Extracellular microRNAs: key players to explore the outcomes of in vitro fertilization

Abstract

Background MicroRNAs (miRNAs) are small RNA molecules that modulate post-transcriptional gene regulation. They are often used as promising non-invasive biomarkers for the early diagnosis of cancer. However, their roles in assisted reproduction are still unknown. Methods This prospective study was designed to evaluate the expression profiles of seven extracellular miRNAs (miR-7-5p, miR-202-5p, miR-378-3p, miR-224, miR-320a, miR-212-3p, and miR-21-5p) in human follicular fluid (FF) to explore the outcomes of in vitro fertilization (IVF). Of 255 women, 145 were without polycystic ovary syndrome (PCOS), and their ovarian assets were normal (NOR), while 110 were with normo-androgenic PCOS. Results The combination of six FF miRNAs expression profile discriminated between PCOS and NOR women with a sensitivity of 79.2% and a specificity of 87.32% (AUC = 0.881 [0.61; 0.92], p = 0.001). MiR-202-5p significantly had a lower abundance level, and miR-378-3p had a high abundance level in pooled FF samples from patients treated with human menopausal gonadotropin (hMG) than those treated with recombinant follicle-stimulating hormone (rFSH) (p < 0.001). Our results showed that miRNA-320a was significantly different in top-quality embryos versus non-top-quality embryos on day 3 in NOR patients with a sensitivity of 80% and specificity of 71%, (AUC = [0.753 (0.651; 0.855)], p = 0.001). For clinical pregnancy outcome prediction, FF miRNA-21 exhibited high sensitivity (74.8%) and specificity (83.7%) with the AUC value of 0.774 (0.682; 0.865). Conclusion Conclusively, our results provide evidence that miR-7-5p, miR-378-3p, miR-224, miR-212-3p were a differentially high expression in normo-androgenic PCOS patients than NOR patients. While miRNA-320a was significantly different in top-quality embryos versus non-top-quality embryos on day 3 (p = 0.001). The expression level of FF miR-212-3p was significantly related to the probability of embryos to develop into a high-quality blastocyst in patients with normal ovarian reserve.

Exosomal miR-143-3p derived from follicular fluid promotes granulosa cell apoptosis by targeting BMPR1A in polycystic ovary syndrome

“…Previous studies have shown that serum, follicular fluid and granulosa cells release large amounts of microvesicles containing both coding and noncoding RNAs, including miRNAs with multiple functional properties 16 – 19 . Thus, we hypothesized that PCOS-FF-exosomes might enhance apoptosis of granulosa cells by transferring specific miRNAs.…”

The Translational Role of miRNA in Polycystic Ovary Syndrome: From Bench to Bedside—A Systematic Literature Review

“…This role was confirmed by the study of Gay and colleagues, in which the knockout of the miR-202-5p gene in medaka ovaries reduced the expression of the Gdf and Foxl2b genes, resulting in either no oogenesis or the reduced production of oocytes that later fail to mature and fertilize [ 82 ]. The recently published prospective study by Khan and coworkers examined the expression profiles of several extracellular miRNAs in human follicular fluid with the aim of investigating the outcomes of the IVF/ICSI [ 115 ]. They examined a panel of several differentially expressed miRNAs (miR-7-5p, miR-202-5p, miR-378-3p, miR-224, miR-320a, miRNA-212-3p and miR-21-5p) that successfully discriminated between women with normoandrogenic PCOS and women with normal ovarian tests.…”

“…There is not yet sufficient and convincing evidence regarding the role of dysregulated miRNA in assisted reproductive technology. The results of Khan et al show the significantly differential expression of miR-320a in best-quality embryos compared with nonbest-quality embryos, with a sensitivity of 80% and a specificity of 71% (AUC = [0.753 (0.651; 0.855)], p = 0.001) [ 115 ]. Although there is growing evidence for the direct contribution of an altered miRNA profile and the potential for tailored IVF treatment strategies in the management of infertility, endometrial receptivity remains a limiting step for the overall success of IVF in humans.…”

“…As for the downregulated molecules, miR-29a, miR-24-3p and miR-574-3p were the most downregulated in women with PCOS compared to controls [ 113 ]. A combination panel of miR-let-7b, miR-30a and miR-140 expression demonstrated acceptable sensitivity and specificity in discriminating between PCOS and normal ovarian reserve, especially in IVF/ICSI [ 59 , 115 ]. Thus, this could be a novel biomarker that predicts outcomes and enables tailored medical care for patients with PCOS.…”

miR‑519d‑3p released by human blastocysts negatively regulates endometrial epithelial cell adhesion by targeting HIF1α

“…Characterized by high stability and disease-specific expression, the detection of extracellular miRNAs may provide novel and non-invasive biomarkers for embryo quality. Until now, several studies have reported that extracellular miRNAs may be associated with embryo development and implantation (15,16,28,29,(40)(41)(42)(43)(44)(45)(46)(47)(48). Rosenbluth et al (40) reported that decreased miR-372-3p and miR-373-3p in the ScM was associated with unsuccessful pregnancies.…”