{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:13:17Z","timestamp":1792800797291,"version":"4.5.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002301","name":"Estonian Research Council","doi-asserted-by":"publisher","award":["PRG1076, EU952516"],"award-info":[{"award-number":["PRG1076, EU952516"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006598","name":"Enterprise Estonia","doi-asserted-by":"publisher","award":["EU48695, 101008193"],"award-info":[{"award-number":["EU48695, 101008193"]}],"id":[{"id":"10.13039\/501100006598","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Reprod. Health"],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The expression of genes in female reproductive organs is influenced by the cyclic changes in hormone levels during the menstrual cycle. While the molecular changes in the endometrium that facilitate embryo implantation have been extensively studied, there is limited knowledge about the impact of the menstrual cycle on cervical cells. Cervical cells can be easily and routinely collected using a cytobrush during gynecological examination, offering a standardized approach for diagnostic testing. In this study we investigated how the transcriptome of cervical cells changes during the menstrual cycle and assessed the utility of these cells to determine endometrial receptivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Endocervical cells were collected with cytobrushes from 16 healthy women at different menstrual cycle phases in natural cycles and from four women undergoing hormonal replacement cycles. RNA sequencing was applied to gain insight into the transcriptome of cervical cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Transcriptome analysis identified four differentially expressed genes (DEGs) between early- and mid-secretory samples, suggesting that the transcriptome of cervical cells does not change significantly during the opening of the implantation window. The most differences appeared during the transition to the late secretory phase (2136 DEGs) before the onset of menstruation. Cervical cells collected during hormonal replacement cycles showed 1899 DEGs enriched in immune system processes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The results of our study suggested that cervical cells undergo moderate transcriptomic changes throughout the menstrual cycle; however, these changes do not reflect the gene expression pattern of endometrial tissue and offer little or no potential for endometrial receptivity diagnostics.<\/jats:p><\/jats:sec>","DOI":"10.3389\/frph.2023.1224919","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T23:07:05Z","timestamp":1689376025000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The cervical transcriptome changes during the menstrual cycle but does not predict the window of implantation"],"prefix":"10.3389","volume":"5","author":[{"given":"Amruta D. S.","family":"Pathare","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merli","family":"Saare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin","family":"Meltsov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Lawarde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayachitra","family":"Modhukur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aive","family":"Kalinina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aire","family":"Sekavin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktorija","family":"Kukushkina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helle","family":"Karro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Salumets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maire","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1093\/molehr\/8.9.871","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","journal-title":"Mol Hum Reprod"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1210\/en.2005-1076","article-title":"Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women","volume":"147","author":"Talbi","year":"2005","journal-title":"Endocrinology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1093\/humrep\/den360","article-title":"Identification of new biomarkers of human endometrial receptivity in the natural cycle","volume":"24","author":"Haouzi","year":"2009","journal-title":"Hum Reprod"},{"key":"B4","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.fertnstert.2010.04.063","article-title":"A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature","volume":"95","author":"D\u00edaz-Gimeno","year":"2011","journal-title":"Fertil Steril"},{"key":"B5","doi-asserted-by":"publisher","first-page":"E2744","DOI":"10.1210\/jc.2014-2155","article-title":"Transcriptomic changes during the pre-receptive to receptive transition in human endometrium detected by RNA-Seq","volume":"99","author":"Hu","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B6","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.fertnstert.2011.04.072","article-title":"Genome-wide identification of micro-ribonucleic acids associated with human endometrial receptivity in natural and stimulated cycles by deep sequencing","volume":"96","author":"Sha","year":"2011","journal-title":"Fertil Steril"},{"key":"B7","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1095\/biolreprod.116.140327","article-title":"Transcriptional profiling of human endocervical tissues reveals distinct gene expression in the follicular and luteal phases of the menstrual cycle","volume":"94","author":"Yildiz-Arslan","year":"2016","journal-title":"Biol Reprod"},{"key":"B8","doi-asserted-by":"publisher","first-page":"13494","DOI":"10.1038\/s41598-019-49647-3","article-title":"Comparative transcriptome analysis of the human endocervix and ectocervix during the proliferative and secretory phases of the menstrual cycle","volume":"9","author":"Mukhopadhyay","year":"2019","journal-title":"Sci