Laue L, Gallucci W, Loriaux D L, Udelsman R, Chrousos G P
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892.
J Clin Endocrinol Metab. 1988 Sep;67(3):602-6. doi: 10.1210/jcem-67-3-602.
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.
糖皮质激素受体拮抗剂RU 486已被用于治疗非垂体性库欣综合征患者的皮质醇增多症。由于许多患有异位促肾上腺皮质激素（ACTH）综合征或肾上腺皮质肿瘤的患者内源性皮质醇分泌会波动，用固定剂量的RU 486治疗这些患者会带来肾上腺功能不全的风险。虽然RU 486除了具有强大的拮抗剂作用外还具有一些糖皮质激素激动剂活性，但尚不清楚这种内在激动剂活性的强度是否足以预防肾上腺功能不全并维持生命。为了回答这个问题，将三组双侧肾上腺切除的食蟹猴（每组n = 5）随机分组，分别每日注射RU 486（5 mg/kg·天）、皮质醇（1.25 mg/kg·天）或生理盐水（安慰剂）。所有肾上腺切除的猴子每周接受一次皮下注射醋氧去氧皮质酮（1 mg）以预防盐皮质激素缺乏。五只假肾上腺切除的猴子作为对照，接受皮下注射生理盐水（安慰剂）。在肾上腺切除或假手术前以及术后每3天采集血液，用于测定血清电解质、血尿素氮和肌酐；血浆促肾上腺皮质激素浓度；以及全血细胞计数和分类细胞计数。所有假手术和接受皮质醇替代的肾上腺切除猴子均存活，且均未出现肾上腺功能不全的明显生化证据。所有接受安慰剂和RU 486替代的肾上腺切除猴子在肾上腺切除后33天内死亡，推测是死于肾上腺功能不全。这些发现表明，虽然RU 486是一种部分糖皮质激素激动剂，但其糖皮质激素激动程度不足以预防肾上腺功能不全并支持肾上腺切除灵长类动物的生命。
