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Aging endometrium in young women: molecular classification of endometrial aging-based markers in women younger than 35 years with recurrent implantation failure

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Background

To explore the differences between a population with premature endometrial aging and a population with normal endometrial status in young women with recurrent implantation failure (< 35 years).

Methods

Systematic analysis of the endometrium transcriptome of 274 RIF women. The NMF algorithm was used for classification based on endometrial-specific aging markers in CellAge, and the endometrial receptivity, gene expression patterns, and clinical data were compared between the classifications.

Results

Two hundred forty-five young RIF women could be divided into two clusters, in which the aging gene expression pattern of cluster 2 was closer to the reference cluster. Cluster 1 was characterized by high immune activity, while cluster 2 was characterized by high metabolic activity. Combined with clinical data, cluster 2 was worse than cluster 1 in window of implantation deviation rate and endometrial receptivity.

Conclusion

Premature aging of the endometrium exists in young women with RIF, and premature aging of the endometrium was associated with poor reproductive outcomes.

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Data availability

The transcriptome sequencing for all of endometrium samples have been deposited with CNGB Sequence Archive of China National GeneBank under reference number CNP0003262.

Abbreviations

ART:

Assisted reproductive technology

RIF:

Recurrent implantation failure

NMF:

Nonnegative matrix factorization

PCA:

Principal component analysis

FDR:

False discovery rate

KEGG:

Kyoto Encyclopedia of Genes and Genomes

GO:

Gene Ontology

DEGs:

Differential expressed genes

WOI:

Window of implantation

Treg:

T regulatory cells

ERA:

Endometrial receptivity assay

References

  1. Dekel N, Gnainsky Y, Granot I, Mor G. Inflammation and implantation. Am J Reprod Immunol. 2010;63(1):17–21.

    Article  CAS  Google Scholar 

  2. Moini A, Zafarani F, Jahangiri N, Jahanian Sadatmahalleh SH, Sadeghi M, Chehrazi M, et al. The effect of vaginal sildenafil on the outcome of assisted reproductive technology cycles in patients with repeated implantation failures: a randomized placebo-controlled trial. Int J Fertil Steril. 2020;13(4):289–95.

    CAS  PubMed  Google Scholar 

  3. Craciunas L, Gallos I, Chu J, Bourne T, Quenby S, Brosens JJ, et al. Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis. Hum Reprod Update. 2019;25(2):202–23.

    Article  CAS  Google Scholar 

  4. Reig A, Franasiak J, Scott RT Jr, Seli E. The impact of age beyond ploidy: outcome data from 8175 euploid single embryo transfers. J Assist Reprod Genet. 2020;37(3):595–602.

    Article  Google Scholar 

  5. Yeh JS, Steward RG, Dude AM, Shah AA, Goldfarb JM, Muasher SJ. Pregnancy outcomes decline in recipients over age 44: an analysis of 27,959 fresh donor oocyte in vitro fertilization cycles from the Society for Assisted Reproductive Technology. Fertil Steril. 2014;101(5):1331–6.

    Article  Google Scholar 

  6. Kawwass JF, Monsour M, Crawford S, Kissin DM, Session DR, Kulkarni AD, et al. Trends and outcomes for donor oocyte cycles in the United States, 2000–2010. JAMA. 2013;310(22):2426–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Devesa-Peiro A, Sebastian-Leon P, Parraga-Leo A, Pellicer A, Diaz-Gimeno P. Breaking the ageing paradigm in endometrium: endometrial gene expression related to cilia and ageing hallmarks in women over 35 years. Hum Reprod. 2022;37:762–76.

  8. Olesen MS, Starnawska A, Bybjerg-Grauholm J, Bielfeld AP, Agerholm I, Forman A, et al. Biological age of the endometrium using DNA methylation. Reproduction. 2018;155(2):167–72.

    Article  Google Scholar 

  9. Li J, Wang Y, Tang R, Peng Y, Wang Y, Liu B, et al. Changes in ultrasound uterine morphology and endometrial thickness during ovarian aging and possible associated factors: findings from a prospective study. Menopause. 2020;27(7):794–800.

    Article  Google Scholar 

  10. Cho A, Park SR, Kim SR, Nam S, Lim S, Park CH, et al. An endogenous anti-aging factor, sonic hedgehog, suppresses endometrial stem cell aging through SERPINB2. Mol Ther. 2019;27(7):1286–98.

    Article  CAS  Google Scholar 

  11. Rawlings TM, Makwana K, Taylor DM, Mole MA, Fishwick KJ, Tryfonos M, et al. Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids. Elife. 2021;10:e69603.

  12. Avelar RA, Ortega JG, Tacutu R, Tyler EJ, Bennett D, Binetti P, et al. A multidimensional systems biology analysis of cellular senescence in aging and disease. Genome Biol. 2020;21(1):91.

