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Geburtshilfe Frauenheilkd 2016; 76(06): 699-703
DOI: 10.1055/s-0042-103752
Review
GebFra Science
Georg Thieme Verlag KG Stuttgart · New York

Diagnosis of Endometrial-Factor Infertility: Current Approaches and New Avenues for Research

Die Bedeutung des Endometriums in der Infertilitätsdiagnostik: aktueller Stand und neue Forschungsansätze
N. Katzorke
1   Fundación Instituto Valenciano de Infertilidad, Department of Obstetrics and Gynecology, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia University, Valencia, Spain
2   Department of Obstetrics and Gynecology, Heinrich Heine University Medical Center, Düsseldorf, Germany
,
F. Vilella
1   Fundación Instituto Valenciano de Infertilidad, Department of Obstetrics and Gynecology, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia University, Valencia, Spain
,
M. Ruiz
1   Fundación Instituto Valenciano de Infertilidad, Department of Obstetrics and Gynecology, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia University, Valencia, Spain
,
J.-S. Krüssel
2   Department of Obstetrics and Gynecology, Heinrich Heine University Medical Center, Düsseldorf, Germany
,
C. Simón
1   Fundación Instituto Valenciano de Infertilidad, Department of Obstetrics and Gynecology, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia University, Valencia, Spain
3   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America
› Author Affiliations
Further Information

Publication History

received 08 January 2016
revised 21 February 2016

accepted 23 February 2016

Publication Date:
27 June 2016 (online)

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Abstract

Over the last decade, research to improve success rates in reproductive medicine has focused predominantly on the understanding and optimization of embryo quality. However, the emergence of personalized medicine in ovulation induction and embryology has shifted the focus to assessing the individual status of the endometrium. The endometrium is considered receptive during an individually defined period, the window of implantation (WOI), when the mother permits a blastocyst to attach and implant. This individual receptivity status can now be objectively diagnosed using the endometrial receptivity array (ERA) developed in 2011. The ERA, together with a computational algorithm, detects the unique transcriptomic signature of endometrial receptivity by analyzing 238 differentially expressed genes and reliably predicting the WOI. We and others have illustrated the utility of this personalized diagnostic approach to discriminate between individual physiological variation in endometrial receptivity and unknown endometrial pathology, deemed as causal in recurrent implantation failure (RIF). An international randomized controlled trial (“The ERA as a diagnostic guide for personalized embryo transfer.” ClinicalTrials.gov Identifier: NCT01954758) is underway to determine the clinical value of this endometrial diagnostic intervention in the work-up for reproductive care. In this review, we analyse the current clinical practice in the diagnosis of the endometrial factor together with new avenues of research.

Zusammenfassung

Die Verbesserung der Erfolgsraten der assistierten Reproduktion hat sich bisher vor allem auf das Verständnis sowie die Optimierung der Embryoqualität konzentriert. Erst durch die Einführung der personalisierten Medizin im Rahmen der Ovulationsinduktion und in der Embryologie hat sich der Fokus auch auf den individuellen Status des Endometriums erweitert. Die endometriale Rezeptivität definiert den persönlichen Zeitraum, in dem sich der im Blastozystenstadium befindliche Embryo an das hormonell regulierte Endometrium einer Frau anheften und einnisten kann. Durch den 2011 patentierten Endometrial Receptivity Array (ERA) steht erstmals ein objektiver diagnostischer Test zur Bestimmung der rezeptiven Phase des Endometriums zur Verfügung. ERA identifiziert das transkriptomische Profil des Endometriums anhand der Signatur von 238 unterschiedlich exprimierten Genen in Verbindung mit einem computerbasierten Prädiktor und klassifiziert darauf beruhend den rezeptiven Status der Patientin. Die Bedeutung dieser personalisierten Untersuchung des Endometriums, die zwischen individueller physiologischer Variabilität der endometrialen Rezeptivität und unbekannter Pathologie des Endometriums unterscheiden kann, konnte sowohl durch uns als auch durch andere Gruppen bisher bei Patientinnen mit rezidivierendem Implantationsversagen (RIF) gezeigt werden. Auf diesen Ergebnissen aufbauend, wird der Nutzen von ERA in der Routinediagnostik bei unerfülltem Kinderwunsch aktuell in einer internationalen, randomisierten, kontrollierten Studie („The ERA as a diagnostic guide for personalized embryo transfer.“ ClinicalTrials.gov Identifier: NCT01954758) untersucht.

