STEROID ANATAGONISTS

存在临床上有用的雌激素、雄激素和 矿物皮质激素。糖皮质激素的拮抗剂或 具有潜在临床用途的孕激素已被发现 只是最近。该项目的目标是开发和开发 研究作用的分子机制及其在人类中的应用 这两类类固醇的拮抗剂。 最初，我们证明了糖皮质激素拮抗剂可以 通过对甾体C的11位进行修饰而形成的 糖皮质激素环。然后我们测试了一个原型 新近开发的糖皮质激素-孕激素拮抗剂(RU 486) 鲁塞尔-UCLAF。这种化合物对人体有很强的亲和力 糖皮质激素和孕激素受体，缺乏激动剂 对小型实验动物的影响。 给非人类灵长类或人类使用RU 486会导致延长 血浆ACTH、皮质醇和精氨酸加压素升高 糖皮质激素可预防的变化 (地塞米松)。这表明抗糖皮质激素可能是 用于挑战下丘脑-垂体-肾上腺轴，当 患有这种疾病的患者需要进行临床测试。 轴心。重症库欣患者的抗糖皮质激素治疗 异位ACTH分泌或肾上腺皮质肿瘤所致综合征 引起缓解的临床表现 皮质醇过多症。我们已经治疗了8名患者，目前正在 扩大治疗系列。 在黄体期每月单次给妇女服用 RU 486周期会导致阴道出血。接下来的周期是 持续时间正常。这表明单剂RU 486 可以用来避孕。

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 8 patients and are currently enlarging the therapy series. 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.