Inflammatory proteomics of uterine fluid is potentially a non-invasive predictor for endometrial receptivity: a pilot study
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE283724 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:Purpose: We compared endometrial transcriptome profiles during the window of implantation (WOI) between women with and without uterine adenomyosis. Methods: We obtained endometrial biopsies luteinizing hormone (LH)-timed to the WOI from women with sonographic features of adenomyosis (n=10) and controls (n=10). Isolated RNA samples were subjected to RNA sequencing (RNA-seq) and endometrial receptivity classification with a molecular tool for menstrual cycle phase dating (beREADY®, CCHT). RNA-seq data were analysed in the setting of the result of accurate endometrial dating. Results: Out of 20 endometrial samples, 2 were dated to the early receptive phase, 13 to the receptive phase and 5 to the late receptive phase. Comparison of the transcriptomics data from all 20 samples provided 909 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group but only 4 enriched pathways (Bonferroni p value < 0.05). The analysis of 13 samples only dated to the receptive phase provided suggestive 382 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group, leading to 33 enriched pathways (Bonferroni p value < 0.05). These included pathways were already associated with endometrial biology, such as “Expression of interferon (IFN)-induced genes” and “Response to IFN-alpha”. Conclusion: Accurate endometrial dating and RNA-seq analysis resulted in the identification of altered response to IFN signalling as the most promising candidate of impaired uterine receptivity in adenomyosis.
2022-01-03 | GSE185392 | GEO
Project description:The molecular mechanisms underlying window of implantation (WOI) displacement in patients with recurrent implantation failure (RIF) remain unclear. This study aims to explore the transcriptomic signatures of endometrium with normal and displaced WOIs during HRT cycles and to identify the causes of endometrial receptivity (ER) abnormalities and WOI displacement in RIF patients. 40 RIF patients were recruited and underwent personalized embryo transfer (pET) guided by the predicted results of endometrial receptivity diagnosis (ERD) model. Transcriptome analysis of endometrium from patients with clinical pregnancies after pET was performed to identify differentially expressed genes (DEGs) associated with WOI displacement. The ERD results indicated that 67.5% of RIF patients (27/40) were non-receptive in the conventional WOI (P+5) of the HRT cycle. The clinical pregnancy rate in RIF patients improved to 65% (26/40) after ERD-guided pET, indicating the effectiveness of transcriptome-based WOI prediction. Among the 26 patients with clinical pregnancy, the gene expression profiles of P+5 endometrium from advanced (n=6), normal (n=10) and delayed (n=10) WOI groups were significantly different from each other. 10 DEGs (CES4A, LRRC1, SLC25A48, TM4SF4, DPP4, CXCR1, CXCR2, OSM, LCN2 and TNFRSF10C ) identified among P+5 endometrium of 3 groups were involved in immunomodulation, transmembrane transport and tissue regeneration, which could accurately classify the endometrium with different WOIs.
2024-01-03 | GSE252280 | GEO
Project description:Purpose: Extracellular vescicles (EVs) of uterine origin have recently been identified, but they are not comprised by current diagnostics on endometrial receptivity. In order to test the possibility to use EVs as biomarker reservoirs for non-invasive monitoring of the endometrial status, we defined two experimental designs: in step a) we aimed at assessing the concordance between the transcriptome of endometrial tissue and uterine fluid-derived EVs (UF-EVs); in step b) we aimed at unraveling the transcriptomic profile of UF-EVs released during the receptive phase and associated with successful implantation Methods: RNAseq analysis was performed on total RNA isolated from a) endometrial biopsies and UF-EVs concomitantly collected from regularly cycling women; b) UF-EVs collected in the pre-receptive (LH+2) versus the receptive (LH+7) phase of provenly fertile women and in the receptive phase (LH+7) of women undergoing assisted reproduction and transfer of an euploid blastocyst. In the latter group, the outcomes of the following embryo transfer attempt were recorded, in order to compare the transcriptomic profile of women with successful versus failed implantation. Differential Gene Expression (DGE) and Gene Set Enrichment (GSEA) analyses were performed. Results: In the first experimental design, a highly significant correlation was found between the transcriptional profiles of endometrial tissue biopsies and corresponding UF-EVs (r=0.71 p<0.001; ρ=0.65 p<0.001). In the second experimental design, using a large group of 73 samples, 16,777 genes were overall found to be expressed in UF-EVs. Of these, DGE analysis showed that 942 were up-regulated and 1,305 down-regulated during the receptive phase in women with proven fertility and 97 were up-regulated and 64 down-regulated during the receptive phase of women achieving successful implantation versus women failing to achieve pregnancy in the subsequent cycle. 