{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:01:41Z","timestamp":1792454501993,"version":"4.5.0"},"reference-count":80,"publisher":"Bioscientifica","issue":"3","license":[{"start":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T00:00:00Z","timestamp":1685923200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["raf.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,7,7]]},"abstract":"<jats:p>Genome-wide analysis of gene expression has been widely applied to study the endometrium, although to our knowledge no systematic reviews have been performed. Here, we identified 74 studies that described transcriptomes from whole (unprocessed) endometrium samples and found that these fitted into three broad investigative categories: endometrium across the menstrual cycle, endometrium in pathology and endometrium during hormone treatment. Notably, key participant information such as menstrual cycle length and body mass index was often not reported. Fertility status was frequently not defined and fertility-related pathologies, such as recurrent implantation failure (RIF) and recurrent pregnancy loss, were variably defined, while hormone treatments differed between almost every study. A range of 1307\u20133637 reported differentially expressed genes (DEGs) were compared in four to seven studies in five sub-categories: (i) secretory vs proliferative stage endometrium, (ii) mid-secretory vs early secretory stage endometrium, (iii) mid-secretory endometrium from ovarian stimulation-treated participants vs controls, (iv) mid-secretory endometrium from RIF patients vs controls, and (v) mid-secretory eutopic endometrium from endometriosis patients vs controls. Only the first two sub-categories yielded consistently reported DEG between \u22653 studies, albeit in small numbers (&lt;40), and these were enriched in developmental process and immune response annotations. This systematic review, though not PROSPERO registered, reveals that limited demographic detail, variable fertility definitions and differing hormone treatments in endometrial transcriptomic studies hinder their comparison, and that the large majority of reported DEG do not advance the identification of underlying biological mechanisms. Future studies should apply network biology approaches and experimental validation to establish causal gene expression signatures.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Lay summary<\/jats:title>\n                    <jats:p>The endometrium lines the inner wall of the uterus and is the site where the fertilised egg implants to establish pregnancy. Disorders of the endometrium cause infertility and chronic pain. Techniques to measure genetic activity, termed transcriptomics, have been applied to better understand the endometrium in health and disease. We collated all studies, totalling 74, that describe transcriptomics of endometrial samples from non-pregnant women and compared study designs and genetic activity measurements. The studies generally looked at small numbers of samples, with most focussing on fertility rather than endometrial disorders. Study designs were variable, comparing women under different definitions of fertility and disease, and under different treatments. Additionally, key participant factors such as BMI were mostly not reported. These and other limitations produced genetic activity measurements that were inconsistent, especially in cases of infertility and endometrial disorders. Addressing these limitations could improve how transcriptomic approaches are used to advance endometrial health.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/raf-22-0115","type":"journal-article","created":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T13:11:34Z","timestamp":1685970694000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-13","source":"Crossref","is-referenced-by-count":29,"title":["A systematic review of transcriptomic studies of the human endometrium reveals inconsistently reported differentially expressed genes"],"prefix":"10.1530","volume":"4","author":[{"given":"Evangeline R","family":"Walker","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine, Old Saint Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mollie","family":"McGrane","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK"},{"name":"Maternal and Fetal Health Research Centre, Saint Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D","family":"Aplin","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK"},{"name":"Maternal and Fetal Health Research Centre, Saint Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R","family":"Brison","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Old Saint Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK"},{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK"},{"name":"Maternal and Fetal Health Research Centre, Saint Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1476-1666","authenticated-orcid":true,"given":"Peter T","family":"Ruane","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK"},{"name":"Maternal and Fetal Health Research Centre, Saint Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib4","series-title":"Human Reproduction Update","first-page":"12","article-title":"Guidelines for the design, analysis and interpretation of 'omics' data: focus on human endometrium","volume":"20","author":"Altm\u00e4e","year":"2014","unstructured":"Altm\u00e4e