Background

Gonadotropin-releasing hormone agonists are used to treat premenopausal uterine leiomyomas; however, leiomyoma volume reduction is not always achieved. The reduction rate after this treatment varies for each leiomyoma, even in the same patient. Therefore, an effective method for predicting uterine leiomyoma volume reduction is required to reduce the adverse hypoestrogenic effects and drug-related economic burden related to gonadotropin-releasing hormone agonists.

Objective

This study aimed to determine the predictive use of MED12 mutations for evaluating the effect of gonadotropin-releasing hormone agonist treatment concerning reducing uterine leiomyoma volume and to predict the MED12 mutation status based on the findings of magnetic resonance imaging performed before treatment.

Study Design

MED12 exon 2 mutation and erythropoietin expression in uterine leiomyomas were evaluated concerning volume reduction, as measured using magnetic resonance imaging. We developed a system for classifying leiomyomas according to T2-weighted magnetic resonance imaging signals to noninvasively predict the presence or absence of MED12 mutations in leiomyomas. Leiomyoma samples (>5 cm) were obtained from 168 patients during surgery (hysterectomy or myomectomy) between 2005 and 2021 at Yokohama City University Hospital. To analyze the rate of leiomyoma volume reduction, 41 patients had been preoperatively administered the gonadotropin-releasing hormone agonist (leuprorelin acetate 3.75 mg, monthly subcutaneous injection) for 3 months; magnetic resonance imaging was performed before and after treatment without contrast material.

Results

Patients with MED12 exon 2 mutations had smaller volume reduction after treatment with the gonadotropin-releasing hormone agonist (P<.001, Mann-Whitney U test) and displayed lower signal intensity on T2-weighted images than those with leiomyomas expressing wild-type MED12 exon 2. The newly proposed magnetic resonance imaging–based classification system showed that MED12 exon 2 mutations were more frequent in the low-signal group than in the high-signal group, with nearly equal proportions of mutated and wild-type MED12 exon 2 leiomyomas noted in the intermediate group. The low-signal group had significantly lower erythropoietin expression levels than the high-signal group (P<.001, Kruskal-Wallis test with the Dunn posthoc analysis).

Conclusion

MED12 mutation status can be a candidate marker for predicting the effect of gonadotropin-releasing hormone agonists on uterine leiomyoma reduction. Magnetic resonance imaging findings can be used to determine MED12 mutation status as a noninvasive strategy to select patients who will most likely benefit from gonadotropin-releasing hormone agonist treatment.

中文翻译：

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子宫肌瘤的 MED12 突变：促性腺激素释放激素激动剂对体积缩小的预测

 背景

促性腺激素释放激素激动剂用于治疗绝经前子宫肌瘤；然而，平滑肌瘤体积缩小并非总能实现。即使是同一患者，每种平滑肌瘤治疗后的缩小率也不同。因此，需要一种有效的方法来预测子宫肌瘤体积缩小，以减少与促性腺激素释放激素激动剂相关的不良雌激素作用和药物相关的经济负担。

 客观的

本研究旨在确定MED12突变的预测用途，以评估促性腺激素释放激素激动剂治疗减少子宫肌瘤体积的效果，并根据治疗前进行的磁共振成像结果预测MED12突变状态。

 学习规划

通过磁共振成像测量，评估了子宫肌瘤中MED12外显子 2 突变和促红细胞生成素表达的体积减少情况。我们开发了一种根据 T2 加权磁共振成像信号对平滑肌瘤进行分类的系统，以无创地预测平滑肌瘤中是否存在MED12突变。平滑肌瘤样本（> 5 cm）取自 2005 年至 2021 年间在横滨市立大学医院进行手术（子宫切除术或子宫肌瘤切除术）的 168 名患者。为分析子宫肌瘤体积缩小率，41例患者术前给予促性腺激素释放激素激动剂（醋酸亮丙瑞林3.75 mg，每月皮下注射）3个月；在没有造影剂的情况下在治疗前后进行磁共振成像。

 结果

与表达野生型MED12的平滑肌瘤患者相比，患有MED12外显子 2 突变的患者在使用促性腺激素释放激素激动剂治疗后体积减少较小（ P <.001，Mann-Whitney U检验），并且在 T2 加权图像上显示出较低的信号强度外显子 2。新提出的基于磁共振成像的分类系统显示， MED12外显子 2 突变在低信号组中比在高信号组中更频繁，突变型和野生型MED12外显子 2 平滑肌瘤的比例几乎相等在中间组中注明。低信号组的促红细胞生成素表达水平显着低于高信号组（ P <.001，采用 Dunn 事后分析的 Kruskal-Wallis 检验）。

 结论

MED12突变状态可以作为预测促性腺激素释放激素激动剂对子宫肌瘤减少效果的候选标记。磁共振成像结果可用于确定MED12突变状态，作为一种无创策略来选择最有可能受益于促性腺激素释放激素激动剂治疗的患者。