The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature

Pantos, Konstantinos; Grigoriadis, Sokratis; Maziotis, Evangelos; Pistola, Kalliopi; Xystra, Paraskevi; Pantou, Agni; Kokkali, Georgia; Pappas, Apostolos; Lambropoulou, María; Sfakianoudis, Konstantinos; Simopoulou, Mara

doi:10.3390/ijms23042198

Cited by 34 publications

(22 citation statements)

References 138 publications

(260 reference statements)

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“…Recurrent implantation failure (RIF) constitutes one of the most challenging pathologies encountered in the field of human reproduction, raising concerns among researchers and clinicians alike. There is a lack of consensus regarding the exact definition of RIF; nonetheless, the most widely accepted definition refers to RIF as the failure to achieve a clinical pregnancy following at least three or more consecutive transfers of good-quality embryos in fresh or frozen cycles for woman younger than 40 years of age [ 18 ]. Hysteroscopy and the treatment of hydrosalpinxes have been proven to be effective tools for the management of RIF cases [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Commercially Available Molecular Approaches to Evaluate Endometrial Receptivity: A Systematic Review and Critical Analysis of the Literature

Maziotis

Kalampokas

Giannelou³

et al. 2022

Diagnostics

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Despite the advances in the field of reproductive medicine, implantation failure represents a challenging condition affecting 10–30% of patients subjected to in vitro fertilization (IVF). Research has focused on the identification of molecules playing crucial roles in endometrial receptivity, with the aim of designing predictive tools for efficient detection of the implantation window. To that end, novel molecular genomic and transcriptomic approaches have been introduced as promising tools to enable personalized approaches with the aim of optimizing embryo transfer dating. However, the clinical value of these approaches remains unclear. The aim of this study is to provide a systematic review and critical analysis of the existing evidence regarding the employment of commercially available novel approaches to evaluate endometrial receptivity. An Embase and PubMed/Medline search was performed on 1 February 2022. From the 475 articles yielded, only 27 were included and analyzed. The considerable heterogeneity of the included articles indicates the uniqueness of the implantation window, showcasing that the optimal time for embryo transfer varies significantly between women. Moreover, this study provides information regarding the technical aspects of these advanced molecular tools, as well as an analysis of novel possible biomarkers for endometrial receptivity, providing a basis for future research in the field.

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Section: Introductionmentioning

confidence: 99%

Commercially Available Molecular Approaches to Evaluate Endometrial Receptivity: A Systematic Review and Critical Analysis of the Literature

Maziotis

Kalampokas

Giannelou³

et al. 2022

Diagnostics

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“…Despite tremendous advances in reproductive medicine, it remains an ongoing conundrum. About 15% of patients seeking IVF treatment are reported to be afflicted by RIF, which is a huge distress and frustration for both patients and clinicians ( 3 ). Statistics have shown that approximately 40% of euploid blastocysts fail to implant in transfers, which suggests the desynchronization between the embryo and the endometrium in the window of implantation (WOI) as a potential cause of RIF ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Deciphering the endometrial immune landscape of RIF during the window of implantation from cellular senescence by integrated bioinformatics analysis and machine learning

Zhao

Zhao²,

Jiang³

et al. 2022

Front. Immunol.

