STEROID ANATAGONISTS

存在临床上有用的雌激素、雄激素和 矿物皮质激素。糖皮质激素或孕激素的拮抗剂 具有潜在临床用途的药物是最近才被发现的。这个 本项目的目的是开发和研究分子机制。 对这两种情况的作用和拮抗剂的人类应用 类固醇的种类。 最初，我们证明了糖皮质激素拮抗剂可以通过 甾体C环11位的修饰 糖皮质激素。然后我们测试了一种糖皮质激素-孕激素的原型 Roussel-UCLAF新近开发的拮抗剂(RU 486)。这种化合物有 对人糖皮质激素和孕激素受体的强烈亲和力 在小型实验动物身上没有激动剂效应。 给非人类灵长类动物或人类RU 486会导致长时间的 血浆ACTH、皮质醇和精氨酸加压素，所有这些变化都是可以预防的 以前使用过糖皮质激素(地塞米松)。这表明 抗糖皮质激素可以用来挑战 下丘脑-垂体-肾上腺轴在需要临床检查时 患有这一轴紊乱的患者。类风湿性关节炎的抗糖皮质激素治疗 促肾上腺皮质激素异位分泌所致严重库欣综合征 肾上腺皮质肿瘤引起的临床症状缓解 皮质醇过多症。我们已经治疗了7名患者，目前正在扩大 治疗系列，包括库欣综合征患者 大手术。 月经周期黄体期每月单剂给妇女服用 RU 486会导致阴道出血。随后的周期是正常的 持续时间。这表明单剂RU 486可用于 避孕。

Clinically useful antagonists exist for estrogens, androgens, and mineralocorticoids. Antagonists for the glucocorticoids or the progestins with potential clinical usefulness have been discovered only recently. The objective of this project is to develop and study the molecular mechanisms of action and the human applications of the antagonists for both of these classes of steroids. Initially, we proved that glucocorticoid antagonists can be developed by modifications of the 11-position of the steroidal C ring of glucocorticoids. Then we tested a prototype glucocorticoid-progestin antagonist (RU 486) developed recently by Roussel-UCLAF. This compound has strong affinities for the human glucocorticoid and progestin receptor and is devoid of agonist effects in small experimental animals. Given to nonhuman primates or man RU 486 causes prolonged elevations of plasma ACTH, cortisol and arginine vasopressin, all changes preventable by previous administration of a glucocorticoid (dexamethasone). This suggests that antiglucocorticoids could be used for challenging the hypothalamic-pituitary-adrenal axis when clinical testing is required in patients with disorders of this axis. Antiglucocorticoid therapy of patients with severe Cushing's syndrome due to ectopic ACTH secretion or adrenocortical tumors causes remission of the clinical manifestations of hypercortisolism. We have treated 7 patients and are currently enlarging the therapy series, including patients with Cushing's syndrome prepared for major surgery. Given to women in single monthly doses during the luteal phase of the cycle RU 486 causes vaginal bleeding. The subsequent cycle is of normal duration. This suggests that single doses of RU 486 could be used for contraception.