Russo Marco, Scollo Claudia, Pellegriti Gabriella, Cotta Oana Ruxandra, Squatrito Sebastiano, Frasca Francesco, Cannavò Salvatore, Gullo Damiano
Department of Experimental and Clinical Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.
Department of Clinical and Experimental Medicine, Endocrinology, University of Messina, Messina, Italy.
Clin Endocrinol (Oxf). 2016 Apr;84(4):614-9. doi: 10.1111/cen.12868. Epub 2015 Aug 18.
Mitotane, a steroidogenesis inhibitor with adrenolytic properties used to treat adrenocortical cancer (ACC), can affect thyroid function. A reduction of FT4 levels with normal FT3 and TSH has been described in these patients. Using an in vitro murine model, the secretory capacity of thyrotrophic cells has been shown to be inhibited by mitotane.
To investigate the pathogenesis of thyroid abnormalities in mitotane-treated patients with ACC.
In five female patients with ACC (median age 47; range 31-65) treated with mitotane (dosage 1·5 g/day; 1·0-3·0), we analysed the pattern of TSH and thyroid function index (FT4, FT3 and FT3/FT4 ratio) compared to an age- and gender-matched control group. The in vivo secretory activity of the thyrotrophic cells was evaluated using a standard TRH test (200 μg), and the response was compared to both a group of age-matched female controls (n = 10) and central hypothyroid patients (n = 10).
Basal TSH (median 1·54 mU/l; range 1·20-2·17) was normal and scattered around our median reference value, FT3 levels (median 3·80 pmol/l; 3·30-4·29) were normal but below the median reference value of 4·37 pmol/l and FT4 levels were below the normal range in all patients (median 8·40 pmol/l; 7·6-9·9). FT3/FT4 ratio was in the upper range in 4 patients and higher than normal in one patient. A blunted TSH response to TRH was observed in mitotane-treated patients. ΔTSH (absolute TSH response, peak TSH minus basal TSH) was 3·65 (range 3·53-5·26), 12·37 (range 7·55-19·97) and 1·32 mU/l (range 0·52-4·66) in mitotane-treated patients, controls and central hypothyroid patients, respectively. PRL secretion was normal.
Mitotane-treated patients with ACC showed low FT4, normal FT3 and TSH and impaired TSH response to TRH, characteristic of central hypothyroidism. Furthermore, the elevated FT3/FT4 ratio of these subjects reflects an enhanced T4 to T3 conversion rate, a compensatory mechanism characteristic of thyroid function changes observed in hypothyroid conditions. This finding thus confirms in vitro studies and may have a therapeutic implication for treatment with thyroid hormones, as suggested by current guidelines for this specific condition.
米托坦是一种具有肾上腺溶解特性的类固醇生成抑制剂，用于治疗肾上腺皮质癌（ACC），它会影响甲状腺功能。在这些患者中已发现游离甲状腺素（FT4）水平降低，而游离三碘甲状腺原氨酸（FT3）和促甲状腺激素（TSH）水平正常。利用体外小鼠模型已证明米托坦可抑制促甲状腺细胞的分泌能力。
研究米托坦治疗的ACC患者甲状腺异常的发病机制。
我们分析了5例接受米托坦治疗（剂量为1.5 g/天；1.0 - 3.0）的女性ACC患者（中位年龄47岁；范围31 - 65岁）的TSH模式以及甲状腺功能指标（FT4、FT3和FT3/FT4比值），并与年龄和性别匹配的对照组进行比较。使用标准促甲状腺激素释放激素（TRH）试验（200 μg）评估促甲状腺细胞的体内分泌活性，并将反应与一组年龄匹配的女性对照组（n = 10）和中枢性甲状腺功能减退患者（n = 10）进行比较。
基础TSH（中位值1.54 mU/l；范围1.20 - 2.17）正常，分散在我们的中位参考值附近，FT3水平（中位值3.80 pmol/l；3.30 - 4.29）正常但低于4.37 pmol/l的中位参考值，所有患者的FT4水平均低于正常范围（中位值8.40 pmol/l；7.6 - 9.9）。4例患者的FT3/FT4比值处于较高范围，1例患者高于正常。在米托坦治疗的患者中观察到TSH对TRH的反应迟钝。米托坦治疗的患者、对照组和中枢性甲状腺功能减退患者的TSH变化量（绝对TSH反应，峰值TSH减去基础TSH）分别为3.65（范围3.53 - 5.26）、12.37（范围7.55 - 19.97）和1.32 mU/l（范围0.52 - 4.66）。催乳素分泌正常。
米托坦治疗的ACC患者表现为FT4降低、FT3和TSH正常以及TSH对TRH的反应受损，这是中枢性甲状腺功能减退的特征。此外，这些受试者升高的FT3/FT4比值反映了T4向T3转化率的提高，这是甲状腺功能减退状态下甲状腺功能变化的一种代偿机制。这一发现从而证实了体外研究结果，并且可能对甲状腺激素治疗具有治疗意义，正如针对这种特定情况的现行指南所建议的那样。