SEsteban FJStavreus-Evers ASim\u00f3n CGiudice LLessey BAHorcajadas JAMacklon NSD'Hooghe TCampoy C2014Guidelines for the design, analysis and interpretation of 'omics' data: focus on human endometrium. Human Reproduction Update2012\u201328. (https:\/\/doi.org\/10.1093\/humupd\/dmt048)"},{"key":"bib5","series-title":"Scientific Reports","article-title":"Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers","volume":"7","author":"Altm\u00e4e","year":"2017","unstructured":"Altm\u00e4e SKoel MV\u00f5sa UAdler PSuhorut\u0161enko MLaisk-Podar TKukushkina VSaare MVelthut-Meikas AKrjut\u0161kov K2017Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers. Scientific Reports7 10077. (https:\/\/doi.org\/10.1038\/s41598-017-10098-3)"},{"key":"bib9","series-title":"Fertility and Sterility","first-page":"817","article-title":"Revised American Society for Reproductive Medicine classification of endometriosis: 1996","volume":"67","year":"1997","unstructured":"American Society for Reproductive Medicine1997Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertility and Sterility67817\u2013821. (https:\/\/doi.org\/10.1016\/s0015-0282(9781391-x)"},{"key":"bib10","series-title":"The Endometrium: Molecular, Cellular and Clinical Perspectives","author":"Aplin","year":"2008","unstructured":"Aplin JDFazleabas ATGlasser SR & Giudice LC, Eds. 2008The Endometrium: Molecular, Cellular and Clinical Perspectives, 2nd ed.London: CRC Press."},{"key":"bib11","series-title":"Human Reproduction","first-page":"644","article-title":"Use of 'omics for endometrial timing: the cycle moves on","volume":"37","author":"Aplin","year":"2022","unstructured":"Aplin JD & Stevens A2022Use of 'omics for endometrial timing: the cycle moves on. Human Reproduction37644\u2013650. (https:\/\/doi.org\/10.1093\/humrep\/deac022)"},{"key":"bib13","series-title":"Reproductive Sciences","article-title":"Potential marker pathways in the endometrium that may cause recurrent implantation failure","volume":"26","author":"Bastu","year":"2019","unstructured":"Bastu EDemiral IGunel TUlgen EGumusoglu EHosseini MKSezerman UBuyru F & Yeh J2019Potential marker pathways in the endometrium that may cause recurrent implantation failure. Reproductive Sciences26 879\u2013890. (https:\/\/doi.org\/10.1177\/1933719118792104)"},{"key":"bib15","series-title":"Human Reproduction","first-page":"1479","article-title":"Repeated implantation failure (RIF): an iatrogenic meaningless definition that generates unnecessary and costly use of add-on procedures","volume":"35","author":"Ben Rafael","year":"2020","unstructured":"Ben Rafael Z2020Repeated implantation failure (RIF): an iatrogenic meaningless definition that generates unnecessary and costly use of add-on procedures. Human Reproduction351479\u20131483. (https:\/\/doi.org\/10.1093\/humrep\/deaa134)"},{"key":"bib16","series-title":"Human Reproduction Open","article-title":"Endometrial Receptivity Analysis (ERA) test: an unproven technology","volume":"2021","author":"Ben Rafael","year":"2021","unstructured":"Ben Rafael Z2021Endometrial Receptivity Analysis (ERA) test: an unproven technology. Human Reproduction Open2021 hoab010. (https:\/\/doi.org\/10.1093\/hropen\/hoab010)"},{"key":"bib19","series-title":"Molecular Human Reproduction","article-title":"Determination of the transcript profile of human endometrium","volume":"9","author":"Borthwick","year":"2003","unstructured":"Borthwick JMCharnock-Jones DSTom BDHull MLTeirney RPhillips SC & Smith SK2003Determination of the transcript profile of human endometrium. Molecular Human Reproduction9 19\u201333. (https:\/\/doi.org\/10.1093\/molehr\/gag004)"},{"key":"bib20","series-title":"eLife","article-title":"Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium","volume":"6","author":"Brighton","year":"2017","unstructured":"Brighton PJMaruyama YFishwick KVrljicak PTewary SFujihara RMuter JLucas ESYamada TWoods L2017Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. eLife6 e31274. (https:\/\/doi.org\/10.7554\/eLife.31274)"},{"key":"bib21","series-title":"Seminars in Cell and Developmental Biology","first-page":"14","article-title":"Maternal selection of human embryos in early gestation: insights from recurrent miscarriage","volume":"131","author":"Brosens","year":"2022","unstructured":"Brosens JJBennett PRAbrahams VMRamhorst RCoomarasamy AQuenby SLucas ES & McCoy RC2022Maternal selection of human embryos in early gestation: insights from recurrent miscarriage. Seminars in Cell and Developmental Biology13114\u201324. (https:\/\/doi.org\/10.1016\/j.semcdb.2022.01.007)"},{"key":"bib22","series-title":"npj Digital Medicine","article-title":"Real-world menstrual cycle characteristics of more than 600,000 menstrual cycles","volume":"2","author":"Bull","year":"2019","unstructured":"Bull JRRowland SPScherwitzl EBScherwitzl RDanielsson KG & Harper J2019Real-world menstrual cycle characteristics of more than 600,000 menstrual cycles. npj Digital Medicine2 83. (https:\/\/doi.org\/10.1038\/s41746-019-0152-7)"},{"key":"bib23","series-title":"Endocrinology","article-title":"Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis","volume":"148","author":"Burney","year":"2007","unstructured":"Burney ROTalbi SHamilton AEVo KCNyegaard MNezhat CRLessey BA & Giudice LC2007Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology148 