Metformin Regulates Key MicroRNAs to Improve Endometrial Receptivity Through Increasing Implantation Marker Gene Expression in Patients with PCOS Undergoing IVF/ICSI

Abstract

To some extent, the use of metformin may improve endometrial receptivity and pregnancy outcomes of women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection. However, the mechanism is not well-known. The endometrium of metformin-treated group (metformin-treated patients with PCOS) and the control group (non-metformin-treated patients with PCOS) were analyzed for the expression of homeobox A10 (HOXA10) and integrin beta-3 (ITGB3) and differential micro RNA (miRNA) expression profiles. On this basis, miRDB and Target Scan databases were used to predict and screen out that miR-491-3p and miR-1910-3p may target HOXA10 and ITGB3. Furthermore, we verified the effects of metformin on the expression of HOXA10 and ITGB3, and regulatory effects of miR-1910-3p and miR-491-3p on HOXA10 and ITGB3 using Ishikawa cell line. Metformin induced a significant dose-dependent upregulation of HOXA10 and ITGB3. The results from the microarray analyses showed there were 40 differentially expressed miRNAs between the 2 groups. Among them, miR-1910-3p and miR-491-3p were the 2 significantly downregulated miRNAs. Bioinformatics prediction indicated that HOXA10 and ITGB3 are potential target genes for miR-1910-3p and miR-491-3p. In Ishikawa cells transfected with miR-491-3p mimics, the expression of HOXA10 and ITGB3 on both messenger RNA (mRNA) and protein level were lower than those in control group ( P < .001). Also, the expression of HOXA10 mRNA and protein was lower in Ishikawa cells transfected with miR-1910-3p mimics ( P < .001). However, no significant changes in ITGB3 levels were observed in cells transfected with miR-1910-3p mimics ( P > .05). Metformin likely improves endometrial receptivity through downregulating the expression of miR-491-3p and miR-1910-3p, thereby increasing the expression of HOXA10 and ITGB3 in the endometrium of PCOS women.

Expression and significance of miR-30d-5p and SOCS1 in patients with recurrent implantation failure during implantation window

“…For example, the results of animal experiments have shown that miR-223-3p suppresses the expression of LIF and pinopodes in the endometrium and may lead to implantation failure [21]. In the endometria of women with PCOS, metformin likely improves endometrial receptivity by downregulating the expression of miR-491-3p and miR-1910-3p, thereby increasing the expression of HOXA10 and ITGB3 [22]. More importantly, many studies have focused on miR-30d, which seems to be a favourable marker of endometrial receptivity.…”

Metformin reduces androgen receptor and upregulates homeobox A10 expression in uterine endometrium in women with polycystic ovary syndrome

“…However, there are no established mechanisms that explain how metformin directly affects the endometrium to regulate HOXA10 expression. Zhai et al has reported that miR-491-3p and miR-1910-3p are potential microRNAs that regulate HOXA10 expression using differential microRNA and target scanning databases [ 34 ]. These researchers have reported that metformin may improve endometrial receptivity by downregulating the expression of miR-491-3p and miR-1910-3p and increasing the expression of HOXA10 in PCOS endometrium [ 34 ].…”

Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next?

“…270 It was observed that metformin interacts with noncoding RNAs to regulate the expression of these genes. 271 It was uncovered that higher expression of endometrial progesterone receptor is associated with anovulation in PCOS patients. 272 Indeed, higher expression of endometrial progesterone receptor implies an underlying progesterone resistance in PCOS patients that can progress to endometrial hyperplasia.…”