Abstract
Although estrogen has crucial functions for endometrium growth, the specific dose and underlying molecular mechanism in intrauterine adhesion (IUA) remain unclear. In this study, we aimed to investigate the effects of estrogen on epithelial-mesenchymal transition (EMT) in normal and fibrotic endometrium, and the role of estrogen and Wnt/β-catenin signaling in the formation of endometrial fibrosis. CCK-8 and immunofluorescence assay were performed to access the proliferation of different concentrations of estrogen on normal human endometrial epithelial cells (hEECs). qRT-PCR and western blot assay were utilized to explore the effect of estrogen on EMT in normal and fibrotic endometrium, and main components of Wnt/β-catenin signaling pathway in vitro. Hematoxylin and eosin and Masson staining were used to evaluate the effect of estrogen on endometrial morphology and fibrosis in vivo. Our results indicated that the proliferation of normal hEECs was inhibited by estrogen at a concentration of 30 nM accompanied by upregulation of mesenchymal markers and downregulation of epithelial markers. Interestingly, in the model of transforming growth factor β1 (TGF-β1)-induced endometrial fibrosis, the same concentration of estrogen inhibited the process of EMT, which might be partially mediated by regulation of the Wnt/β-catenin pathway. In addition, relatively high doses of estrogen efficiently increased the number of endometrial glands and reduced the area of fibrosis as determined by the reduction of EMT in IUA animal models. Taken together, our results demonstrated that an appropriate concentration of estrogen may prevent the occurrence and development of IUA by inhibiting the TGF-β1-induced EMT and activating the Wnt/β-catenin pathway.
Highlights
The endometrium is the inner layer of the uterus composed of epithelium and stromal components that under the effect of hormones receive embryo implantation [1,2]
Several treatment options including hysteroscopic adhesiolysis combined with intrauterine device and estrogen and progesterone have been effective for Intrauterine adhesion (IUA), its incidence and recurrence rates are still notably high [21]
We elucidated the influence of estrogen on the establishment and maintenance of epithelial-mesenchymal transition (EMT) in normal endometrium and fibrotic endometrium induced by TGFb1
Summary
The endometrium is the inner layer of the uterus composed of epithelium and stromal components that under the effect of hormones receive embryo implantation [1,2]. Intrauterine adhesion (IUA) is characterized by endometrial fibrosis. It is one of the most serious complications in patients with injuries of the endometrial basal layer, and repetitive injuries result in the formation of scar tissues that can partially or completely obstruct the uterine cavity [3]. The incidence of IUA among women of reproductive age in China has increased in recent years due to trauma and infections [4]. The current therapeutic lines mainly use hysteroscopic adhesiolysis combined with postoperative hormone therapies to prevent endometrial fibrosis and facilitate endometrial regeneration. Patients with severe adhesions still have a high recurrence rate and poor prognosis [6]
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