3814\u20133826. (https:\/\/doi.org\/10.1210\/en.2006-1692)"},{"key":"bib24","series-title":"Molecular Human Reproduction","article-title":"Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening","volume":"8","author":"Carson","year":"2002","unstructured":"Carson DDLagow EThathiah AAl-Shami RFarach-Carson MCVernon MYuan LFritz MA & Lessey B2002Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Molecular Human Reproduction8 871\u2013879. (https:\/\/doi.org\/10.1093\/molehr\/8.9.871)"},{"key":"bib26","series-title":"Reproductive Sciences","first-page":"18","article-title":"Genome-wide profiling of long noncoding RNA expression patterns in women with repeated implantation failure by RNA sequencing","volume":"26","author":"Chen","year":"2019","unstructured":"Chen MYLiao GDZhou BKang LNHe YM & Li SW2019Genome-wide profiling of long noncoding RNA expression patterns in women with repeated implantation failure by RNA sequencing. Reproductive Sciences2618\u201325. (https:\/\/doi.org\/10.1177\/1933719118756752)"},{"key":"bib28","series-title":"PLoS One","article-title":"Integrative analyses of uterine transcriptome and MicroRNAome reveal compromised LIF-STAT3 signaling and progesterone response in the endometrium of patients with recurrent\/repeated implantation failure (RIF)","volume":"11","author":"Choi","year":"2016","unstructured":"Choi YKim HRLim EJPark MYoon JAKim YSKim EKShin JEKim JHKwon H2016Integrative analyses of uterine transcriptome and MicroRNAome reveal compromised LIF-STAT3 signaling and progesterone response in the endometrium of patients with recurrent\/repeated implantation failure (RIF). PLoS One11 e0157696. (https:\/\/doi.org\/10.1371\/journal.pone.0157696)"},{"key":"bib29","series-title":"Systems Biology in Reproductive Medicine","first-page":"347","article-title":"Comparing endometrial receptivity array to histologic dating of the endometrium in women with a history of implantation failure","volume":"66","author":"Cohen","year":"2020","unstructured":"Cohen AMYe XYColgan TJGreenblatt EM & Chan C2020Comparing endometrial receptivity array to histologic dating of the endometrium in women with a history of implantation failure. Systems Biology in Reproductive Medicine66347\u2013354. (https:\/\/doi.org\/10.1080\/19396368.2020.1824032)"},{"key":"bib30","series-title":"Obstetrics and Gynecology Clinics of North America","first-page":"163","article-title":"Evidence for corpus luteal and endometrial origins of adverse pregnancy outcomes in women conceiving with or without assisted reproduction","volume":"47","author":"Conrad","year":"2020","unstructured":"Conrad KP2020Evidence for corpus luteal and endometrial origins of adverse pregnancy outcomes in women conceiving with or without assisted reproduction. Obstetrics and Gynecology Clinics of North America47163\u2013181. (https:\/\/doi.org\/10.1016\/j.ogc.2019.10.011)"},{"key":"bib31","series-title":"Human Reproduction Update","first-page":"202","article-title":"Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis","volume":"25","author":"Craciunas","year":"2019","unstructured":"Craciunas LGallos IChu JBourne TQuenby SBrosens JJ & Coomarasamy A2019Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis. Human Reproduction Update25202\u2013223. (https:\/\/doi.org\/10.1093\/humupd\/dmy044)"},{"key":"bib32","series-title":"International Journal of Gynaecology and Obstetrics","article-title":"Revised FIGO staging for carcinoma of the endometrium","volume":"105","author":"Creasman","year":"2009","unstructured":"Creasman W2009Revised FIGO staging for carcinoma of the endometrium. International Journal of Gynaecology and Obstetrics105 109. (https:\/\/doi.org\/10.1016\/j.ijgo.2009.02.010)"},{"key":"bib33","series-title":"Physiological Reviews","first-page":"1149","article-title":"Physiology of the endometrium and regulation of menstruation","volume":"100","author":"Critchley","year":"2020","unstructured":"Critchley HODMaybin JAArmstrong GM & Williams ARW2020Physiology of the endometrium and regulation of menstruation. Physiological Reviews1001149\u20131179. (https:\/\/doi.org\/10.1152\/physrev.00031.2019)"},{"key":"bib37","series-title":"Gene","first-page":"140","article-title":"Analysis of long non-coding RNA expression profiles using RNA sequencing in ovarian endometriosis","volume":"673","author":"Cui","year":"2018","unstructured":"Cui DMa JLiu YLin KJiang XQu YLin J & Xu K2018Analysis of long non-coding RNA expression profiles using RNA sequencing in ovarian endometriosis. Gene673140\u2013148. (https:\/\/doi.org\/10.1016\/j.gene.2018.06.046)"},{"key":"bib38","series-title":"Fertility and Sterility","first-page":"508","article-title":"The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity","volume":"99","author":"D\u00edaz-Gimeno","year":"2013","unstructured":"D\u00edaz-Gimeno PRuiz-Alonso MBlesa DBosch NMart\u00ednez-Conejero JAAlam\u00e1 PGarrido NPellicer A & Sim\u00f3n C2013The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. Fertility and Sterility99508\u2013517. (https:\/\/doi.org\/10.1016\/j.fertnstert.2012.09.046)"},{"key":"bib39","series-title":"International Journal of Developmental Biology","first-page":"127","article-title":"Transcriptomics of the human endometrium","volume":"58","author":"D\u00edaz-Gimeno","year":"2014","unstructured":"D\u00edaz-Gimeno PRu\u00edz-Alonso MBlesa D & Sim\u00f3n C2014Transcriptomics of the human endometrium. International