Key words

endometrial receptivity array (ERA) - microRNA - window of implantation - implantation failure - assisted reproduction

Schlüsselwörter

endometriale Rezeptivität - Implantationsfenster (WOI) - assistierte Reproduktionstechniken (ART) - micro-Ribonucleinsäure (RNA)
 

  • References

  • 1 Cha J, Vilella F, Dey SK, Simón C. Molecular Interplay in successful Implantation. In: Sanders S, ed. Ten critical Topics in reproductive Medicine. Washington, DC: Science/AAAS; 2013: 44-48
    Google Scholar
  • 2 Niakan KK, Han J, Pedersen RA et al. Human pre-implantation embryo development. Development 2012; 139: 829-841
    CrossrefPubMedGoogle Scholar
  • 3 Thouas GA, Dominguez F, Green MP et al. Soluble ligands and their receptors in human embryo development and implantation. Endocr Rev 2015; 36: 92-130
    CrossrefPubMedGoogle Scholar
  • 4 Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 1999; 340: 1796-1799
    CrossrefPubMedGoogle Scholar
  • 5 Direito A, Bailly S, Mariani A et al. Relationships between the luteinizing hormone surge and other characteristics of the menstrual cycle in normally ovulating women. Fertil Steril 2013; 99: 279-285
    CrossrefPubMedGoogle Scholar
  • 6 Ruiz-Alonso M, Blesa D, Diaz-Gimeno P et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril 2013; 100: 818-824
    CrossrefPubMedGoogle Scholar
  • 7 Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update 2006; 12: 731-746
    CrossrefPubMedGoogle Scholar
  • 8 Noyes RW, Herting AT, Rock J. Dating the endometrial biopsy. Fertil Steril 1950; 1: 3-25
    PubMedGoogle Scholar
  • 9 Coutifaris C, Myers ER, Guzick DS et al. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004; 1264-1272
    PubMedGoogle Scholar
  • 10 Murray MJ, Meyer WR, Zaino RJ et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril 2004; 81: 1333-1343
    CrossrefPubMedGoogle Scholar
  • 11 Balasch J, Fabregues F, Creus M et al. The usefulness of endometrial biopsy for luteal phase evaluation in infertility. Hum Reprod 1992; 7: 973-977
    CrossrefPubMedGoogle Scholar
  • 12 Balasch J, Vanrell JA, Creus M et al. The endometrial biopsy for diagnosis of luteal phase deficiency. Fertil Steril 1985; 44: 699-701
    PubMedGoogle Scholar
  • 13 Scott RT, Snyder RR, Strickland DM et al. The effect of interobserver variation in dating endometrial histology on the diagnosis of luteal phase defects. Fertil Steril 1988; 50: 888-892
    PubMedGoogle Scholar
  • 14 Scott RT, Snyder RR, Bagnall JW et al. Evaluation of the impact of intraobserver variability on endometrial dating and the diagnosis of luteal phase defects. Fertil Steril 1993; 60: 652-657
    PubMedGoogle Scholar
  • 15 Gibson M, Badger GJ, Byrn F et al. Error in histologic dating of secretory endometrium: variance component analysis. Fertil Steril 1991; 56: 242-247
    PubMedGoogle Scholar
  • 16 Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33: 159-174
    CrossrefPubMedGoogle Scholar
  • 17 Ordi J, Creus M, Quinto L et al. Within-subject between-cycle variability of histological dating, alpha versus beta 3 integrin expression, and pinopod formation in the human endometrium. J Clin Endocrinol Metab 2003; 88: 2119-2125
    CrossrefPubMedGoogle Scholar
  • 18 Aghajanova L, Simon C, Horcajadas J. Are favourite molecules of endometrial receptivity still in favour?. Expert Rev Obstet Gynecol 2008; 3: 487-501
    PubMedGoogle Scholar
  • 19 Ruiz-Alonso M, Blesa D, Simon C. The genomics of the human endometrium. Biochim Biophys Acta 2012; 1822: 1931-1942
    CrossrefPubMedGoogle Scholar
  • 20 Galliano D, Pellicer A. MicroRNA and implantation. Fertil Steril 2014; 101: 1531-1544
    CrossrefPubMedGoogle Scholar
  • 21 Borthwick JM, Charnock-Jones DS, Tom BD et al. Determination of the transcript profile of human endometrium. Mol Hum Reprod 2003; 9: 19-33
    CrossrefPubMedGoogle Scholar
  • 22 Ponnampalam AP, Weston GC, Trajstman AC et al. Molecular classification of human endometrial cycle stages by transcriptional profiling. Mol Hum Reprod 2004; 10: 879-893
    CrossrefPubMedGoogle Scholar
  • 23 Horcajadas JA, Pellicer A, Simon C. Wide genomic analysis of human endometrial receptivity: new times, new opportunities. Hum Reprod Update 2007; 13: 77-86
    CrossrefPubMedGoogle Scholar
  • 24 Koler M, Achache H, Tsafrir A et al. Disrupted gene pattern in patients with repeated in vitro fertilization (IVF) failure. Hum Reprod 2009; 24: 2541-2548
    CrossrefPubMedGoogle Scholar
