Tamoxifen Alleviates Endometrial Fibrosis Induced by Anhydrous Ethanol in Rats.

Abstract

As an estrogen receptor modulator, tamoxifen has been utilized in the treatment of fibrotic diseases. However, there is a limited body of research focusing on its potential application in addressing endometrial fibrosis conditions. Our research aims to investigate the effects of tamoxifen at different dosage levels in alleviating endometrial fibrosis and to elucidate its mechanisms of action during the initial stages of endometrial damage. A total of thirty sexually mature, unmated female Sprague-Dawley (SD) rats were divided into six distinct groups. To establish the rat uterine adhesion model, the uterine cavity was subjected to perfusion with anhydrous ethanol. The control group received a saline solution, while the treatment group was administered oral estrogen in combination with tamoxifen at doses of 4 mg/kg/d, 20 mg/kg/d, and 40 mg/kg/d. Various techniques, including Hematoxylin and Eosin (HE) staining, Masson's Trichrome staining, Western Blotting analysis, and immunohistochemistry, were employed to assess changes in endometrial thickness, fibrosis, as well as alterations in indicators related to epithelial-mesenchymal transition (EMT), fibrosis, estrogen receptors within the endometrium, and vascular endothelial growth factor (VEGF). In the model group, the levels of endometrial thickness, E-cadherin, Vimentin, estrogen receptor α (ERα), G protein-coupled receptor 30 (GPR30), and VEGF proteins were significantly lower compared to the control group. Conversely, the levels of collagen accumulation, Smooth Muscle Actin (SMA), Transforming Growth Factor β1 (TGFβ1), Drosophila mothers against decapentaplegic protein 2 (Smad2) , and Smad3 were markedly higher than those observed in the control group (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). In contrast, the low-dose tamoxifen group demonstrated significant increases in endometrial thickness, E-cadherin, Vimentin, ERα, GPR30, and VEGF when compared to the model group (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). Moreover, the levels of collagen accumulation, TGFβ1, SMA, Smad2, and Smad3, which are indicative of fibrosis and the TGFβ1/Drosophila mothers against decapentaplegic (smad) pathway, were notably reduced compared to the model group (p < 0.05, p < 0.0001). The results of this study suggest that the administration of a low dose (4 mg/kg/d) of tamoxifen in the early stages of endometrial injury may mitigate epithelial-mesenchymal transition (EMT) indicators and reduce fibrosis within the endometrium induced by anhydrous ethanol.