Journal of Developmental Biology58127\u2013137. (https:\/\/doi.org\/10.1387\/ijdb.130340pd)"},{"key":"bib40","series-title":"International Journal of Molecular Sciences","article-title":"The role of mTOR and eIF signaling in benign endometrial diseases","volume":"23","author":"Driva","year":"2022","unstructured":"Driva TSSchatz CSobo\u010dan M & Haybaeck J2022The role of mTOR and eIF signaling in benign endometrial diseases. International Journal of Molecular Sciences23 3416. (https:\/\/doi.org\/10.3390\/ijms23073416)"},{"key":"bib43","series-title":"Human Reproduction","first-page":"452","article-title":"Does the endometrial gene expression of fertile women vary within and between cycles?","volume":"33","author":"Evans","year":"2018","unstructured":"Evans GEPhillipson GTMSykes PHMcNoe LAPrint CG & Evans JJ2018Does the endometrial gene expression of fertile women vary within and between cycles?Human Reproduction33452\u2013463. (https:\/\/doi.org\/10.1093\/humrep\/dex385)"},{"key":"bib44","series-title":"Journal of Obstetrics and Gynaecology of the British Commonwealth","first-page":"673","article-title":"The blood supply of the uterus. 1. Arterial vasculature","volume":"77","author":"Farrer-Brown","year":"1970","unstructured":"Farrer-Brown GBeilby JO & Tarbit MH1970The blood supply of the uterus. 1. Arterial vasculature. Journal of Obstetrics and Gynaecology of the British Commonwealth77673\u2013681. (https:\/\/doi.org\/10.1111\/j.1471-0528.1970.tb03592.x)"},{"key":"bib45","series-title":"Annals of the New York Academy of Sciences","first-page":"6","article-title":"Histology of the human endometrium: from birth to senescence","volume":"622","author":"Ferenczy","year":"1991","unstructured":"Ferenczy A & Bergeron C1991Histology of the human endometrium: from birth to senescence. Annals of the New York Academy of Sciences6226\u201327. (https:\/\/doi.org\/10.1111\/j.1749-6632.1991.tb37847.x)"},{"key":"bib46","series-title":"Frontiers in Endocrinology","article-title":"Killer timing: the temporal uterine natural killer cell differentiation pathway and implications for female reproductive health","volume":"13","author":"Fraser","year":"2022","unstructured":"Fraser R & Zenclussen AC2022Killer timing: the temporal uterine natural killer cell differentiation pathway and implications for female reproductive health. Frontiers in Endocrinology13 904744. (https:\/\/doi.org\/10.3389\/fendo.2022.904744)"},{"key":"bib49","series-title":"Nature Genetics","first-page":"1698","article-title":"Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro","volume":"53","author":"Garcia-Alonso","year":"2021","unstructured":"Garcia-Alonso LHandfield LFRoberts KNikolakopoulou KFernando RCGardner LWoodhams BArutyunyan APolanski KHoo R, 2021Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro. Nature Genetics531698\u20131711. (https:\/\/doi.org\/10.1038\/s41588-021-00972-2)"},{"key":"bib50","series-title":"Endocrine Reviews","first-page":"851","article-title":"Cyclic decidualization of the human endometrium in reproductive health and failure","volume":"35","author":"Gellersen","year":"2014","unstructured":"Gellersen B & Brosens JJ2014Cyclic decidualization of the human endometrium in reproductive health and failure. Endocrine Reviews35851\u2013905. (https:\/\/doi.org\/10.1210\/er.2014-1045)"},{"key":"bib51","series-title":"Cold Spring Harbor Perspectives in Medicine","first-page":"a022996","article-title":"Human endometrial transcriptomics: implications for embryonic implantation","volume":"5","author":"G\u00f3mez","year":"2015","unstructured":"G\u00f3mez ERu\u00edz-Alonso MMiravet J & Sim\u00f3n C2015Human endometrial transcriptomics: implications for embryonic implantation. Cold Spring Harbor Perspectives in Medicine5a022996. (https:\/\/doi.org\/10.1101\/cshperspect.a022996)"},{"key":"bib52","series-title":"BMC Medicine","article-title":"The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study","volume":"16","author":"Hann","year":"2018","unstructured":"Hann MRoberts SAD'Souza SWClayton PMacklon N & Brison DR2018The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study. BMC Medicine16 224. (https:\/\/doi.org\/10.1186\/s12916-018-1203-7)"},{"key":"bib57","series-title":"Human Reproduction","first-page":"198","article-title":"Identification of new biomarkers of human endometrial receptivity in the natural cycle","volume":"24","author":"Haouzi","year":"2009","unstructured":"Haouzi DMahmoud KFourar MBendhaou KDechaud HDe Vos JR\u00e8me TDewailly D & Hamamah S2009Identification of new biomarkers of human endometrial receptivity in the natural cycle. Human Reproduction24198\u2013205. (https:\/\/doi.org\/10.1093\/humrep\/den360)"},{"key":"bib60","series-title":"Molecular Human Reproduction","article-title":"Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles","volume":"11","author":"Horcajadas","year":"2005","unstructured":"Horcajadas JARiesewijk APolman Jvan Os RPellicer AMosselman S & Sim\u00f3n C2005Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles. Molecular Human Reproduction11 195\u2013205. (https:\/\/doi.org\/10.1093\/molehr\/gah150)"},{"key":"bib61","series-title":"Journal of Clinical Endocrinology and Metabolism","article-title":"Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications","volume":"93","author":"Horcajadas","year":"2008","unstructured":"Horcajadas JAM\u00ednguez PDopazo JEsteban