    Article  CAS  Google Scholar 

  13. Chen P, Chen P, Guo Y, Fang C, Li T. Interaction between chronic endometritis caused endometrial microbiota disorder and endometrial immune environment change in recurrent implantation failure. Front Immunol. 2021;12:748447.

    Article  CAS  Google Scholar 

  14. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 2011;17(1):10–2.

  15. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12(4):357–60.

    Article  CAS  Google Scholar 

  16. Liao Y, Smyth GK, Shi W. The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 2013;41(10):e108.

    Article  Google Scholar 

  17. Gaujoux R, Seoighe C. A flexible R package for nonnegative matrix factorization. BMC Bioinformatics. 2010;11:367.

    Article  Google Scholar 

  18. Brunet J-P, Tamayo P, Golub TR, Mesirov JP. Metagenes and molecular pattern discovery using matrix factorization. Proc Natl Acad Sci. 2004;101(12):4164–9.

    Article  CAS  Google Scholar 

  19. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.

    Article  Google Scholar 

  20. Ogata H, Goto S, Sato K, Fujibuchi W, Bono H, Kanehisa M. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 1999;27(1):29–34.

    Article  CAS  Google Scholar 

  21. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium Nat Genet. 2000;25(1):25–9.

    CAS  PubMed  Google Scholar 

  22. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc: Ser B (Methodol). 1995;57(1):289–300.

    Google Scholar 

  23. Team R C. R: A language and environment for statistical computing[J]. 2013.

  24. He A, Zou Y, Wan C, Zhao J, Zhang Q, Yao Z, et al. The role of transcriptomic biomarkers of endometrial receptivity in personalized embryo transfer for patients with repeated implantation failure. J Transl Med. 2021;19(1):176.

    Article  CAS  Google Scholar 

  25. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7.

    Article  CAS  Google Scholar 

  26. Parks DH, Tyson GW, Hugenholtz P, Beiko RG. STAMP: statistical analysis of taxonomic and functional profiles. Bioinformatics. 2014;30(21):3123–4.

    Article  CAS  Google Scholar 

  27. Diaz-Gimeno P, Horcajadas JA, Martinez-Conejero JA, Esteban FJ, Alama P, Pellicer A, et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2011;95(1):50-60e1-15.

    Article  CAS  Google Scholar 

  28. Wang YA, Farquhar C, Sullivan EA. Donor age is a major determinant of success of oocyte donation/recipient programme. Hum Reprod. 2012;27(1):118–25.

    Article  Google Scholar 

  29. Soares SR, Troncoso C, Bosch E, Serra V, Simon C, Remohi J, et al. Age and uterine receptiveness: predicting the outcome of oocyte donation cycles. J Clin Endocrinol Metab. 2005;90(7):4399–404.

    Article  CAS  Google Scholar 

  30. Devesa-Peiro A, Sebastian-Leon P, Parraga-Leo A, Pellicer A, Diaz-Gimeno P. Breaking the ageing paradigm in endometrium: endometrial gene expression related to cilia and ageing hallmarks in women over 35 years. Hum Reprod. 2022;37(4):762–76.

    Article  CAS  Google Scholar 

  31. Kammerer U, von Wolff M, Markert UR. Immunology of human endometrium. Immunobiology. 2004;209(7):569–74.

    Article  Google Scholar 

  32. Robertson SA, Moldenhauer LM. Immunological determinants of implantation success. Int J Dev Biol. 2014;58(2–4):205–17.

    Article  CAS  Google Scholar 

  33. Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S, et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity. 2011;34(5):794–806.

    Article  CAS  Google Scholar 

  34. Benner M, Ferwerda G, Joosten I, van der Molen RG. How uterine microbiota might be responsible for a receptive, fertile endometrium. Hum Reprod Update. 2018;24(4):393–415.

    Article  CAS  Google Scholar 

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Funding

Supported by the National Natural Science Foundation of China (grant number 81871214).

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Authors and Affiliations

Authors

Contributions

Cong Fang, Tingting Li, and Peigen Chen carried out the study. Peigen Chen analyzed and interpreted the data and drafted the manuscript. Meng Yang and Yingchun Guo collected the samples. Yanfang Wang and Yun Liu followed up and collected the clinical data. Cong Fang, Tingting Li, and Peigen Chen coordinated the study, participated in the design, and reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Cong Fang or Tingting Li.

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Ethics approval and consent to participate

The Ethics Committee approved the study of Sixth Affiliated Hospital of Sun Yat-Sen University (L2021ZSLYEC-280).

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Not applicable.

Competing interests

The authors declare no competing interests.

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Cite this article

Chen, P., Yang, M., Wang, Y. et al. Aging endometrium in young women: molecular classification of endometrial aging-based markers in women younger than 35 years with recurrent implantation failure. J Assist Reprod Genet 39, 2143–2151 (2022). https://doi.org/10.1007/s10815-022-02578-x

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  • DOI: https://doi.org/10.1007/s10815-022-02578-x

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