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.
Similar content being viewed by others
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
Dekel N, Gnainsky Y, Granot I, Mor G. Inflammation and implantation. Am J Reprod Immunol. 2010;63(1):17–21.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 2011;17(1):10–2.
Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12(4):357–60.
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.
Gaujoux R, Seoighe C. A flexible R package for nonnegative matrix factorization. BMC Bioinformatics. 2010;11:367.
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.
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.
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.
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.
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.
Team R C. R: A language and environment for statistical computing[J]. 2013.
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.
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.
Parks DH, Tyson GW, Hugenholtz P, Beiko RG. STAMP: statistical analysis of taxonomic and functional profiles. Bioinformatics. 2014;30(21):3123–4.
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.
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.
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.
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.
Kammerer U, von Wolff M, Markert UR. Immunology of human endometrium. Immunobiology. 2004;209(7):569–74.
Robertson SA, Moldenhauer LM. Immunological determinants of implantation success. Int J Dev Biol. 2014;58(2–4):205–17.
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.
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.
Funding
Supported by the National Natural Science Foundation of China (grant number 81871214).
Author information
Authors and Affiliations
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
Ethics declarations
Ethics approval and consent to participate
The Ethics Committee approved the study of Sixth Affiliated Hospital of Sun Yat-Sen University (L2021ZSLYEC-280).
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-022-02578-x