Rep"},{"key":"B9","doi-asserted-by":"publisher","first-page":"574","DOI":"10.3390\/genes9120574","article-title":"A two-cohort RNA-Seq study reveals changes in endometrial and blood miRNome in Fertile and infertile women","volume":"9","author":"Rekker","year":"2018","journal-title":"Genes (Basel)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1111\/j.1471-0528.1993.tb15272.x","article-title":"Concentration of endometrial protein PP14 in uterine flushings throughout the menstrual cycle in normal, fertile women","volume":"100","author":"Ling","year":"1993","journal-title":"BJOG An Int J Obstet Gynaecol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s12958-023-01070-0","article-title":"Can biomarkers identified from the uterine fluid transcriptome be used to establish a noninvasive endometrial receptivity prediction tool? A proof-of-concept study","volume":"21","author":"He","year":"2023","journal-title":"Reprod Biol Endocrinol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2022.06.13.22276318","DOI":"10.1101\/2022.06.13.22276318","article-title":"Targeted gene expression profiling for accurate endometrial receptivity testing","author":"Meltsov","year":"2022","journal-title":"medRxiv"},{"key":"B13","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1038\/s41587-020-0439-x","article-title":"The nf-core framework for community-curated bioinformatics pipelines","volume":"38","author":"Ewels","year":"2020","journal-title":"Nat Biotechnol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-Seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"W193","DOI":"10.1093\/nar\/gkm226","article-title":"G: profiler\u2013a web-based toolset for functional profiling of gene lists from large-scale experiments","volume":"35","author":"Reimand","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13059-017-1349-1","article-title":"Xcell: digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/biolre\/ioz072","article-title":"A molecular tool for menstrual cycle phase dating of endometrial samples in endometriosis transcriptome studies\u2020","volume":"101","author":"Saare","year":"2019","journal-title":"Biol Reprod"},{"key":"B19","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1093\/molehr\/5.7.656","article-title":"Secretory leukocyte protease inhibitor (SLPI) concentrations in cervical mucus of women with normal menstrual cycle","volume":"5","author":"Moriyama","year":"1999","journal-title":"Mol Hum Reprod"},{"key":"B20","doi-asserted-by":"publisher","first-page":"478.e1","DOI":"10.1016\/j.ajog.2016.04.053","article-title":"A new paradigm for the role of smooth muscle cells in the human cervix","volume":"215","author":"Vink","year":"2016","journal-title":"Am J Obstet Gynecol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.3389\/fonc.2022.864820","article-title":"Molecular detection methods in HPV-related cancers","volume":"12","author":"Williams","year":"2022","journal-title":"Front Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13412","article-title":"Impact of the menstrual cycle and ethinyl estradiol\/etonogestrel contraceptive vaginal ring on granulysin and other mucosal immune mediators","volume":"86","author":"Hughes","year":"2021","journal-title":"Am J Reprod Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1016\/S0015-0282(16)54005-9","article-title":"Expression of estrogen receptors, progesterone receptors, and an estrogen receptor-associated protein in the human cervix during the menstrual cycle and menopause","volume":"54","author":"Cano","year":"1990","journal-title":"Fertil Steril"},{"key":"B24","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/j.rbmo.2016.03.004","article-title":"Endometrial transcriptome analysis indicates superiority of natural over artificial cycles in recurrent implantation failure patients undergoing frozen embryo transfer","volume":"32","author":"Altm\u00e4e","year":"2016","journal-title":"Reprod Biomed Online"},{"key":"B25","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1177\/1933719118792104","article-title":"Potential marker pathways in the endometrium that may cause recurrent implantation failure","volume":"26","author":"Bastu","year":"2019","journal-title":"Reprod Sci"},{"key":"B26","doi-asserted-by":"publisher","first-page":"10082","DOI":"10.3390\/ijms221810082","article-title":"Biomolecular markers of recurrent implantation failure-A review","volume":"22","author":"Mrozikiewicz","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1093\/humrep\/dep039","article-title":"Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients","volume":"24","author":"Haouzi","year":"2009","journal-title":"Hum Reprod"},{"key":"B28","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s43032-020-00252-0","article-title":"Customized frozen embryo transfer after identification of the receptivity window with a transcriptomic approach improves the implantation and live birth rates in patients with repeated implantation failure","volume":"28","author":"Haouzi","year":"2021","journal-title":"Reprod Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/s12985-020-1282-x","article-title":"Improvement in RNA quantity and quality in cervico-vaginal cytology","volume":"17","author":"Chong","year":"2020","journal-title":"Virol J"}],"container-title":["Frontiers in Reproductive Health"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/frph.2023.1224919\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T23:07:12Z","timestamp":1689376032000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/frph.2023.1224919\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,14]]},"references-count":29,"alternative-id":["10.3389\/frph.2023.1224919"],"URL":"https:\/\/doi.org\/10.3389\/frph.2023.1224919","relation":{},"ISSN":["2673-3153"],"issn-type":[{"value":"2673-3153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,14]]},"article-number":"1224919"}}