The Association Between Gene Expression in Cumulus Oophorus Cells and Human Embryo Developmental Potential: A Systematic Review of its Prognostic Utility for Intracytoplasmic Sperm Injection Success

Abstract

Background: The developmental potential of human embryos following intracytoplasmic sperm injection (ICSI) is influenced by both oocyte and follicular microenvironmental factors. Cumulus oophorus cells (COCs), which surround the oocyte and communicate bidirectionally with it through gap junctions, play a crucial regulatory role in oocyte maturation, fertilization, and early embryogenesis. The gene expression profiles of COCs have recently emerged as potential non-invasive biomarkers for assessing oocyte competence and predicting ICSI outcomes. Objective: This systematic review aims to evaluate the association between gene expression patterns in cumulus oophorus cells and embryo developmental potential, focusing on their prognostic utility for predicting fertilization success, embryo quality, and implantation rates in ICSI cycles. Methods: A comprehensive search was conducted in PubMed, Scopus, Web of Science, and Embase databases up to October 2025. Eligible studies included observational, prospective, and experimental studies investigating gene expression in COCs obtained from women undergoing ICSI. Data extraction included sample size, patient characteristics, ovarian stimulation protocols, analyzed genes, detection methods (e.g., RT-qPCR, microarray, RNA sequencing), and reported outcomes. Risk of bias was assessed using the Newcastle–Ottawa Scale for observational studies and the SYRCLE tool for animal models. Results: A total of 32 studies were included, encompassing over 2,800 oocyte–cumulus complexes. Several genes were consistently correlated with oocyte and embryo quality. Elevated expression of HAS2, GREM1, PTX3, CYP19A1, and AREG was associated with higher rates of fertilization and blastocyst formation. Conversely, altered expression of apoptotic and stress-related genes such as BAX, FAS, and HSP70 correlated with reduced developmental competence. Transcriptomic and microarray analyses identified distinct molecular signatures capable of discriminating between developmentally competent and incompetent oocytes. Despite promising findings, heterogeneity in study design, stimulation regimens, and normalization methods limited cross-study comparability. Conclusion: Gene expression profiling of cumulus oophorus cells provides a valuable, minimally invasive tool for predicting oocyte quality and embryonic developmental potential in ICSI cycles. However, the current evidence is limited by methodological variability and small sample sizes. Standardized molecular targets and validation across diverse populations are needed before clinical application. Future research integrating transcriptomic, proteomic, and metabolomic data may enhance the accuracy of non-invasive biomarkers for assisted reproductive technology (ART) outcomes.