Role of endometrial microRNAs in repeated implantation failure (mini-review)

Abstract

MicroRNAs (miRNAs) play various roles in the implantation and pregnancy process. Abnormal regulation of miRNAs leads to reproductive disorders such as repeated implantation failure (RIF). During the window of implantation, different miRNAs are released from the endometrium, which can potentially reflect the status of the endometrium for in vitro fertilization (IVF). The focus of this review is to determine whether endometrial miRNAs may be utilized as noninvasive biomarkers to predict the ability of endometrium to implant and provide live birth during IVF cycles. The levels of certain miRNAs in the endometrium have been linked to implantation potential and pregnancy outcomes in previous studies. Endometrial miRNAs could be employed as non-invasive biomarkers in the assisted reproductive technology (ART) cycle to determine the optimal time for implantation. Few human studies have evaluated the association between ART outcomes and endometrial miRNAs in RIF patients. This review may pave the way for more miRNA transcriptomic studies on human endometrium and introduce a specific miRNA profile as a multivariable prediction model for choosing the optimal time in the IVF cycle.

Keywords: art; endometrial receptivity; miRNAs; pregnancy; transcriptome.

FIGURE 1

Types of RIF and their causes. The failure of an embryo to implant into the uterine wall after multiple transfers during IVF treatment is referred to as RIF or recurrent implantation failure. RIF types are divided into three categories: Endometrial RIF, which occurs due to the low thickness (≤6 mm) of the endometrium; idiopathic RIF, which is unexplained failure to achieve pregnancy after the transfer of good quality embryos; multifactorial RIF, which is caused by a wide variety of reasons (male-related factors, genetic abnormalities, infections, immunological factors, psychological factors, lifestyle, and other similar variables).

FIGURE 2

Relationship between the endometrial miRNA expression and implantation. (A) Pro-implantation miRNA. The expression of the miRNA has a positive association with the implantation outcome. (B) Anti-implantation miRNA. The expression of the miRNA has a negative association with the implantation outcome. (C) Endometrial miRNAs lead to implantation failure through their effect on target mRNA in the endometrial tissue of RIF patients. The red circle represents miRNA, the green and purple circles represent mRNA, the orange circle represents hormones, the yellow circle represents the drug, the blue circle represents the signaling pathway, and the navy blue circle represents infection. The miRNA-mRNA network is based on Section 4in this article.

FIGURE 3

MiRNAs as biomarkers. In this graph, mRNAs and miRNAs are compared as two biomarker candidates. MiRNAs can be used as therapeutic targets in a number of ways. Depending on whether the miRNA is upregulated or downregulated in the disease, there are generally two approaches: miRNA inhibition and miRNA replacement. If an increase in the miRNA expression leads to pathology (e.g., RIF), the use of miRNA antagomirs in therapeutic methods will prevent the binding of miRNAs to the target mRNA and will reduce the symptoms of the disease. On the other hand, if a reduction in miRNA expression leads to pathology, a miRNA delivery system (miRNA mimic) can be used. There are several techniques for detecting miRNAs (northern blotting, reverse transcription quantitative real-time PCR (RT-qPCR), microarray technology, nanomaterial-based methods, and nucleic acid amplification).