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

Abstract

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.

Keywords: Endometrium; gene expression profiling; implantation; menstrual cycle; uterine aspiration.