FJDom\u00ednguez FGiudice LCPellicer A & Sim\u00f3n C2008Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. Journal of Clinical Endocrinology and Metabolism93 4500\u20134510. (https:\/\/doi.org\/10.1210\/jc.2008-0588)"},{"key":"bib62","series-title":"Journal of Clinical Endocrinology and Metabolism","article-title":"Transcriptomic changes during the pre-receptive to receptive transition in human endometrium detected by RNA-Seq","volume":"99","author":"Hu","year":"2014","unstructured":"Hu SYao GWang YXu HJi XHe YZhu QChen Z & Sun Y2014Transcriptomic changes during the pre-receptive to receptive transition in human endometrium detected by RNA-Seq. Journal of Clinical Endocrinology and Metabolism99 E2744\u2013E2753. (https:\/\/doi.org\/10.1210\/jc.2014-2155)"},{"key":"bib63","series-title":"Nature Protocols","first-page":"44","article-title":"Systematic and integrative analysis of large gene lists using David bioinformatics resources","volume":"4","author":"Huang","year":"2009","unstructured":"Huang DSherman BT & Lempicki RA2009Systematic and integrative analysis of large gene lists using David bioinformatics resources. Nature Protocols444\u201357. (https:\/\/doi.org\/10.1038\/nprot.2008.211)"},{"key":"bib67","series-title":"Nature","first-page":"600","article-title":"Human blastoids model blastocyst development and implantation","volume":"601","author":"Kagawa","year":"2022","unstructured":"Kagawa HJavali AKhoei HHSommer TMSestini GNovatchkova MScholte Op Reimer YCastel GBruneau AMaenhoudt N2022Human blastoids model blastocyst development and implantation. Nature601600\u2013605. (https:\/\/doi.org\/10.1038\/s41586-021-04267-8)"},{"key":"bib69","series-title":"Endocrinology","article-title":"Global gene profiling in human endometrium during the window of implantation","volume":"143","author":"Kao","year":"2002","unstructured":"Kao LCTulac SLobo SImani BYang JPGermeyer AOsteen KTaylor RNLessey BA & Giudice LC2002Global gene profiling in human endometrium during the window of implantation. Endocrinology143 2119\u20132138. (https:\/\/doi.org\/10.1210\/endo.143.6.8885)"},{"key":"bib68","series-title":"Endocrinology","article-title":"Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility","volume":"144","author":"Kao","year":"2003","unstructured":"Kao LCGermeyer ATula SLobo SYang JPTaylor RNOsteen KLessey BA & Giudice LC2003Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology144 2870\u20132881. (https:\/\/doi.org\/10.1210\/en.2003-0043)"},{"key":"bib70","series-title":"Journal of Clinical Endocrinology and Metabolism","first-page":"2932","article-title":"Central role of interleukin-15 in postovulatory recruitment of peripheral blood CD16(-) natural killer cells into human endometrium","volume":"90","author":"Kitaya","year":"2005","unstructured":"Kitaya KYamaguchi T & Honjo H2005Central role of interleukin-15 in postovulatory recruitment of peripheral blood CD16(-) natural killer cells into human endometrium. Journal of Clinical Endocrinology and Metabolism902932\u20132940. (https:\/\/doi.org\/10.1210\/jc.2004-2447)"},{"key":"bib71","series-title":"Human Reproduction","first-page":"2541","article-title":"Disrupted gene pattern in patients with repeated in vitro fertilization (IVF) failure","volume":"24","author":"Koler","year":"2009","unstructured":"Koler MAchache HTsafrir ASmith YRevel A & Reich R2009Disrupted gene pattern in patients with repeated in vitro fertilization (IVF) failure. Human Reproduction242541\u20132548. (https:\/\/doi.org\/10.1093\/humrep\/dep193)"},{"key":"bib72","series-title":"Scientific Reports","article-title":"An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF","volume":"6","author":"Koot","year":"2016","unstructured":"Koot YEvan Hooff SRBoomsma CMvan Leenen DGroot Koerkamp MJGoddijn MEijkemans MJFauser BCHolstege FC & Macklon NS2016An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF. Scientific Reports6 19411. (https:\/\/doi.org\/10.1038\/srep19411)"},{"key":"bib77","series-title":"Journal of Pathology","first-page":"554","article-title":"Specific and extensive endometrial deregulation is present before conception in IVF\/ICSI repeated implantation failures (IF) or recurrent miscarriages","volume":"225","author":"L\u00e9d\u00e9e","year":"2011","unstructured":"L\u00e9d\u00e9e NMunaut CAubert JS\u00e9razin VRahmati MChaouat GSandra O & Foidart JM2011Specific and extensive endometrial deregulation is present before conception in IVF\/ICSI repeated implantation failures (IF) or recurrent miscarriages. Journal of Pathology225554\u2013564. (https:\/\/doi.org\/10.1002\/path.2948)"},{"key":"bib78","series-title":"Nature Reviews. Genetics","first-page":"733","article-title":"Tackling the widespread and critical impact of batch effects in high-throughput data","volume":"11","author":"Leek","year":"2010","unstructured":"Leek JTScharpf RBBravo HCSimcha DLangmead BJohnson WEGeman DBaggerly K & Irizarry RA2010Tackling the widespread and critical impact of batch effects in high-throughput data. Nature Reviews. Genetics11733\u2013739. (https:\/\/doi.org\/10.1038\/nrg2825)"},{"key":"bib79","series-title":"Journal of Assisted Reproduction and Genetics","first-page":"21","article-title":"Transcriptome sequencing of endometrium revealed alterations in mRNAs and lncRNAs after ovarian stimulation","volume":"37","author":"Li","year":"2020","unstructured":"Li LWang PLiu SBai XZou B & Li