41 genes had a statistically significant different expression in both comparisons. We additionally tested wether transcripts used by current endometrial receptivity tests based on endometrial biopsies (Endometrial Receptivity Assay, ERA test) could also be detected in UF-EVs: out of 238 ERA test gene data-set, GSEA highlighted 219 genes with similar transcriptional profile in UF-EVs. We then performed another comparison adding the list of genes consisting of the ‘metasignature’ transcriptome derived from the published meta-analysis of endometrial receptivity associated transcripts, comprising 57 genes. This last intersection identified 38 genes expressed in UF-EVs that i) show differential expression with the same transcriptional profile (same trends) in both EVs and ERA test assay; ii) belong to the leading edge of genes with the most significant enrichment score in our analysis; iii) are identified as receptivity-associated genes by the current meta-analysis on endometrial transcriptome. Conclusions: This is the first study showing the capacity of UF-EVs to reflect the endometrial tissue transcriptional status and to establish a signature of genes expressed in UF-EVs that might serve as putative biomarkers for non-invasive endometrial receptivity tests.
2021-07-01 | GSE158958 | GEO
Project description:The current diagnostic tools used to determine the precise timing of embryo transfer for in vitro fertilization (IVF)-frozen embryo transfer (FET) patients are not non-invasive or accurate. As uterine fluid is collected via a minimally invasive procedure and reflects alterations in the molecular composition of the endometrium during the menstrual cycle, it can be considered an accurate diagnostic source for identifying endometrial receptivity-related proteins. Therefore, we aimed to identify a panel of molecular biomarkers for endometrial receptivity by investigating uterine fluid lavage (UFL). The UFLs of 18 IVF-FET patients were collected two days before FET. After seven weeks, the patients were divided into receptive and non-receptive groups on the basis of ultrasonography results for clinical pregnancy. Protein profiling of the collected UFLs was performed via tandem mass tag labeling and mass spectrometry liquid chromatography. Next, differentially abundant proteins between the two groups were identified. Additionally, the largest contributions of the variable to the differences based on the variable of importance in projection (VIP) score value were inspected. The candidate protein panel was selected on the basis of the VIP score and protein database analysis. The accuracy of the candidate panel was assessed via logistic regression as a machine learning approach. Finally, western blot analysis confirmed the results.
2025-06-02 | PXD060077 | Pride
Project description:The inner uterine lining (endometrium) has been shown to have a distinct methylation pattern that changes throughout the menstrual cycle. However, not much is known about how the endometrial methylome affects endometrial receptivity to implanting embryo in the second half of the menstrual cycle. The aim of the present study was to use genome-wide technologies and a paired study design to characterize the endometrial methylome in pre-receptive and receptive endometrium sampled from 17 healthy women within the same menstrual cycle.
2017-06-20 | GSE90060 | GEO
Project description:Receptivity of the uterus is essential for embryo implantation and progression of pregnancy. Acquisition of receptivity involves major molecular and cellular changes in the endometrial lining of the uterus from its non-receptive state at ovulation, to its receptive state four days later. The precise molecular mechanisms underlying this transition remain to be fully characterized. Here, we aimed to generate a comprehensive profile of the uterine transcriptome in the peri-ovulatory and peri-implantation states, and to define the differences between them, in the mouse. High throughput RNA-sequencing was utilized to identify genes and pathways expressed in the endometrium of C57Bl/6 female mice on day 3.5 post-coitum after mating with BALB/c males, compared to the endometrium of unmated estrous females (n=3-4 biological replicates). RNA-sequencing and analysis using Ingenuity Pathway Analysis software revealed that, compared to the endometrium at estrus, 388 genes were differentially expressed in the endometrium on day 3.5 post-coitum (FDR ≤ 0.05). Several upstream regulators are implicated in the transition to receptivity including several cytokines, steroid hormones, prostaglandin E2, and vascular endothelial growth factor A. The transcriptional changes indicate substantial changes in the uterine immune and vascular systems during the pre-implantation phase, with the functional terms Angiogenesis, Chemotaxis, and Lymphangiogenesis predominating. This analysis confirms that the transcriptome of a receptive uterus is vastly different to the non-receptive uterus and identifies several genes and regulatory pathways not previously associated with implantation. This dataset will serve as a valuable tool and resource for future research on the molecular mechanisms of uterine receptivity.
