Paul Emmanuel N, Carpenter Tyler J, Bossick Andrew, Allo Ghassan, Wegienka Ganesa R, Teixeira Jose M
Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA.
Department of Public Health Sciences, Henry Ford Health, Detroit, MI, 48202, USA.
Reprod Sci. 2025 Jun 5. doi: 10.1007/s43032-025-01893-9.
Uterine fibroids, or leiomyomas, are noncancerous tumors of the myometrium and the most common tumors in women, with a cumulative incidence of approximately 80% by age 50. Currently, hysterectomy is the only definitive cure, and effective non-hormonal therapeutics are lacking. Understanding the etiology of fibroids may lead to alternative, less invasive treatments. Several obstetric disorders, including polycystic ovary syndrome (PCOS), have been linked to uterine fibroids, and women with PCOS often exhibit hormonal imbalances, particularly elevated serum testosterone levels. However, the impact of testosterone on the myometrium remains poorly understood. We hypothesize that elevated testosterone may increase the risk of developing uterine fibroids. Using RNA sequencing and MethylationEPIC array analyses, we compared myometrial tissue from women without fibroids (MyoN, n = 33), with fibroids (MyoF, n = 66), and after testosterone therapy as part of clinical care for gender dysphoria (MyoT, n = 7). The transcriptomic and methylation profiles of MyoT clustered with MyoF and were distinct from MyoN. We identified 1,321 differentially expressed protein-coding genes between MyoT and MyoN, while only 494 were found between MyoT and MyoF. Disease ontology analysis of MyoT vs. MyoN revealed enrichment of the fibroid tumor gene set. Fibroid associated genes including TGFβ3, CCND1, SERPINE1, and FGFR1 were upregulated in MyoT and MyoF samples compared to MyoN samples. The DNA methylation profiles of MyoT were closer to those of MyoF, but no correlation was observed between methylation status and gene expression. Our preliminary data suggest that exogenous testosterone induces transcriptional and methylation changes in the myometrium consistent with those observed in MyoF tissues. These findings suggest that elevated testosterone may be associated with an increased risk of developing uterine fibroids.
子宫肌瘤，又称平滑肌瘤，是子宫肌层的非癌性肿瘤，也是女性最常见的肿瘤，到50岁时累计发病率约为80%。目前，子宫切除术是唯一的根治方法，且缺乏有效的非激素治疗方法。了解肌瘤的病因可能会带来替代性的、侵入性较小的治疗方法。包括多囊卵巢综合征（PCOS）在内的几种产科疾病已与子宫肌瘤相关联，患有PCOS的女性通常表现出激素失衡，尤其是血清睾酮水平升高。然而，睾酮对子宫肌层的影响仍知之甚少。我们假设睾酮水平升高可能会增加患子宫肌瘤的风险。通过RNA测序和MethylationEPIC阵列分析，我们比较了无肌瘤女性（MyoN，n = 33）、有肌瘤女性（MyoF，n = 66）以及作为性别焦虑临床护理一部分接受睾酮治疗后的女性（MyoT，n = 7）的子宫肌层组织。MyoT的转录组和甲基化谱与MyoF聚类，与MyoN不同。我们在MyoT和MyoN之间鉴定出1321个差异表达的蛋白质编码基因，而在MyoT和MyoF之间仅发现494个。MyoT与MyoN的疾病本体分析显示肌瘤肿瘤基因集富集。与MyoN样本相比，包括TGFβ3、CCND1、SERPINE1和FGFR1在内的肌瘤相关基因在MyoT和MyoF样本中上调。MyoT的DNA甲基化谱更接近MyoF，但未观察到甲基化状态与基因表达之间的相关性。我们的初步数据表明，外源性睾酮会诱导子宫肌层的转录和甲基化变化，这与在MyoF组织中观察到的变化一致。这些发现表明，睾酮水平升高可能与患子宫肌瘤的风险增加有关。
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