Y2020Transcriptome sequencing of endometrium revealed alterations in mRNAs and lncRNAs after ovarian stimulation. Journal of Assisted Reproduction and Genetics3721\u201332. (https:\/\/doi.org\/10.1007\/s10815-019-01616-5)"},{"key":"bib80","series-title":"Fertility and Sterility","article-title":"Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles","volume":"90","author":"Liu","year":"2008","unstructured":"Liu YLee KFNg EHYYeung WSB & Ho PC2008Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles. Fertility and Sterility90 2152\u20132164. (https:\/\/doi.org\/10.1016\/j.fertnstert.2007.10.020)"},{"key":"bib81","series-title":"Reproductive Sciences","article-title":"The impact of ovarian stimulation with recombinant FSH in combination with GnRH antagonist on the endometrial transcriptome in the window of implantation","volume":"15","author":"Macklon","year":"2008","unstructured":"Macklon NSvan der Gaast MHHamilton AFauser BCJM & Giudice LC2008The impact of ovarian stimulation with recombinant FSH in combination with GnRH antagonist on the endometrial transcriptome in the window of implantation. Reproductive Sciences15 357\u2013365. (https:\/\/doi.org\/10.1177\/1933719107311781)"},{"key":"bib83","series-title":"Journal of Clinical Endocrinology and Metabolism","article-title":"Gene expression profiles and structural\/functional features of the peri-implantation endometrium in natural and gonadotropin-stimulated cycles","volume":"89","author":"Mirkin","year":"2004","unstructured":"Mirkin SNikas GHsiu JGD\u00edaz J & Oehninger S2004Gene expression profiles and structural\/functional features of the peri-implantation endometrium in natural and gonadotropin-stimulated cycles. Journal of Clinical Endocrinology and Metabolism89 5742\u20135752. (https:\/\/doi.org\/10.1210\/jc.2004-0605)"},{"key":"bib82","series-title":"Human Reproduction","first-page":"2104","article-title":"In search of candidate genes critically expressed in the human endometrium during the window of implantation","volume":"20","author":"Mirkin","year":"2005","unstructured":"Mirkin SArslan MChurikov DCorica ADiaz JIWilliams SBocca S & Oehninger S2005In search of candidate genes critically expressed in the human endometrium during the window of implantation. Human Reproduction202104\u20132117. (https:\/\/doi.org\/10.1093\/humrep\/dei051)"},{"key":"bib85","series-title":"Journal of Biological Chemistry","first-page":"9596","article-title":"The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells","volume":"295","author":"Murata","year":"2020","unstructured":"Murata HTanaka STsuzuki-Nakao TKido TKakita-Kobayashi MKida NHisamatsu YTsubokura HHashimoto YKitada M2020The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells. Journal of Biological Chemistry2959596\u20139605. (https:\/\/doi.org\/10.1074\/jbc.RA120.012753)"},{"key":"bib88","series-title":"Gynecological Endocrinology","article-title":"Human endometrium mRNA profile assessed by oligonucleotide three-dimensional microarray","volume":"23","author":"Otsuka","year":"2007","unstructured":"Otsuka AYAndrade PMVillanova FEBorra RC & Silva IDCG2007Human endometrium mRNA profile assessed by oligonucleotide three-dimensional microarray. Gynecological Endocrinology23 527\u2013534. (https:\/\/doi.org\/10.1080\/09513590701550221)"},{"key":"bib91","series-title":"Scientific Reports","article-title":"Transcriptome meta-analysis reveals differences of immune profile between eutopic endometrium from stage I\u2013II and III\u2013IV endometriosis independently of hormonal milieu","volume":"10","author":"Poli-Neto","year":"2020","unstructured":"Poli-Neto OBMeola JRosa-E-Silva JC & Tiezzi D2020Transcriptome meta-analysis reveals differences of immune profile between eutopic endometrium from stage I\u2013II and III\u2013IV endometriosis independently of hormonal milieu. Scientific Reports10 313. (https:\/\/doi.org\/10.1038\/s41598-019-57207-y)"},{"key":"bib95","series-title":"Nucleic Acids Research","first-page":"W191","article-title":"g:profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update)","volume":"47","author":"Raudvere","year":"2019","unstructured":"Raudvere UKolberg LKuzmin IArak TAdler PPeterson H & Vilo J2019g:profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Research47W191\u2013W198. (https:\/\/doi.org\/10.1093\/nar\/gkz369)"},{"key":"bib96","series-title":"Reproduction and Fertility","first-page":"R85","article-title":"Organoids to model the endometrium: implantation and beyond","volume":"2","author":"Rawlings","year":"2021","unstructured":"Rawlings TMMakwana KTryfonos M & Lucas ES2021Organoids to model the endometrium: implantation and beyond. Reproduction and Fertility2R85\u2013R101. (https:\/\/doi.org\/10.1530\/RAF-21-0023)"},{"key":"bib97","series-title":"Human Reproduction","first-page":"dead083","article-title":"Personalized Embryo transfer reduces success rates because endometrial receptivity analysis fails to accurately identify the window of implantation","author":"Richter","year":"2023","unstructured":"Richter KS & Richter ML2023Personalized Embryo transfer reduces success rates because endometrial receptivity analysis fails to accurately identify the window of implantation. Human Reproduction. dead083. (https:\/\/doi.org\/10.1093\/humrep\/dead083)"},{"key":"bib98","series-title":"Molecular Human