MicroRNAs as Biomarkers and Therapeutic Targets in Female Infertility

Abstract

The study of microRNAs (miRNAs) has emerged in recent decades as a key approach to understanding the pathophysiology of many diseases, exploring their potential role as biomarkers, and testing their use as future treatments. Not only have neurological, cardiovascular diseases, or cancer benefited from this research but also infertility. Female infertility, as a disease, involves alterations at multiple levels, such as ovarian and uterine alterations. This review compiles the latest studies published in humans that link female disorders that affect fertility with altered miRNA profiles. Studies on ovarian alterations, including diminished ovarian reserve (DOR), poor ovarian response to stimulation (POR), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are summarized and classified based on the expression and type of sample analyzed. Regarding uterine disorders, this review highlights upregulated and downregulated miRNAs primarily identified as biomarkers for endometriosis, adenomyosis, decreased endometrial receptivity, and implantation failure. However, despite the large number of studies in this field, the same limitations that reduce reproducibility are often observed. Therefore, at the end of this review, the main limitations of this type of study are described, as well as specific precautions or safety measures that should be considered when handling miRNAs.

Keywords: infertility; microRNA; ovarian alterations; uterine disorders.

Figure 1

Biogenesis of miRNAs and their regulatory function of gene expression. (a) miRNAs obtention and maturation process. In the canonical pathway, RNA-polymerase II transcribes the miRNA gene; the initial transcript generated is called pri-miRNA. Then, thanks to the type III ribonuclease activity of Drosha, the double-stranded RNA will be recognized and removed from the poly-A tail, giving rise to the pre-miRNA. This pre-miRNA is exported from the cell nucleus to the cytoplasm bound to Exportin-5 via the RanGTP/RanGDP transport system. Once in the cytoplasm, another type III ribonuclease, Dicer, cleaves the stem-loop-terminal region and generates a double-stranded miRNA. One of the two strands that form the mature miRNA will be degraded (called the passenger strand) by the argonaute protein with endonuclease activity or RNases present in the cytoplasm. The other strand of the miRNA will remain bound to the argonaute protein to perform its function. (b) Gene silencing. Post-transcriptional regulation of the expression of different genes can occur in two ways. (Left) When the complementarity of bases between the miRNA and the target mRNA is total, the argonaute protein itself, with its endonuclease activity, will destroy the miRNA. (Right) However, if this complementarity is not total, the RISC complex will remain and impede the progress of the translation process.