Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Expert Opin Emerg Drugs. 2009 Dec;14(4):661-71. doi: 10.1517/14728210903413522.
Cushing's syndrome is a complex endocrine condition with potential serious complications if untreated or inadequately treated. Transsphenoidal surgery with resection of a pituitary adenoma is successful in 75 - 80% of patients, but approximately 20 - 25% show persistence of Cushing's, and a similar proportion may experience recurrence within 2 - 4 years post-op. When surgery fails, medical treatment can temporarily suppress excessive cortisol production and ameliorate its clinical manifestations while more definitive therapy becomes effective. We describe pharmacological approaches to the treatment of Cushing's syndrome. Drugs used to suppress cortisol secretion are mostly inhibitors of steroidogenesis. Ketoconazole, fluconazole aminoglutethimide, metyrapone, mitotane and etomidate are in that category. Ketoconazole is in current use while other drugs, although mostly available in the past, continue to have a potential role either alone or in combination. Drugs that suppress adrenocorticotropic hormone (ACTH) secretion are less popular as standard treatment and include cyproheptadine, valproic acid, cabergoline, somatostatin analogs, PPAR-gamma agonists, vasopressin antagonists. Some of these drugs have been tested in limited clinical trials but there is potential therapeutic benefit in analogs with better specificity for the class of receptors present in ACTH-secreting tumors. A third category of drugs is glucocorticoid receptor antagonists. Mifepristone is currently being tested in clinical trials in patients with persistent or recurrent Cushing's disease and in patients with metastatic adrenal cortical carcinoma or ectopic ACTH syndrome not amenable to surgery. We also review replacement therapy after surgery and non-specific drugs to treat complications in patients with severe hypercortisol. The review provides a complete survey of the drugs used in the medical treatment of Cushing's, and new advances in the development of pituitary-active drugs as well as receptor blockers of glucocorticoid action. It also provides avenues for exploration of new drugs active on somatostatin, dopamine and vasopressin receptors. There are effective pharmacological agents capable of chronically reversing biochemical and clinical manifestations of hypercortisolemia in Cushing's syndrome but new drugs are needed with action at the pituitary level.
库欣综合征是一种复杂的内分泌疾病，如果未经治疗或治疗不充分，可能会导致严重的并发症。经蝶窦手术切除垂体腺瘤对 75-80%的患者有效，但约 20-25%的患者存在库欣病持续存在，类似比例的患者可能在术后 2-4 年内复发。当手术失败时，药物治疗可以暂时抑制皮质醇的过度产生，并改善其临床表现，同时使更明确的治疗方法变得有效。我们描述了治疗库欣综合征的药理学方法。用于抑制皮质醇分泌的药物大多是类固醇生成抑制剂。酮康唑、氟康唑、氨基导眠能、美替拉酮和依托咪酯属于这一类。酮康唑目前正在使用，而其他药物虽然过去大多有供应，但在单独使用或联合使用时仍具有潜在作用。抑制促肾上腺皮质激素（ACTH）分泌的药物作为标准治疗方法不太受欢迎，包括赛庚啶、丙戊酸、卡麦角林、生长抑素类似物、过氧化物酶体增殖物激活受体-γ激动剂、血管加压素拮抗剂。这些药物中的一些已在有限的临床试验中进行了测试，但在针对 ACTH 分泌肿瘤中存在的受体类别的药物中具有潜在的治疗益处。第三类药物是糖皮质激素受体拮抗剂。米非司酮目前正在临床试验中测试用于治疗持续性或复发性库欣病患者，以及无法手术的转移性肾上腺皮质癌或异位 ACTH 综合征患者。我们还回顾了手术后的替代治疗以及治疗严重皮质醇过多的并发症的非特异性药物。该综述提供了库欣氏病药物治疗中使用的药物的完整调查，以及开发垂体活性药物和糖皮质激素作用受体阻滞剂的新进展。它还为探索对生长抑素、多巴胺和血管加压素受体有活性的新药提供了途径。有有效的药理制剂能够长期逆转库欣综合征中皮质醇过多的生化和临床表现，但需要新的药物作用于垂体水平。