2023-09-12 | GSE223136 | GEO
Project description:Study question : Are there changes in transcript levels as endometrial receptivity changes in patients with recurrent implantation failure (RIF), particularly in alternative splicing events (ASEs), differential expression genes (DEGs) and immune cells levels? Summary answer: Changes in endometrial receptivity affect alternative splicing (AS), differential gene expression and immune cells, and the RNA-binding protein (RBP) KHDRBS3 likelymaybe？ Likely？ is involved in the dysregulation of alternative splicing. What is known already: Endometrial receptivity is critical for RIF patients. Researchers have developed transcript level-based models to predict personalized endometrial assessment at WOI. Investigating alternative splicing dysregulation, immune cells and other transcriptional biomarkers in RIF patients may further help to predict endometrial receptivity and improve embryo implantation success. Study design, size, duration: 90 endometrial samples were collected from fertile healthy controls (HC) during the menstrual cycle, including pre-receptive (PR) (luteinising hormone (LH)+3 days/LH+5 days), receptive (R) (LH+7 days) and post-receptive (PS) (LH+9 days) phases. 73 endometrial samples were taken from RIF patients on hormone replacement therapy (HRT) cycles, including PR (progesterone (P)+3 days), R (P+5 days) and PS (P+7 days) phases. Participants/materials, setting, methods: Total RNA was extracted and sequenced for all 163 endometrial samples . Bioinformatic analysis was used to comprehensively investigate the endometrial transcriptome at different stages of receptivity. We elucidated the biological significance of the universal alteration of alternative splicing in endometrial receptivity and further analyzed the role of immune cells and gene expression in this process. In addition, an ASEs-RBPs correlation network was constructed in the endometrial receptive period to evaluate the dysregulation of AS by RBPs. Main results and the role of chance: Global splicing profiling of the four subgroups (HC: PR vs. R; HC: PS vs. R; RIF: PR vs. R; RIF: PS vs. R) consistently showed that skipped exons (SE) and mutually exclusive exons (MXE) were the most common changes in splicing events. These different ASEs occurred at high frequency and some of them could affect the coding potential of a transcript. A greater number of genes with different alternative splicing events (ASEGs) were identified between PR and R phases than between PS and R phases, and the same trend was observed for differentially expressed genes (DEGs). Both ASEGs and DEGs showed enrichment for pathways associated with cell function and adhesion, while DEGs were also enriched for cytokine and immune-related pathways. Immune cell prediction shows that changes in endometrial receptivity phases result in differences in the levels of CD8 T cells, resting NK cells and other immune cells. During the R phase, there was a significant decrease in CD8 T cells and resting NK cells, whereas monocytes and M0 macrophages were significantly increased compared to the endometrial PR phase in RIF patients. Similarly, analysis of immune cells showed a significant increase in CD8 T cells, M1 and M2 macrophages and a significant decrease in activated NK cells in the R phase compared to the PS phase of the endometrium in RIF patients. Some of these immune cells, such as NK cells and monocytes, are highly correlated with certain ASEs. Investigation of ASEs-RBPs networks suggested that KHDRBS3 may be a key regulator of splicing events. Limitations, reasons for caution: The sample size needs to be increased and cover a variety of situations, such as different age, pathology, dietary habits, etc., and alsothe molecular experimental validation needs to be considered. The lack of direct comparisons between natural and HRT cycles in the same sample and molecular experimental validation need to be considered. Wider implications of the findings: Comprehensive transcriptional analysis of the endometrium provide valuable insight into potential biomarkers related to endometrial receptivity and potential treatments for RIF patients. Study funding/competing interest(s): This study was supported by Supported by the Program of National Natural Science of China (Grant No. 81701409). All authors declared that they have no conflicts of interest.
