 21205.

Address requests for reprints to: Louisa Laue, M.D., National Institutes of Health, Building 10, Room 1ON262, Bethesda, Maryland 20892.

The glucocorticoid receptor antagonist RU 486 has been used to treat the hypercortisolism of patients with nonpituitary Cushing's syndrome. Since endogenous cortisol production fluctuates in many patients with either the ectopic ACTH syndrome or adrenocortical tumors, treatment of these patients with a fixed dose of RU 486 introduces the risk of adrenal insufficiency. While RU 486 possesses some glucocorticoid agonist activity in addition to its potent antagonist effects, it is not known whether this intrinsic agonist activity is of sufficient magnitude to prevent adrenal insufficiency and sustain life. To answer this question three groups of bilaterally adrenalectomized cynomolgus monkeys (n = 5/ group) were randomized to receive a daily injection of RU 486 (5 mg/kg·day), cortisol (1.25 mg/kg·day), or saline (placebo). All adrenalectomized monkeys received weekly im injections of deoxycorticosterone pivalate (1 mg) to prevent mineralocorticoid deficiency. Five sham-adrenalectomized monkeys served as controls and received im injections of saline (placebo). Blood was collected before adrenalectomy or sham operation and every 3 days postoperatively for measurement of serum electrolytes, blood urea nitrogen, and creatinine; plasma ACTH concentrations; and complete blood and differential cell counts. All sham-operated and cortisol-replaced adrenalectomized monkeys survived, and none developed overt biochemical evidence of adrenal insufficiency. All placebo and RU 486-replaced adrenalectomized monkeys expired within 33 days after adrenalectomy, presumably from adrenal insufficiency. These findings suggest that while RU 486 is a partial glucocorticoid agonist, its degree of glucocorticoid agonism is inadequate to prevent adrenal insufficiency and support life in adrenalectomized primates.

Received January 14, 1988.

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