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Recurrent implantation failure (RIF) is an extremely thorny issue in in-vitro fertilization (IVF)-embryo transfer (ET). However, its intricate etiology and pathological mechanisms are still unclear. Nowadays, there has been extensive interest in cellular senescence in RIF, and its involvement in endometrial immune characteristics during the window of implantation (WOI) has captured scholars’ growing concerns. Therefore, this study aims to probe into the pathological mechanism of RIF from cellular senescence and investigate the correlation between cellular senescence and endometrial immune characteristics during WOI based on bioinformatics combined with machine learning strategy, so as to elucidate the underlying pathological mechanisms of RIF and to explore novel treatment strategies for RIF. Firstly, the gene sets of GSE26787 and GSE111974 from the Gene Expression Omnibus (GEO) database were included for the weighted gene correlation network analysis (WGCNA), from which we concluded that the genes of the core module were closely related to cell fate decision and immune regulation. Subsequently, we identified 25 cellular senescence-associated differentially expressed genes (DEGs) in RIF by intersecting DEGs with cellular senescence-associated genes from the Cell Senescence (CellAge) database. Moreover, functional enrichment analysis was conducted to further reveal the specific molecular mechanisms by which these molecules regulate cellular senescence and immune pathways. Then, eight signature genes were determined by the machine learning method of support vector machine-recursive feature elimination (SVM-RFE), random forest (RF), and artificial neural network (ANN), comprising LATS1, EHF, DUSP16, ADCK5, PATZ1, DEK, MAP2K1, and ETS2, which were also validated in the testing gene set (GSE106602). Furthermore, distinct immune microenvironment abnormalities in the RIF endometrium during WOI were comprehensively explored and validated in GSE106602, including infiltrating immunocytes, immune function, and the expression profiling of human leukocyte antigen (HLA) genes and immune checkpoint genes. Moreover, the correlation between the eight signature genes with the endometrial immune landscape of RIF was also evaluated. After that, two distinct subtypes with significantly distinct immune infiltration characteristics were identified by consensus clustering analysis based on the eight signature genes. Finally, a “KEGG pathway–RIF signature genes–immune landscape” association network was constructed to intuitively uncover their connection. In conclusion, this study demonstrated that cellular senescence might play a pushing role in the pathological mechanism of RIF, which might be closely related to its impact on the immune microenvironment during the WOI phase. The exploration of the molecular mechanism of cellular senescence in RIF is expected to bring new breakthroughs for disease diagnosis and treatment strategies.

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“…In fact, the majority of these patients do not achieve a successful pregnancy despite the transfer of normally developing highquality embryos. Impaired maternal endometrial receptivity is the key reason for the failure of embryo implantation in these patients [4][5][6]. Endometrial epithelial cells, which are under the control of oestrogen and progesterone, play a key role in the establishment of endometrial receptivity in the mid-secretory phase and mediate the first contact between the blastocyst and the maternal uterus [7].…”

Section: Introductionmentioning

confidence: 99%

FHL1 mediates HOXA10 deacetylation via SIRT2 to enhance blastocyst-epithelial adhesion

et al. 2022

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Recurrent implantation failure (RIF) is a rather thorny problem in the clinical practice of assisted reproductive technology. Due to the complex aetiology of RIF, its pathogenesis is far from fully understood, and there is no effective treatment available. Here, We explored the regulatory mechanism of the four half-domains of LIM domain 1 (FHL1), which is significantly downregulated in the endometrium of RIF patients, in blastocyst-epithelial adhesion. Indeed, FHL1 expression was dramatically increased in normal female mid-secretory endometrial epithelial cells and was abnormally reduced in RIF patients. Furthermore, FHL1 overexpression promoted blastocyst-epithelial adhesion, and interfering with FHL1 expression in the mouse uterus significantly inhibited embryo implantation. Mechanistically, FHL1 did not regulate HOXA10 mRNA expression but increased HOXA10 protein stability and activated HOXA10, thereby promoting its regulation of downstream gene expression and the β3 integrin/FAK pathway. Meanwhile, FHL1 regulates HOXA10 function by increasing HOXA10 deacetylation through enhanced binding of HOXA10 and SIRT2. SIRT2-specific inhibitors can significantly inhibit this effect. In the endometrial epithelial cells of RIF patients, the correlation between FHL1 and HOXA10 and its downstream target genes has also been verified. Finally, our data indicated FHL1 is a regulatory molecule that promotes blastocyst-epithelial adhesion. Altogether, downstream dysfunction due to aberrant FHL1 expression is an important molecular basis for embryo implantation failure in patients with RIF and to provide new potential therapeutic targets.

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The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature

Cited by 34 publications

References 138 publications

Commercially Available Molecular Approaches to Evaluate Endometrial Receptivity: A Systematic Review and Critical Analysis of the Literature

Commercially Available Molecular Approaches to Evaluate Endometrial Receptivity: A Systematic Review and Critical Analysis of the Literature

Deciphering the endometrial immune landscape of RIF during the window of implantation from cellular senescence by integrated bioinformatics analysis and machine learning

FHL1 mediates HOXA10 deacetylation via SIRT2 to enhance blastocyst-epithelial adhesion

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