2025-10-15 | GSE287072 | GEO
Project description:Despite great advances in assisted reproductive technology (ART), unexplained recurrent implantation failure (RIF) due to disorder of endometrial receptivity still cannot be effectively avoided. More importantly, cell characteristics and cell communication that regulate endometrial receptivity and differentiation, and its disorders in RIF at the window of implantation (WOI) remain rudimentary. Here we characterized the transcriptomes of four major cells in human endometrium from healthy control and RIF patients at single-cell resolution. We discovered the dynamic change characteristics of four major endometrial fibroblast-like cells with different endometrial receptivity, reported a novel pluripotent endometrial glandular epithelial cell with high levels of progesterone receptor and exosomes, and defined a unique ITGA1+CXCR4+ NK cell for connecting endometrial nonimmune cells and immune cell infiltration at the WOI. Additionally, we developed a systematic repository of cell-cell communication for endometrial differentiation and the opening of endometrial receptivity via the ligand-receptor complexes interactions. Our study provides deeper insights into aberrant molecular and cellular characterizations, and the endometrial microenvironmental disorders of RIF patients that are potentially applicable to improve the etiological diagnosis and therapeutics of unexplained RIF.
2022-09-16 | GSE183837 | GEO
Project description:Embryo implantation is a key step in establishing pregnancy and a major limiting factor in IVF. Implantation requires the endometrium, the inner lining of the uterus, to transform from a non-receptive to a receptive state, to allow embryos to attach to the surface and enter into the tissue. However, the fundamental mechanisms governing receptivity are not well understood. Here we show that transmembrane protein podocalyxin is a major and clinically significant factor regulating human endometrial receptivity. Podocalyxin is expressed in all endometrial epithelial cells in the non-receptive state but is selectively down-regulated in the luminal epithelium at receptivity. We present evidence that podocalyxin critically governs the barrier function of the endometrial epithelium, likely as an intrinsic protective mechanism, rendering it non-receptive to an embryo. In addition, podocalyxin suppresses genes promoting receptivity (eg LIF, CSF1) but stimulates those inhibiting implantation (eg WNT7A, LEFTY2). Down-regulation of podocalyxin in the luminal epithelium, likely mediated by progesterone, selectively converts the endometrial surface to a more adhesive state that facilitates embryo attachment and penetration. Furthermore, inadequate down-regulation of podocalyxin in the endometrial luminal epithelium is associated with poorer implantation rates in IVF. We thus propose that podocalyxin promotes the barrier function of human endometrial epithelial cells and critically regulates receptivity for embryo implantation.
2021-04-01 | GSE148274 | GEO
Project description:Embryo implantation is a complex process which involves biochemical and physiological interactions between an implantation-competent blastocyst and a receptive uterus. However, the exact biochemical changes of uterine fluid, uterus, and plasma during peri-implantation remain unclear. This study aims to characterize the biochemical and metabolic changes that occur during the peri-implantation period of early pregnancy, using mice as an animal model. Gas chromatography-mass spectrometry was used to analyze the metabolite profiles of the uterus, uterine fluid, and maternal plasma at pre-implantation and implantation. The multivariate analyses, ANOVA and Tukey's HSD test, were applied to detect significant changes in metabolites and metabolic pathways. The metabolic networks were reconstructed in silico based on the identified metabolites and KEGG metabolic framework. Between pre-implantation day 1 and day 4, dramatic metabolic changes were observed in the uterine fluid that could be important for blastocyst development and protection against the harsh uterine environment. Palmitoleic acid, fumaric acid, and glutaric acid changed levels at day 4 in the uterus, suggesting that they may be associated with endometrial receptivity. Both the uterus and maternal plasma showed profound changes in cellular metabolism at the early implantation period, including upregulation of branched-chain amino acids and intermediates of one-carbon metabolism, an upregulation of glyoxylate and dicarboxylate metabolism, and downregulation of aerobic respiration; all of which could be involved in the regulation of the maternal-fetal interface, alternative nutrient utilization, and energy preservation for implantation as well as later placentation and fetal development to ensure successful embryo implantation.
2020-05-04 | MTBLS627 | MetaboLights