Biomarkers Assessing the Role of Cumulus Cells on IVF Outcomes: A Systematic Review

PURPOSE: Although significant improvements in assisted reproductive technology (ART) outcomes have been accomplished, a critical question remains: which embryo is most likely to result in a pregnancy? Embryo selection is currently based on morphological and genetic criteria; however, these criteria do not fully predict good-quality embryos and additional objective criteria are needed. The cumulus cells are critical for oocyte and embryo development. This systematic review assessed biomarkers in cumulus-oocyte complexes and their association with successful IVF outcomes. METHODS: A comprehensive search was conducted using PubMed, Embase, Scopus, and Web of Science from inception until November 2022. Only English-language publications were included. Inclusion criteria consisted of papers that evaluated genetic biomarkers associated with the cumulus cells (CCs) in humans and the following three outcomes of interest: oocyte quality, embryo quality, and clinical outcomes, including fertilization, implantation, pregnancy, and live birth rates. RESULTS: The search revealed 446 studies of which 42 met eligibility criteria. Nineteen studies correlated genetic and biochemical biomarkers in CCs with oocyte quality. A positive correlation was reported between oocyte quality and increased mRNA expression in CCs of genes encoding for calcium homeostasis (CAMK1D), glucose metabolism (PFKP), extracellular matrix (HAS2, VCAN), TGF-β family (GDF9, BMP15), and prostaglandin synthesis (PTGS2). Nineteen studies correlated genetic and biochemical biomarkers in CCs with embryo quality. A positive correlation was reported between embryo quality and increased mRNA expression in CCs of genes encoding for extracellular matrix (HAS2), prostaglandin synthesis (PTGS2), steroidogenesis (GREM1), and decreased expression of gene encoding for hormone receptor (AMHR2). Twenty-two studies assessed genetic and biochemical biomarkers in CCs with clinical outcomes. Increased expression of genes encoding for extracellular matrix (VCAN), and TGF-β family (GDF9, BMP15) were positively correlated with pregnancy rate. CONCLUSION: Genetic biomarkers from cumulus cells were associated with oocyte quality (CAMK1D, PFKP, HAS2, VCAN, GDF-9, BMP-15, PTGS2), embryo quality (GREM1, PTGS2, HAS2), and pregnancy rate (GDF9, BMP15, VCAN). These results might help guide future studies directed at tests of cumulus cells to devise objective criteria to predict IVF outcomes.