The mid-secretory endometrial transcriptomic landscape in endometriosis: a meta-analysis

Abstract

Study Question Do women with endometriosis have a different endometrial gene expression profile at the time of embryo implantation than women without endometriosis? Summary Answer The endometrial gene expression profile of women with endometriosis differs from that of women without endometriosis at the mid-secretory phase, although the differences are small. What Is Known Already About 50% of women with endometriosis suffer infertility. Several molecular studies have suggested impaired endometrial receptivity in women with endometriosis, while others have detected no dys-regulation of endometrial receptivity. Nevertheless, the previous endometrial transcriptome studies comparing women with and without endometriosis have been performed in small sample size with limited statistical power. We set out to systematically search and compile data of endometrial gene expression signatures at the receptive phase in women with endometriosis versus control women. Based on the obtained data, we conducted a meta-analysis of differentially expressed genes in order to raise the power of the analysis for identifying the molecular profiles of receptive phase endometria in endometriosis. Study Design, Size, Duration A systematic literature search was conducted up to February 2022 following PRISMA criteria and included PubMed, Cochrane, and Web of Science databases. For the systematic search, the term “endometriosis” was paired with the terms “transcriptomics”, “transcriptome”, “gene expression”, “RNA-seq”, “sequencing” and “array”, by using the Boolean operator “AND” to connect them. Articles written in English were screened and interrogated for data extraction. Participants/Materials, Setting, Methods A meta-analysis was performed on the selected studies to extract the differentially expressed genes described at the mid-secretory phase in women with endometriosis versus women without endometriosis in natural cycles, using the robust rank aggregation (RRA) method. In total, transcriptome data of 125 women (78 patients and 47 controls) were meta-analysed, with a special focus on endometrial receptivity-specific genes based on commercial endometrial receptivity tests. Main Results And The Role Of Chance In total, 8 studies were eligible for the quantitative meta-analysis, gathering transcriptome data from the mid-secretory phase endometria of 125 women. A total of 7779 differentially expressed transcripts between the study groups were retrieved (3496 up-regulated and 4283 down-regulated) and were meta-analysed. After stringent multiple correction, there was no differential expression of any single molecule in the endometrium of women with endometriosis versus controls, while enrichment analysis detected that the pathways of chemotaxis and locomotion are dys-regulated in endometriosis. Further analysis of endometrial receptivity-specific genes highlighted dysregulation of C4BPA, MAOA and PAEP and enrichment of immune and defence pathways in women with endometriosis. Limitations, Reasons For Caution Most of the studies included into the meta-analysis were relatively small and had different study designs, which might have contributed to a bias. Wider Implications Of The Findings The current meta-analysis supports the hypothesis that endometrial receptivity is altered in women with endometriosis, although the changes are small. The molecules and pathways identified could serve as future biomarkers and therapeutical targets in detecting and treating endometriosis-associated infertility. Study Funding/Competing Interest(s) The authors declare no competing interests. This work was supported by the Spanish Ministry of Education, Culture and Sport [grant FPU15/01193] and the Margarita Salas program for the Requalification of the University Spanish system [grant UJAR01MS]; Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE SAF2017-87526; Programa Operativo FEDER Andalucía (B-CTS-500-UGR18; A-CTS-614-UGR20); the Junta de Andalucía [BIO-302; and PAIDI P20_00158]; the University of Jaén [PAIUJA-EI_CTS02_2017]; the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and by the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ERDF), ref. SOMM17/6107/UGR; the Estonian Research Council (grant PRG1076); Horizon 2020 innovation (ERIN, grant no. EU952516) of the European Commission and Enterprise Estonia (grant EU48695). Trial Registration Number The systematic review was registered at PROSPERO (identifier: CRD42020122054). Lay summary This study investigates whether the gene expression profile of the endometrium (the inner lining of the uterus) of women with endometriosis is different from that of control women during the phase of the menstrual cycle when the uterus is receptive for embryo to implantation. Our extensive systematic review and meta-analysis identified endometrial receptivity-associated genes and molecular pathways that seem to be altered in women with endometriosis. The study findings could help to explain endometriosis-associated infertility in women suffering from this common gynaecological disease and could lead to the development of molecular biomarkers for detecting and treating infertility in endometriosis.

Expression Differences Between the Eutopic Endometrium With and Without Endometriosis and the Ectopic Endome-trium. A Re-Analysis of Arrays

“…Our observation that there are only very few differences in eutopic endometrium with and without endometriosis is supported by a recently published meta-analysis, which did not show a single differently expressed gene in the mid-secretory phase [46]. Remarkably two other studies about miRNAs [47] and methylation patterns [48] also reported similar results.…”

Identification of immune- and autophagy-related genes and effective diagnostic biomarkers in endometriosis: a bioinformatics analysis

“…HTR2B is related to neovascularization and immunomodulation as well as neurotransmission ( 47 ), indicating that it could be involved in the pathogenesis of endometriosis. MAOA is a putative endometrial receptivity biomarker, which is also linked to endometriosis ( 48 ). PPP1R13L is a member of the apoptosis-stimulating proteins of the p53 ( ASPP ) family and was identified as a novel RelA-associated inhibitor (RAI) that binds to the NF-κB subunit p65/RelA and inhibits its transcriptional activity ( 49 ).…”

Concomitant Autoimmunity in Endometriosis Impairs Endometrium–Embryo Crosstalk at the Implantation Site: A Multicenter Case-Control Study

“…These factors include alterations in the balance of proinflammatory and anti-inflammatory cytokines, changes in the composition and/or activity of specific endometrial immune cells, and aberrant expression of adhesion molecules at the implantation site [39]. Recent studies have, in fact, shown that women with endometriosis present dysregulation of key endometrial receptivity-specific genes often belonging to immunological pathways [40]. A meta-analysis of the endometrial transcriptome has shown that women with endometriosis exhibit a pro-inflammatory profile characterized by increased levels of uterine natural killer (uNK) cells in the eutopic endometrium [41].…”