  • 25 Altmäe S, Martinez-Conejero JA, Salumets A et al. Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility. Mol Hum Reprod 2010; 16: 178-187
    CrossrefPubMedGoogle Scholar
  • 26 Tapia A, Vilos C, Marín JC et al. Bioinformatic detection of E47, E2F1 and SREBP1 transcription factors as potential regulators of genes associated to acquisition of endometrial receptivity. Reprod Biol Endocrinol 2011; 27: 9-14
    PubMedGoogle Scholar
  • 27 Matsuzaki S. DNA microarray analysis in endometriosis for development of more effective targeted therapies. Front Biosci (Elite Ed) 2011; 3: 1139-1153
    PubMedGoogle Scholar
  • 28 Habermann JK, Bündgen NK, Gemoll T et al. Genomic instability influences the transcriptome and proteome in endometrial cancer subtypes. Mol Cancer 2011; 10: 132
    CrossrefPubMedGoogle Scholar
  • 29 Simon C, Oberyé J, Bellver J et al. Similar endometrial development in oocyte donors treated with either high- or standard-dose GnRH antagonist compared to treatment with a GnRH agonist or in natural cycles. Human Reprod 2005; 20: 3318-3327
    CrossrefPubMedGoogle Scholar
  • 30 Horcajadas JA, Riesewijk A, Polman J et al. Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles. Mol Hum Reprod 2005; 11: 195-205
    CrossrefPubMedGoogle Scholar
  • 31 Diaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril 2011; 95: 50-60
    CrossrefPubMedGoogle Scholar
  • 32 Diaz-Gimeno P, Ruiz-Alonso M, Blesa D et al. The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. Fertil Steril 2013; 99: 508-517
    CrossrefPubMedGoogle Scholar
  • 33 Ruiz-Alonso M, Galindo N, Pellicer A et al. What a difference two days make: “personalized” embryo transfer (pET) paradigm: a case report and pilot study. Hum Reprod 2014; 29: 1244-1247
    CrossrefPubMedGoogle Scholar
  • 34 Hu S, Yao G, Wang Y et al. Transcriptomic changes during the pre-receptive to receptive transition in human endometrium detected by RNA-Seq. J Clin Endocrinol Metabol 2014; 99: E2744-E2753
    CrossrefPubMedGoogle Scholar
  • 35 Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843-854
    CrossrefPubMedGoogle Scholar
  • 36 Ambros V. microRNAs: tiny regulators with great potential. Cell 2001; 107: 823-826
    CrossrefPubMedGoogle Scholar
  • 37 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281-297
    CrossrefPubMedGoogle Scholar
  • 38 Chen X, Liang H, Zhang J et al. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol 2012; 22: 125-132
    CrossrefPubMedGoogle Scholar
  • 39 Rosenbluth EM, Shelton DN, Sparks AE et al. MicroRNA expression in the human blastocyst. Fertil Steril 2013; 99: 855-861
    CrossrefPubMedGoogle Scholar
  • 40 Lim LP, Lau NC, Garrett-Engele P et al. Microarray analysis shows that some microRNAs downregulate large numbers of traget mRNAs. Nature 2005; 7027: 769-773
    PubMedGoogle Scholar
  • 41 Ambros V, Chen X. The regulation of genes and genomes by small RNAs. Development 2007; 134: 1635-1641
    CrossrefPubMedGoogle Scholar
  • 42 Lee JY, Kim S, Hwang do W et al. Development of a dual-luciferase reporter system for in vivo visualization of MicroRNA biogenesis and posttranscriptional regulation. J Nucl Med 2008; 49: 285-294
    CrossrefPubMedGoogle Scholar
  • 43 Vilella F, Moreno-Moya JM, Balaguer N et al. Hsa-miR-30d, secreted by the human endometrium, is taken up by the pre-implantation embryo and might modify its transcriptome. Development 2015; 142: 3210-3221
    CrossrefPubMedGoogle Scholar
  • 44 Kuokkanen S, Chen B, Ojalvo L et al. Genomic profiling of microRNAs and messenger RNAs reveals hormonal regulation in microRNA expression in human endometrium. Biol Reprod 2010; 82: 791-801
    CrossrefPubMedGoogle Scholar
  • 45 Altmae S, Martinez-Conejero JA, Esteban FJ et al. MicroRNAs miR-30b, miR-30d, and miR-494 regulate human endometrial receptivity. Reprod Sci 2013; 20: 308-317
    CrossrefPubMedGoogle Scholar
  • 46 Sha AG, Liu JL, Jiang XM et al. Genome-wide identification of micro-ribonucleic acids associated with human endometrial receptivity in natural and stimulated cycles by deep sequencing. Fertil Steril 2011; 96: 150-155
    CrossrefPubMedGoogle Scholar
  • 47 Revel A, Achache H, Stevens J et al. MicroRNAs are associated with human embryo implantation defects. Human Reprod 2011; 26: 2830-2840
    CrossrefPubMedGoogle Scholar
  • 48 Rosenbluth EM, Shelton DN, Wells LM et al. Human embryos secrete microRNAs into culture media-a potential biomarker for implantation. Fertil Steril 2014; 101: 1493-1500
    CrossrefPubMedGoogle Scholar