ReviewInsights into human endometrial receptivity from transcriptomic and proteomic data
Introduction
Despite the many advances in assisted reproductive technology, lower implantation rates per transferred embryo remain a major problem in IVF. Implantation failure is thought to result, in large part, from abnormal uterine receptivity. Several parameters for assessing endometrial receptivity, such as endometrial morphology and endometrial and subendometrial blood flow, are commonly used in clinical practice, but are unsatisfactory due to their poor predictive value (Aghajanova et al., 2008, Ng et al., 2006, Quinn and Casper, 2009). Omics technologies, such as transcriptomic and proteomic approaches, have recently been used to identify biomarkers of human endometrial receptivity. In this way, some studies have identified new biomarkers of endometrial receptivity by analysing the gene- or protein-expression-profile shift between the pre-receptive and receptive stages of natural cycles (Carson et al., 2002, Domínguez et al., 2009, Díaz-Gimeno et al., 2011, Haouzi et al., 2009a, Li et al., 2006, Mirkin et al., 2005, Riesewijk et al., 2003, Talbi et al., 2006). A transcriptomic approach has been used to identify the impact of the different ovarian stimulation protocols used in IVF treatment on endometrial receptivity, by comparing either the receptive gene-expression profile between natural and stimulated cycles in different groups of patients (Horcajadas et al., 2005, Horcajadas et al., 2008, Liu et al., 2008, Mirkin et al., 2004, Simon et al., 2005) or the gene-expression-profile shift during the pre-receptive and receptive stages of natural versus stimulated cycles in the same patients (Haouzi et al., 2009b, Haouzi et al., 2010).
The aim of this review was to analyse the new insights on endometrial receptivity brought about by omics technologies, namely: (i) gene, protein or molecular signature used as biomarkers of endometrial receptivity and their predictive value in forecasting pregnancy outcome during IVF treatments; and (ii) transcriptomic profiling to determine the impact of ovarian stimulation protocols during IVF cycles.
Section snippets
Natural cycles
Recently, transcriptomic approaches have been used to identify biomarkers of the implantation window. Several studies have reported modifications in gene-expression profiles associated with the transition of the human endometrium from a pre-receptive (LH + 1/5) to a receptive (LH + 7/9) stage (Carson et al., 2002, Díaz-Gimeno et al., 2011, Haouzi et al., 2009a, Mirkin et al., 2005, Riesewijk et al., 2003, Talbi et al., 2006). However, only two genes were common to all these studies (Figure 1, Table
Endometrial biopsies
Previously, very few investigators have applied large-scale proteomic techniques to study endometrial receptivity. Of these reports, one focused on comparison between proliferative and secretory-phase endometrium using isotope-coded affinity-tag technology (DeSouza et al., 2005), whereas two others used two-dimensional differential in-gel electrophoresis (2D DIGE) followed by matrix-assisted laser desorption/ionization tandem time-of-flight MS to compare either late-proliferative and
Conclusions and perspectives
The use of omics tools to explore endometrial receptivity under stimulated cycles for IVF/ICSI contributes to improving the implantation and pregnancy success rate. Gene- as well as protein-expression profiles of endometrial receptivity under natural and stimulated cycles reveal significant differences. To date, transcriptomic and proteomic data have provided a set of genes or proteins that can be used as biomarkers for the assessment of the receptive status of the human endometrium. In
Acknowledgements
The authors thank the University-Hospital of Montpellier, the Association Française contre les Myopathies (AFM), Vitrolife, Genevrier, CCD and Ferring Pharmaceutical Companies for their support.
References (92)
- et al.
Uterine receptivity to human embryonic implantation: histology, biomarkers, and transcriptomics
Semin. Cell Dev. Biol.
(2008) - et al.
Endometrial morphology and hormonal profiles in in vitro fertilization patients
Eur. J. Obstet. Gynecol. Reprod. Biol.
(1992) - et al.
Local injury of the endometrium doubles the incidence of successful pregnancies in patients undergoing in-vitro fertilization
Fertil. Steril.
(2003) - et al.
Cytokine profiling in endometrial secretions: a non-invasive window on endometrial receptivity
Reprod. Biomed. Online
(2009) - et al.
Endometrial hormone receptors and proliferation index in the periovulatory phase of stimulated embryo transfer cycles in comparison with natural cycles and relation to clinical pregnancy outcome
Fertil. Steril.
(2002) - et al.
Meta-analysis of microarray results: challenges, opportunities, and recommendations for standardization
Gene
(2007) - et al.
The study of monoamine oxidase activity by histochemical procedures
Biochem. Pharmacol.
(1965) - et al.
Endometrial estrogen and progesterone receptor and pinopode expression in stimulated cycles of oocyte donors
Fertil. Steril.
(1999) - et al.
GnRH agonists and antagonists in assisted reproduction: pregnancy rate
Reprod. Biomed. Online
(2006) - et al.
