Ambrosi Bruno, Dall'Asta Chiara, Cannavo Salvatore, Libe Rossella, Vigo Teresa, Epaminonda Paolo, Chiodini Iacopo, Ferrero Stefano, Trimarchi Francesco, Arosio Maura, Beck-Peccoz Paolo
Endocrinology Unit, Department of Medical and Surgical Sciences, University of Milan, Istituto Policlinico San Donato, San Donato Milanese, Milan, Italy.
Eur J Endocrinol. 2004 Aug;151(2):173-8. doi: 10.1530/eje.0.1510173.
Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD).
Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration.
In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells.
The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.
罗格列酮是一种噻唑烷二酮类化合物，与过氧化物酶体增殖物激活受体γ（PPAR-γ）具有结合亲和力，能够抑制经治疗小鼠及AtT20垂体瘤细胞中促肾上腺皮质激素（ACTH）的分泌。这些观察结果提示噻唑烷二酮类药物可能对库欣病（CD）有效。
对14例活动性CD患者（13例女性，1例男性，年龄18 - 68岁）给予罗格列酮（8毫克/天）治疗。在服用罗格列酮前及服药期间每月测量血浆ACTH、血清皮质醇（F）和尿游离皮质醇（UFC）水平。
6例患者在开始服用罗格列酮30 - 60天后，观察到ACTH和F水平降低，UFC恢复正常：UFC治疗前与治疗后的值有显著差异（1238±211 vs 154±40纳摩尔/24小时，P<0.03），但ACTH（15.9±3.7 vs 7.9±0.9皮摩尔/升）和F水平（531±73 vs 344±58纳摩尔/升）无显著差异。6例中的2例随访7个月，显示有轻度临床改善。8例患者在罗格列酮治疗30 - 60天后无反应：其ACTH, F和UFC水平在给药前和给药期间无差异。对2例有反应和2例无反应患者切除的垂体瘤进行免疫组织化学分析显示，约50%的细胞中PPAR-γ有相似的强免疫反应性。
罗格列酮给药似乎能使部分CD患者的皮质醇分泌恢复正常，至少在短期内如此。罗格列酮激活PPAR-γ是否能作为CD的慢性药物治疗有效，需要通过随机对照研究进行更广泛的调查。
