Abstract
BackgroundWomen with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation. To understand the mechanisms involved in this process, we aimed to compare endometrial transcriptome profiles during the window of implantation (WOI) between women with and without adenomyosis.MethodsWe obtained endometrial biopsies 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) by the Illumina NovaSeq 6000 platform and endometrial receptivity classification with a molecular tool for menstrual cycle phase dating (beREADY®, CCHT). The program language R and Bioconductor packages were applied to analyse RNA-seq data in the setting of the result of accurate endometrial dating. To suggest robust candidate pathways, the identified differentially expressed genes (DEGs) associated with the adenomyosis group in the receptive phase were further integrated with 151, 173 and 42 extracted genes from published studies that were related to endometrial receptivity in healthy uterus, endometriosis and adenomyosis, respectively. Enrichment analyses were performed using Cytoscape ClueGO and CluePedia apps.ResultsOut 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”. Data integration revealed pathways indicating a unique effect of adenomyosis on endometrial molecular organization (e.g., “Expression of IFN-induced genes”) and its interference with endometrial receptivity establishment (e.g., “Extracellular matrix organization” and “Tumour necrosis factor production”).ConclusionsAccurate 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.
Highlights
Women with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation
Lists of Differentially expressed gene (DEG) associated with the adenomyosis group that were identified by analysing RNA sequencing (RNA-seq) datasets in the setting of the endometrial dating results were applied for enrichment pathway analyses to predict their role in the context of endometrial molecular organization
We identified 382 DEGs that we believe more accurately represent the effect of adenomyosis on the gene expression signature of endometrial receptivity compared to 909 DEGs associated with the adenomyosis group, which were identified by comparing transcriptomics data of samples derived from receptive, early- and late-receptive phases
Summary
Women with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation. Several functional and molecular aberrations could be responsible for altered endometrial receptivity to embryo implantation and lower fecundity in women with adenomyosis. It has been suggested that the disruption of the junctional zone architecture by adenomyosis could lead to altered contractility and interrupt endometrial receptivity [7, 8]. Other suggested causes affecting endometrial receptivity in women with adenomyosis could be increased levels of oxidative stress [9,10,11], abnormal endometrial vascularity [12, 13] and functional disorganization at the molecular level [14,15,16,17]
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