Reproduction","article-title":"Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology","volume":"9","author":"Riesewijk","year":"2003","unstructured":"Riesewijk AMart\u00edn Jvan Os RHorcajadas JAPolman JPellicer AMosselman S & Sim\u00f3n C2003Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Molecular Human Reproduction9 253\u2013264. (https:\/\/doi.org\/10.1093\/molehr\/gag037)"},{"key":"bib99","series-title":"Fertility and Sterility","first-page":"1107","article-title":"Immune determinants of endometrial receptivity: a biological perspective","volume":"117","author":"Robertson","year":"2022","unstructured":"Robertson SAMoldenhauer LMGreen ESCare AS & Hull ML2022Immune determinants of endometrial receptivity: a biological perspective. Fertility and Sterility1171107\u20131120. (https:\/\/doi.org\/10.1016\/j.fertnstert.2022.04.023)"},{"key":"bib100","series-title":"Human Reproduction","first-page":"41","article-title":"Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)","volume":"19","year":"2004","unstructured":"Rotterdam ESHRE\/ASRM-Sponsored PCOS Consensus Workshop Group2004Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction1941\u201347. (https:\/\/doi.org\/10.1093\/humrep\/deh098)"},{"key":"bib101","series-title":"Reproduction","first-page":"301","article-title":"Tissue injury and repair in the female human reproductive tract","volume":"125","author":"Salamonsen","year":"2003","unstructured":"Salamonsen LA2003Tissue injury and repair in the female human reproductive tract. Reproduction125301\u2013311. (https:\/\/doi.org\/10.1530\/rep.0.1250301)"},{"key":"bib103","series-title":"Seminars in Reproductive Medicine","first-page":"227","article-title":"Endometrial factor in unexplained infertility and recurrent implantation failure","volume":"39","author":"Santamaria","year":"2021","unstructured":"Santamaria X & Sim\u00f3n C2021Endometrial factor in unexplained infertility and recurrent implantation failure. Seminars in Reproductive Medicine39227\u2013232. (https:\/\/doi.org\/10.1055\/s-0041-1735199)"},{"key":"bib104","series-title":"Human Reproduction","first-page":"1063","article-title":"Global gene analysis of late secretory phase, eutopic endometrium does not provide the basis for a minimally invasive test of endometriosis","volume":"23","author":"Sherwin","year":"2008","unstructured":"Sherwin JRASharkey AMMihalyi ASimsa PCatalano RD & DHooghe TM2008Global gene analysis of late secretory phase, eutopic endometrium does not provide the basis for a minimally invasive test of endometriosis. Human Reproduction231063\u20131068. (https:\/\/doi.org\/10.1093\/humrep\/den078)"},{"key":"bib105","series-title":"Biology of Reproduction","first-page":"24","article-title":"Comprehensive RNA sequencing of healthy human endometrium at two time points of the menstrual cycle","volume":"96","author":"Sigurgeirsson","year":"2017","unstructured":"Sigurgeirsson B\u00c5mark HJemt AUjvari DWestgren MLundeberg J & Gidl\u00f6f S2017Comprehensive RNA sequencing of healthy human endometrium at two time points of the menstrual cycle. Biology of Reproduction9624\u201333. (https:\/\/doi.org\/10.1095\/biolreprod.116.142547)"},{"key":"bib107","series-title":"Cell","first-page":"26","article-title":"The missing diversity in human genetic studies","volume":"177","author":"Sirugo","year":"2019","unstructured":"Sirugo GWilliams SM & Tishkoff SA2019The missing diversity in human genetic studies. Cell17726\u201331. (https:\/\/doi.org\/10.1016\/j.cell.2019.02.048)"},{"key":"bib108","series-title":"Reproductive Biomedicine Online","first-page":"32","article-title":"Repeated implantation failure at the crossroad between statistics, clinics and over-diagnosis","volume":"36","author":"Somigliana","year":"2018","unstructured":"Somigliana EVigano PBusnelli APaffoni AVegetti W & Vercellini P2018Repeated implantation failure at the crossroad between statistics, clinics and over-diagnosis. Reproductive Biomedicine Online3632\u201338. (https:\/\/doi.org\/10.1016\/j.rbmo.2017.09.012)"},{"key":"bib109","series-title":"Reproductive Medicine","first-page":"40","article-title":"The human early maternal-embryonic interactome","volume":"4","author":"Stevens","year":"2023","unstructured":"Stevens AKhashkhusha TSharps MGarner TRuane PT & Aplin JD2023The human early maternal-embryonic interactome. Reproductive Medicine440\u201356. (https:\/\/doi.org\/10.3390\/reprodmed4010006)"},{"key":"bib110","series-title":"Human Reproduction","first-page":"2074","article-title":"Endometrial receptivity revisited: endometrial transcriptome adjusted for tissue cellular heterogeneity","volume":"33","author":"Suhorutshenko","year":"2018","unstructured":"Suhorutshenko MKukushkina VVelthut-Meikas AAltm\u00e4e SPeters MM\u00e4gi RKrjut\u0161kov KKoel MCodo\u00f1er FMMartinez-Blanch JF, 2018Endometrial receptivity revisited: endometrial transcriptome adjusted for tissue cellular heterogeneity. Human Reproduction332074\u20132086. (https:\/\/doi.org\/10.1093\/humrep\/dey301)"},{"key":"bib112","series-title":"Endocrinology","article-title":"Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women","volume":"147","author":"Talbi","year":"2006","unstructured":"Talbi SHamilton AEVo KCTulac SOvergaard MTDosiou CLe Shay NNezhat CNKempson RLessey BA, 2006Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology147 1097\u20131121. (https:\/\/doi.org\/10.1210\/en.2005-1076)"},{"key":"bib129","series-title":"Journal of Assisted