GnRH agonist versus GnRH antagonist in poor ovarian responders: a meta-analysis
Reprod. Biomed. Online
(2006)
Local injury of the endometrium induces an inflammatory response that promotes successful implantation
Fertil. Steril.
Embryo-maternal signalling: how the embryo starts talking to its mother to accomplish implantation
Reprod. Biomed. Online
Regulation of endometrial cancer cell growth by insulin-like growth factors and the luteinizing hormone-releasing hormone antagonist SB-75
Regul. Pept.
Ultrastructural characteristics of the luteal phase endometrium in patients undergoing controlled ovarian hyperstimulation
Fertil. Steril.
Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up
Fertil. Steril.
Evidence for cycle-dependent expression of full-length human chorionic gonadotropin/luteinizing hormone receptor mRNA in human endometrium and decidua
Fertil. Steril.
Is human chorionic gonadotropin directly involved in the regulation of human implantation?
Mol. Cell. Endocrinol.
Biochemical evaluation of endometrial function at the time of implantation
Fertil. Steril.
Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles
Fertil. Steril.
The apolipoprotein L gene cluster has emerged recently in evolution and is expressed in human vascular tissue
Genomics
A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women
Fertil. Steril.
Embryo-induced alterations in the molecular phenotype of primate endometrium
J. Reprod. Immunol.
Hormonal patterns, steroid receptors and morphological pictures of endometrium in hyperstimulated IVF cycles
Eur. J. Obstet. Gynecol. Reprod. Biol.
Dating the endometrial biopsy
Fertil. Steril.
Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin)
Fertil. Steril.
GnRH agonist versus GnRH antagonist in controlled ovarian hyperstimulation: their role in patients with an unfavorable prognosis a priori
Fertil. Steril.
Protein profiling of human endometrial tissues in the midsecretory and proliferative phases of the menstrual cycle
Fertil. Steril.
Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period
Fertil. Steril.
Accelerated endometrial maturation in the luteal phase of cycles utilizing controlled ovarian hyperstimulation: impact of gonadotropin-releasing hormone agonists versus antagonists
Fertil. Steril.
Cyclical variations in endometrial monoamine oxidase: correlation of histochemical and quantitative biochemical assays
Biochem. Pharmacol.
Messenger ribonucleic acid for the gonadal luteinizing hormone/human chorionic gonadotropin receptor is not present in human endometrium
Fertil. Steril.
Luteinizing hormone affects uterine receptivity independently of ovarian function
Reprod. Biomed. Online
Endometrial osteopontin, a ligand of beta3-integrin, is maximally expressed around the time of the ‘implantation window’
Fertil. Steril.
Gonadotrophin-releasing hormone antagonists for assisted conception
Cochrane Database Syst. Rev.
Is there a uniform basal endometrial gene expression profile during the implantation window in women who became pregnant in a subsequent ICSI cycle?
Hum. Reprod.
Embryo implantation: the molecular mechanism remains elusive
Reprod. Biomed. Online
Morphometric analysis of peri-implantation endometrium in patients having excessively high oestradiol concentrations after ovarian stimulation
Hum. Reprod.
Status of hCG/LH receptor and G proteins in human endometrium during artificial cycles of hormone replacement therapy
J. Soc. Gynecol. Investig.
Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening
Mol. Hum. Reprod.
Proteomic characterization of midproliferative and midsecretory human endometrium
J. Proteome Res.
Effects of luteal estradiol on the secretory transformation of human endometrium and plasma gonadotropins
J. Clin. Endocrinol. Metab.
Proteomic analysis of the proliferative and secretory phases of the human endometrium: protein identification and differential protein expression
Proteomics
Improving the patient’s experience of IVF/ICSI: a proposal for an ovarian stimulation protocol with GnRH antagonist co-treatment
Hum. Reprod.
Pathogenic role of anti-beta 2-glycoprotein I antibodies in antiphospholipid associated fetal loss: characterisation of beta 2-glycoprotein I binding to trophoblast cells and functional effects of anti-beta 2-glycoprotein I antibodies in vitro
Ann. Rheum. Dis.
Pathogenic role of anti-beta2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin
Hum. Reprod. Update
A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature
Fertil. Steril.
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2022, PlacentaCitation Excerpt :The endometrium is composed of multiple cell types and undergoes profound morphological regeneration and remodeling in response to cyclic hormonal changes [32,33] (Fig. 1B). Over the past two decades, investigations on the transcriptional signature of endometrial biopsies (bulk RNA-sequencing) have provided insights into the repertoire of molecules expressed throughout the menstrual cycle, in both physiological and pathological conditions [34–47]. Nevertheless, reproducibility has proven challenging, leading to discrepancies in gene expression profiles amongst studies [48,49].
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Delphine Haouzi obtained her PhD from the University of Paris 7. Since 2007, she has been working on human endometrial receptivity and embryonic implantation. Her investigations have focused on the identification of biomarkers of human endometrial receptivity using microarray technology. She also investigated the impact of ovarian stimulation on endometrial receptivity as well as the understanding of early dialogues between trophectoderm and endometrial cells during the implantation period.