Vargas E, García-Moreno E, Aghajanova L, Salumets A, Horcajadas J A, Esteban F J, Altmäe S
Systems Biology Unit, Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaén, Jaén, Spain.
Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Granada, Granada, Spain.
Hum Reprod Open. 2022 Apr 4;2022(2):hoac016. doi: 10.1093/hropen/hoac016. eCollection 2022.
Do women with endometriosis have a different endometrial gene expression profile at the time of embryo implantation than women without endometriosis?
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.
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 dysregulation 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.
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 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.
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 dysregulated in endometriosis. Further analysis of endometrial receptivity-specific genes highlighted dysregulation of , and and enrichment of immune and defence pathways in women with endometriosis.
Most of the studies included into the meta-analysis were relatively small and had different study designs, which might have contributed to a bias.
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 INTERESTS: 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 Spanish University 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-R; 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).
The systematic review was registered at PROSPERO (identifier: CRD42020122054).
子宫内膜异位症女性在胚胎植入时的子宫内膜基因表达谱与非子宫内膜异位症女性是否不同？
子宫内膜异位症女性的子宫内膜基因表达谱在分泌中期与非子宫内膜异位症女性不同，尽管差异较小。
约50%的子宫内膜异位症女性患有不孕症。多项分子研究表明子宫内膜异位症女性的子宫内膜容受性受损，而其他研究未检测到子宫内膜容受性的失调。然而，之前比较有和没有子宫内膜异位症女性的子宫内膜转录组研究样本量较小，统计效力有限。我们着手系统地搜索和汇编子宫内膜异位症女性与对照女性在容受期的子宫内膜基因表达特征数据。基于获得的数据，我们对差异表达基因进行了荟萃分析，以提高分析效力，从而确定子宫内膜异位症中容受期子宫内膜的分子特征。
研究设计、规模、持续时间：按照PRISMA标准，截至2022年2月进行了系统的文献检索，包括PubMed、Cochrane和科学网数据库。对于系统检索，使用布尔运算符“AND”将“子宫内膜异位症”一词与“转录组学”、“转录组”、“基因表达”、“RNA测序”、“测序”和“阵列”等词配对。筛选并查阅了英文撰写的文章以提取数据。
参与者/材料、设置、方法：对选定的研究进行荟萃分析，采用稳健秩聚合方法提取自然周期中子宫内膜异位症女性与非子宫内膜异位症女性在分泌中期描述的差异表达基因。总共对125名女性（78例患者和47例对照）的转录组数据进行了荟萃分析，特别关注基于商业子宫内膜容受性检测的子宫内膜容受性特异性基因。
总共有8项研究符合定量荟萃分析的条件，收集了125名女性分泌中期子宫内膜的转录组数据。在研究组之间共检索到7779个差异表达转录本（3496个上调和4283个下调）并进行了荟萃分析。经过严格的多重校正后，子宫内膜异位症女性与对照女性的子宫内膜中没有任何单个分子存在差异表达，而富集分析检测到子宫内膜异位症中趋化性和运动途径失调。对子宫内膜容受性特异性基因的进一步分析突出了子宫内膜异位症女性中[具体基因]的失调以及免疫和防御途径的富集。
局限性、谨慎的原因：纳入荟萃分析的大多数研究规模相对较小且研究设计不同，这可能导致了偏差。
当前的荟萃分析支持子宫内膜异位症女性子宫内膜容受性发生改变这一假设，尽管变化较小。所确定的分子和途径可作为未来检测和治疗子宫内膜异位症相关不孕症的生物标志物和治疗靶点。
研究资金/利益冲突：作者声明无利益冲突。本研究得到西班牙教育、文化和体育部[FPU15/01193资助]以及西班牙大学系统重新资格认定的玛格丽塔·萨拉斯计划[UJAR01MS资助]；西班牙经济、工业和竞争力部（MINECO）和欧洲区域发展基金（FEDER）：RYC - 2016 - 21199和ENDORE SAF2017 - 87526 - R资助；安达卢西亚运营计划FEDER（B - CTS - 500 - UGR18；A - CTS - 614 - UGR20）；安达卢西亚自治区[BIO -
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