15 years of transcriptomic analysis on endometrial receptivity: what have we learnt?

Over the course of the last four decades, IVF has allowed an increasing number of infertile couples the chance to conceive. Considering the extensive research and advances in ART, too many IVF attempts still do not result in a successful pregnancy [1, 2]. Embryo implantation is a crucial event in the establishment of a pregnancy. It is now clear that embryo implantation relies upon cross-talk and synchronicity between the implanting embryo and a receptive endometrium [3]. This embryo-maternal cross-talk involves an elaborate and coordinated network of communication via timely released embryonic, maternal-derived signals, and well-targeted actions [4]. If the clinical and culture conditions to obtain a “good quality” embryo are well advanced today, ER remains the last barrier in ART. When a high-quality embryo is transferred, impaired uterine receptivity is believed to be one of the major reasons behind failure of the establishment of pregnancy [5, 6]. It has been suggested in a few studies that up to two-thirds of implantation failures are due to defects in ER whereas the quality of the embryo itself is responsible for only one-third of failures [7, 8]. An endometrium is receptive to an embryo in a spatially and temporally restricted period called the window of implantation (WOI). In natural cycles, this period, occurring during the mid-secretory phase, is limited to approximately 48 h, starting around the seventh day after the LH (luteinizing hormone) surge [9, 10]. The dynamic transition from a non-receptive to a receptive endometrium is still poorly understood. Several reports have shown that ER is defined by specific changes in factors involved in adhesion, invasion, survival, growth, differentiation, decidualization and immuno-modulation. The correct spatio-temporal synthesis and balance of these various factors are thought to play an important role in human uterine preparation for implantation [4, 11]. Extensive efforts have been made to understand and characterize a receptive endometrium, from the first histological dating methods to the ‘omics’ technologies [3, 7, 12]. Several endometrial dating criteria have been commonly used in clinical practice. One or more panels of biomarkers, predictive of optimal ER, have been analyzed in blood and uterine fluid. Leukaemia inhibitor factor (LIF) is an example of a potential biomarker of the WOI [13]. However, this approach has been judged unsatisfactory by several studies because LIF measurements in serum do not reflect fertility status and similar conclusions were reported for other biomarkers [3, 14]. Cervical mucus has also been used to date ER by analyzing cytokines and growth factors produced by a receptive endometrium and their transport to the cervical mucus [15]. However, other studies have been unable to detect these growth factors in cervical secretions throughout the menstrual cycle and in these studies no correlation was observed between cytokine levels in cervico-vaginal secretions and serum and between the cytokines gene expression level in the secretory endometrium and the concentrations in serum [3, 16]. Another group evaluated ER during IVF cycles using three-dimensional power Doppler ultrasound [17]. However, Sterzik et al. concluded that ultrasonography is an inadequate method to predict ER in IVF cycles since neither the endometrial thickness nor the echogenic pattern correlate with histological findings [18]. As demonstrated, endometrial dating criteria have been questioned in various randomized studies. This has encouraged further investigation and application of new technologies to try to objectively diagnose ER. Omics technologies, such as transcriptomics, have been used to identify biomarkers of human endometrium [7, 19]. Based on the transcriptomic signature identified in these studies, only two ER diagnostic tools have been commercialized in order to personalize the frozen embryo transfer (FET): the ERA test (Endometrial Receptivity Array) [20] and the Win-Test (Window Implantation Test) [21]. In this review, we screened publications of the transcriptomic profiles of fertile and infertile women during the secretory phase of natural and stimulated cycles in order to understand lessons learned from endometrial gene profiling.

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