Discovery of biomarkers of endometrial receptivity through a minimally invasive approach: a validation study with implications for assisted reproduction

Objective: To determine whether a minimally invasive approach to sampling endometrial cells that can be applied during an active conception cycle can generate robust biomarker candidates for endometrial receptivity by genomewide gene expression profiling. Design: Longitudinal study comparing gene expression profiles of cells isolated from uterine aspirates collected during the prereceptive and receptive phases of a natural cycle. Setting: University-affiliated hospital. Patient(s): Healthy volunteers, <= 40 years of age, with regular menstrual cycles and no history of infertility. Intervention(s): One menstrual cycle monitored with urinary kits to identify the luteinizing hormone (LH) surge; uterine aspirations collected at LH + 2 days (LH + 2) and at LH + 7; endometrial biopsy obtained on LH + 7; RNA extraction from the cellular material for gene expression profiling, and differential gene expression validated by NanoString assay and cross-validated against a publically available data set. Main Outcome Measure(s): Differentially expressed genes between LH + 2 and LH + 7 samples. Result(s): NanoString assay validated 96% of the 245 genes found differentially expressed at LH + 7. Unsupervised hierarchical clustering of aspiration and biopsy samples demonstrated the concordance of the sampling methods. A predictor gene cassette derived by a shrunken centroid class prediction technique correctly classified the receptive phase within an external data set. Conclusion(s): Uterine aspiration, which can be performed during an active conception cycle, identified robust candidate biomarkers of endometrial receptivity, and will enable their validation by direct correlation with clinical outcomes. ((C) 2013 by American Society for Reproductive Medicine.)