Reproduction and Genetics","first-page":"683","article-title":"The role of the endometrial receptivity array (ERA) in patients who have failed euploid embryo transfers","volume":"35","year":"2018","unstructured":"Tan JKan AHitkari JTaylor BTallon NWarraich GYuzpe A & Nakhuda G2018The role of the endometrial receptivity array (ERA) in patients who have failed euploid embryo transfers. Journal of Assisted Reproduction and Genetics35683\u2013692. (https:\/\/doi.org\/10.1007\/s10815-017-1112-2)"},{"key":"bib113","series-title":"Human Reproduction","first-page":"340","article-title":"Differences in the endometrial transcript profile during the receptive period between women who were refractory to implantation and those who achieved pregnancy","volume":"23","author":"Tapia","year":"2008","unstructured":"Tapia AGangi LMZegers-Hochschild FBalmaceda JPommer RTrejo LPacheco IMSalvatierra AMHenr\u00edquez SQuezada M, 2008Differences in the endometrial transcript profile during the receptive period between women who were refractory to implantation and those who achieved pregnancy. Human Reproduction23340\u2013351. (https:\/\/doi.org\/10.1093\/humrep\/dem319)"},{"key":"bib114","series-title":"Human Reproduction Update","first-page":"153","article-title":"Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies","volume":"28","author":"Tempest","year":"2022","unstructured":"Tempest NHill CJMaclean AMarston KPowell SGAl-Lamee H & Hapangama DK2022Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies. Human Reproduction Update28153\u2013171. (https:\/\/doi.org\/10.1093\/humupd\/dmab039)"},{"key":"bib115","series-title":"Fertility and Sterility","first-page":"351","article-title":"Revised American Fertility Society classification of endometriosis: 1985","volume":"43","year":"1985","unstructured":"The American Fertility Society1985Revised American Fertility Society classification of endometriosis: 1985. Fertility and Sterility43351\u2013352. (https:\/\/doi.org\/10.1016\/s0015-0282(1648430-x)"},{"key":"bib116","series-title":"Fertility and Sterility","article-title":"Genome-based expression profiling as a single standardized microarray platform for the diagnosis of endometrial disorder: an array of 126-gene model","volume":"94","author":"Tseng","year":"2010","unstructured":"Tseng LHChen IChen MYYan HWang CN & Lee CL2010Genome-based expression profiling as a single standardized microarray platform for the diagnosis of endometrial disorder: an array of 126-gene model. Fertility and Sterility94 114\u2013119. (https:\/\/doi.org\/10.1016\/j.fertnstert.2009.01.130)"},{"key":"bib120","series-title":"Human Reproduction Open","article-title":"The mid-secretory endometrial transcriptomic landscape in endometriosis: a meta-analysis","volume":"2022","author":"Vargas","year":"2022","unstructured":"Vargas EGarc\u00eda-Moreno EAghajanova LSalumets AHorcajadas JAEsteban FJ & Altm\u00e4e S2022The mid-secretory endometrial transcriptomic landscape in endometriosis: a meta-analysis. Human Reproduction Open2022 hoac016. (https:\/\/doi.org\/10.1093\/hropen\/hoac016)"},{"key":"bib128","series-title":"International Journal of Developmental Biology","first-page":"117","article-title":"Evolution of mammalian pregnancy and the origin of the decidual stromal cell","volume":"58","year":"2014","unstructured":"Wagner GPKin KMuglia L & Pavlicev M2014Evolution of mammalian pregnancy and the origin of the decidual stromal cell. International Journal of Developmental Biology58117\u201326. (https:\/\/doi.org\/10.1387\/ijdb.130335gw)"},{"key":"bib123","series-title":"Nature Medicine","first-page":"1644","article-title":"Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle","volume":"26","author":"Wang","year":"2020","unstructured":"Wang WVilella FAlama PMoreno IMignardi MIsakova APan WSimon C & Quake SR2020Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle. Nature Medicine261644\u20131653. (https:\/\/doi.org\/10.1038\/s41591-020-1040-z)"},{"key":"bib122","series-title":"Cellular and Molecular Immunology","first-page":"2101","article-title":"Biology and pathology of the uterine microenvironment and its natural killer cells","volume":"18","author":"Wang","year":"2021","unstructured":"Wang FQualls AEMarques-Fernandez L & Colucci F2021Biology and pathology of the uterine microenvironment and its natural killer cells. Cellular and Molecular Immunology182101\u20132113. (https:\/\/doi.org\/10.1038\/s41423-021-00739-z)"},{"key":"bib125","series-title":"Fertility and Sterility","first-page":"393","article-title":"The international glossary on infertility and fertility Care, 2017","volume":"108","author":"Zegers-Hochschild","year":"2017","unstructured":"Zegers-Hochschild FAdamson GDDyer SRacowsky Cde Mouzon JSokol RRienzi LSunde ASchmidt LCooke ID2017The international glossary on infertility and fertility Care, 2017. Fertility and Sterility108393\u2013406. (https:\/\/doi.org\/10.1016\/j.fertnstert.2017.06.005)"},{"issue":"Web Server Issue","key":"bib126","series-title":"Nucleic Acids Research","first-page":"W741","article-title":"WebGestalt: an integrated system for exploring gene sets in various biological contexts","volume":"33","author":"Zhang","year":"2005","unstructured":"Zhang BKirov S & Snoddy J2005WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Research33(Web Server Issue) W741\u2013W748. 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