Faculté de Médecine Paris-Sud, Unité Mixte de Recherche S693, and Institut National de la Santé et de la Recherche Médicale Unité 693, Université Paris-Sud, Le Kremlin Bicêtre F-94276, France.
J Clin Endocrinol Metab. 2011 Sep;96(9):2796-804. doi: 10.1210/jc.2011-0536. Epub 2011 Jul 13.
Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism.
Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushing's syndrome.
PATIENTS, DESIGN, AND SETTING: Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital.
High-dose therapy combining mitotane (3.0-5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 μg/24 h) was monitored.
Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 μg/24 h (range 853-22,605) at baseline to 50 μg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 μg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively).
When surgical treatment for severe ACTH-dependent Cushing's syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.
米托坦在库欣综合征的长期治疗中非常有效，但起效缓慢。米托坦联合作用迅速的类固醇生成抑制剂，可能避免在严重皮质醇增多症患者中紧急进行双侧肾上腺切除术的需要。
我们的目的是评估米托坦、美替拉酮和酮康唑联合治疗严重 ACTH 依赖性库欣综合征的疗效和安全性。
患者、设计和环境：11 例严重库欣综合征患者在一家三级转诊医院参与了这项随访研究。
同时起始高剂量联合治疗，包括米托坦（3.0-5.0 g/24 h）、美替拉酮（3.0-4.5 g/24 h）和酮康唑（400-1200 mg/24 h）。监测 24 小时尿游离皮质醇（UFC）排泄量（正常值为 10-65 μg/24 h）。
数据以中位数（范围）报告。所有 11 例患者均获得显著临床改善。UFC 排泄量从基线时的 2737 μg/24 h（范围 853-22605）迅速下降至治疗开始后 24-48 小时的 50 μg/24 h（范围 18-298）（P = 0.001），且在联合治疗期间保持低至正常水平。在 7 例患者中，在联合治疗 3.5 个月（范围 3.0-6.0）后停用美替拉酮和酮康唑，米托坦单药治疗仍能控制 UFC 排泄（UFC 17 μg/24 h，范围 5-85；P = 0.016）。5 例患者能够接受病因治疗手术，目前处于缓解期。其中 4 例在停用米托坦后恢复正常肾上腺功能。不良反应可耐受，主要为胃肠道不适和总胆固醇和γ-谷氨酰转移酶水平显著升高（P = 0.012 和 P = 0.002）。
当严重 ACTH 依赖性库欣综合征的手术治疗不可行时，米托坦、美替拉酮和酮康唑联合治疗是双侧肾上腺切除术的有效替代方法，后者与显著的发病率和永久性肾上腺功能减退相关。
