Metformin Alleviates Endometriosis and Potentiates Endometrial Receptivity via Decreasing VEGF and MMP9 and Increasing Leukemia Inhibitor Factor and HOXA10.

Jing Cheng,Yingfen Ying,Eileen Mcgowan,Yiguang Lin,Chunyang Li,Jieqiang Lv,Xueqiong Zhu,Xianqin Qu

doi:10.3389/fphar.2022.750208

Abstract

Background: Endometriosis affects endometrial receptivity, a key factor for successful embryo implantation. Metformin treatment is associated with alleviating the symptoms of endometriosis; however the mechanism of metformin action is unclear. Neoangiogenesis plays an important role in the development and recurrence of endometriosis. In addition, the leukemia inhibitor factor (LIF) and HOXA10 genes are also distinguishing markers of endometriosis (decrease) and endometrial receptivity (increase). This study investigated the therapeutic potentials of metformin and the underlying mechanism using an in vivo rat endometriosis model. Methods: Female Wistar albino mature rats with experimentally induced endometriosis were used in this study. Metformin was administered at doses of 100 mg/kg/d and 200 mg/kg/d. The volume of endometriotic implants was assessed. The protein and mRNA expression of the vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), the endometrial receptivity markers, LIF and HOXA10, were measured in the endometrium of rats with endometriosis. Results: Metformin treatment significantly suppressed the growth of endometriotic implants. Further, the expression of VEGF and MMP-9 protein and mRNA in endometriotic implants were significantly reduced. Metformin also significantly upregulated LIF and HOXA10 expression in endometrium from rats with endometriosis. The inhibitory effect of metformin on the growth of endometriotic implants, VEGF and MMP-9, and upregulating effect on LIF and HOXA10, was optimal at a dose of 100 mg/kg/d. Conclusion: Our in vivo data demonstrates that metformin treatment alleviates endometriosis and potentiates endometrial receptivity. The underlying mechanisms are associated with decreased expression of VEGF and MMP-9 genes and upregulation of the LIF and HOXA10 genes. The effect of metformin was optimal at 100 mg/kg/d. These findings provide a potential alternative for women with endometriosis with the potential to increase fertility. Metformin is an approved drug by FDA for diabetes and this study may add another potential clinical use for metformin.

Highlights

Endometriosis is a common disorder among women of reproductive age and is a major contributor to pelvic pain and infertility
At the end of the treatments, implant volumes were significantly lower in rats with both dosages of metformin treatment (Control: 198.39 mm3 ± 73.75, ML: 78.60 mm3 ± 25.11, MH: 117.18 mm3 ± 55.12; p < 0.001) (Table 1) with 100 mg/kg the optimal dosage
This study revealed that improvement in endometrial receptivity in rats with endometriosis treated with metformin correlated with an increase in the expression of the implantation markers, leukemia inhibitor factor (LIF) and homeobox A10 (HOXA10), within the endometrium

Summary

Introduction

Endometriosis is a common disorder among women of reproductive age and is a major contributor to pelvic pain and infertility. Endometriosis affects approximately 10–15% of women of reproductive age (Giudice, 2010; Dmitrieva et al, 2014; Sarria-Santamera et al, 2020; Rowlands et al, 2021). Neoangiogenesis plays an important role in the development and recurrence of endometriosis, as angiogenic stimuli provides the blood flow required for implantation and enables endometrial cells to attach and grow on the mesothelial surface. One important member of the MMPs family, MMP-9, is known to participate in both invasion and metastasis of various tumours, and potentially plays a crucial role in both occurrence and progression of endometriosis (Machado et al, 2016; Kim et al, 2017). Endometriosis affects endometrial receptivity, a key factor for successful embryo implantation. Neoangiogenesis plays an important role in the development and recurrence of endometriosis. This study investigated the therapeutic potentials of metformin and the underlying mechanism using an in vivo rat endometriosis model

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