Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
J Clin Endocrinol Metab. 2013 Jan;98(1):161-71. doi: 10.1210/jc.2012-2851. Epub 2012 Nov 16.
Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane] is the first-line treatment for metastatic adrenocortical carcinoma (ACC) and is also regularly used in the adjuvant setting after presumed complete removal of the primary tumor. Mitotane is considered an adrenolytic substance, but there is limited information on distinct effects on steroidogenesis. However, adrenal insufficiency and male hypogonadism are widely recognized side effects of mitotane treatment.
Our objective was to define the impact of mitotane treatment on in vivo steroidogenesis in patients with ACC.
At seven European specialist referral centers for adrenal tumors, we analyzed 24-h urine samples (n = 127) collected from patients with ACC before and during mitotane therapy in the adjuvant setting (n = 23) or for metastatic ACC (n = 104). Urinary steroid metabolite excretion was profiled by gas chromatography/mass spectrometry in comparison with healthy controls (n = 88).
We found a sharp increase in the excretion of 6β-hydroxycortisol over cortisol (P < 0.001), indicative of a strong induction of the major drug-metabolizing enzyme cytochrome P450 3A4. The contribution of 6β-hydroxycortisol to total glucocorticoid metabolites increased from 2% (median, interquartile range 1-4%) to 56% (39-71%) during mitotane treatment. Furthermore, we documented strong inhibition of systemic 5α-reductase activity, indicated by a significant decrease in 5α-reduced steroids, including 5α-tetrahydrocortisol, 5α-tetrahydrocorticosterone, and androsterone (all P < 0.001). The degree of inhibition was similar to that in patients with inactivating 5α-reductase type 2 mutations (n = 23) and patients receiving finasteride (n = 5), but cluster analysis of steroid data revealed a pattern of inhibition distinct from these two groups. Longitudinal data showed rapid onset and long-lasting duration of the observed effects.
Cytochrome P450 3A4 induction by mitotane results in rapid inactivation of more than 50% of administered hydrocortisone, explaining the need for doubling hydrocortisone replacement in mitotane-treated patients. Strong inhibition of 5α-reductase activity is in line with the clinical observation of relative inefficiency of testosterone replacement in mitotane-treated men, calling for replacement by 5α-reduced androgens.
米托坦[1-(2-氯苯基）-1-(4-氯苯基）-2,2-二氯乙烷]是转移性肾上腺皮质癌（ACC）的一线治疗药物，也常用于推定原发性肿瘤完全切除后的辅助治疗环境中。米托坦被认为是一种肾上腺溶解物质，但关于其对类固醇生成的具体作用的信息有限。然而，肾上腺功能不全和男性性腺功能减退症是米托坦治疗的广泛公认的副作用。
我们的目的是确定米托坦治疗对 ACC 患者体内类固醇生成的影响。
在欧洲七个肾上腺肿瘤专科转诊中心，我们分析了 23 例辅助治疗（n=23）或转移性 ACC（n=104）患者在米托坦治疗前和治疗期间收集的 24 小时尿液样本（n=127）。通过气相色谱/质谱法与健康对照（n=88）比较分析尿中类固醇代谢产物的排泄情况。
我们发现 6β-羟基皮质醇对皮质醇的排泄明显增加（P<0.001），表明主要药物代谢酶细胞色素 P450 3A4 被强烈诱导。6β-羟基皮质醇在总糖皮质激素代谢物中的贡献从 2%（中位数，四分位距 1-4%）增加到 56%（39-71%）在米托坦治疗期间。此外，我们记录到全身 5α-还原酶活性的强烈抑制，表现为 5α-还原类固醇的显著减少，包括 5α-四氢皮质醇、5α-四氢皮质酮和雄酮（均 P<0.001）。抑制程度与具有失活 5α-还原酶 2 型突变的患者（n=23）和接受非那雄胺治疗的患者（n=5）相似，但类固醇数据的聚类分析显示抑制模式与这两组不同。纵向数据显示，观察到的作用迅速发生并持续很长时间。
米托坦诱导细胞色素 P450 3A4 导致超过 50%的给予的氢化可的松迅速失活，这解释了为什么需要在接受米托坦治疗的患者中加倍氢化可的松替代治疗。5α-还原酶活性的强烈抑制与米托坦治疗男性中睾酮替代相对无效的临床观察一致，需要用 5α-还原雄激素替代。
