{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:09:40Z","timestamp":1791468580993,"version":"4.3.4"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T00:00:00Z","timestamp":1620259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>The aging of the organism is a complex and multifactorial process. It can be viewed in the context of the whole organism, but also of individual tissues and organs. The problem of vaginal aging and the related genitourinary syndrome of menopause significantly reduces the quality of women\u2019s lives. The aging process of the vagina includes estrogen deficiencies, changes in the microbiome, and changes at the genetic level associated with DNA methylation. During the menopause, the number of Lactobacillus colonies decreases, and the number of pathological bacteria colonies increases. The decrease in estrogen levels results in a decrease in vaginal epithelial permeability, perfusion, and elastin levels, resulting in vaginal dryness and atrophy. Changes at the molecular level are the least clear. It can also be assumed that, similarly to the tissues studied so far, there are changes in cytosine methylation and TET (ten-eleven translocation) expression. The interrelationships between DNA methylation, hormonal changes, and the vaginal microbiome have not yet been fully elucidated.<\/jats:p>","DOI":"10.3390\/ijerph18094935","type":"journal-article","created":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T11:10:27Z","timestamp":1620299427000},"page":"4935","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Vaginal Aging\u2014What We Know and What We Do Not Know"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1118-7013","authenticated-orcid":false,"given":"Jacek K.","family":"Szyma\u0144ski","sequence":"first","affiliation":[{"name":"First Department of Obstetrics and Gynecology, Centre of Postgraduate Medical Education, \u017belazna 90 Str., 01-004 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneta","family":"S\u0142abuszewska-J\u00f3\u017awiak","sequence":"additional","affiliation":[{"name":"First Department of Obstetrics and Gynecology, Centre of Postgraduate Medical Education, \u017belazna 90 Str., 01-004 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6094-2273","authenticated-orcid":false,"given":"Grzegorz","family":"Jakiel","sequence":"additional","affiliation":[{"name":"First Department of Obstetrics and Gynecology, Centre of Postgraduate Medical Education, \u017belazna 90 Str., 01-004 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.tig.2019.11.005","article-title":"Emerging Role of C\/EBP\u03b2 and Epigenetic DNA Methylation in Ageing","volume":"36","author":"Niehrs","year":"2020","journal-title":"Trends Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"423","DOI":"10.2217\/epi-2019-0131","article-title":"Alterations in 5 hmC level and genomic distribution in aging-related epigenetic drift in human adipose stem cells","volume":"12","author":"Borkowska","year":"2020","journal-title":"Epigenomics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00281-020-00814-z","article-title":"Microbiomes other than the gut: Inflammaging and age-related diseases","volume":"42","author":"Santoro","year":"2020","journal-title":"Semin. Immunopathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1136\/gutjnl-2018-317503","article-title":"Role of the microbiome in human development","volume":"68","author":"Knight","year":"2019","journal-title":"Gut"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"S\u0142abuszewska-J\u00f3\u017awiak, A., Szyma\u0144ski, J., Ciebiera, M., Sarecka-Hujar, B., and Jakiel, G. (2020). Pediatrics Consequences of Caesarean Section\u2014A Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17218031"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.smim.2011.01.011","article-title":"Commensal flora and the regulation of inflammatory and autoimmune responses","volume":"23","author":"Kranich","year":"2011","journal-title":"Semin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1126\/science.aac8469","article-title":"Gut microbiota and aging","volume":"350","author":"Jeffery","year":"2015","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00018-017-2674-y","article-title":"Gut microbiota changes in the extreme decades of human life: A focus on centenarians","volume":"75","author":"Santoro","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.arr.2011.03.004","article-title":"The aging gut microbiota: New perspectives","volume":"10","author":"Biagi","year":"2011","journal-title":"Ageing Res. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1186\/s12934-020-01464-4","article-title":"Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health","volume":"19","author":"Chee","year":"2020","journal-title":"Microb. Cell Factories"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12941-020-0347-4","article-title":"Microbiota in vaginal health and pathogenesis of recurrent vulvovaginal infections: A critical review","volume":"19","author":"Kalia","year":"2020","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"471.e1","DOI":"10.1016\/j.ajog.2019.10.008","article-title":"Associations between the vaginal microbiome and Candida colonization in women of reproductive age","volume":"222","author":"Tortelli","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/1471-0528.15981","article-title":"The vaginal metabolome and microbiota of cervical HPV-positive and HPV-negative women: A cross-sectional analysis","volume":"127","author":"Borgogna","year":"2020","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Masha, S.C., Owuor, C., Ngoi, J.M., Cools, P., Sanders, E.J., Vaneechoutte, M., Crucitti, T., and De Villiers, E.P. (2019). Comparative analysis of the vaginal microbiome of pregnant women with either Trichomonas vaginalis or Chlamydia trachomatis. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0225545"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"305","DOI":"10.3389\/fcimb.2020.00305","article-title":"The Vaginal Microbiota Among Adolescent Girls in Tanzania Around the Time of Sexual Debut","volume":"10","author":"Francis","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Barrientos-Dur\u00e1n, A., Fuentes-L\u00f3pez, A., De Salazar, A., Plaza-D\u00edaz, J., and Garc\u00eda, F. (2020). Reviewing the Composition of Vaginal Microbiota: Inclusion of Nutrition and Probiotic Factors in the Maintenance of Eubiosis. Nutrients, 12.","DOI":"10.3390\/nu12020419"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.ajog.2018.11.1089","article-title":"Ecological dynamics of the vaginal microbiome in relation to health and disease","volume":"220","author":"Greenbaum","year":"2019","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103696","DOI":"10.1016\/j.micpath.2019.103696","article-title":"Crosstalk between Vaginal Microbiome and Female Health: A review","volume":"136","author":"Gupta","year":"2019","journal-title":"Microb. Pathog."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/1471-0528.15854","article-title":"The vaginal microbiota, human papillomavirus and cervical dysplasia: A systematic review and network meta-analysis","volume":"127","author":"Norenhag","year":"2020","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e00097-15","DOI":"10.1128\/mBio.00097-15","article-title":"Vaginal Microbiota of Adolescent Girls Prior to the Onset of Menarche Resemble Those of Reproductive-Age Women","volume":"6","author":"Hickey","year":"2015","journal-title":"mBio"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.trsl.2018.12.005","article-title":"Establishment of vaginal microbiota composition in early pregnancy and its association with subsequent preterm prelabor rupture of the fetal membranes","volume":"207","author":"Brown","year":"2019","journal-title":"Transl. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1038\/s41591-019-0450-2","article-title":"The vaginal microbiome and preterm birth","volume":"25","author":"Fettweis","year":"2019","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hummelen, R., Macklaim, J.M., Bisanz, J.E., Hammond, J.-A., McMillan, A., Vongsa, R., Koenig, D., Gloor, G.B., and Reid, G. (2011). Vaginal Microbiome and Epithelial Gene Array in Post-Menopausal Women with Moderate to Severe Dryness. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026602"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1097\/GME.0b013e3182a4690b","article-title":"Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy","volume":"21","author":"Brotman","year":"2014","journal-title":"Menopause"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3389\/fmicb.2019.00193","article-title":"Comparison of the Vaginal Microbiomes of Premenopausal and Postmenopausal Women","volume":"10","author":"Gliniewicz","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1097\/GME.0000000000001037","article-title":"Associations between improvement in genitourinary symptoms of menopause and changes in the vaginal ecosystem","volume":"25","author":"Mitchell","year":"2018","journal-title":"Menopause"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1095\/biolreprod.114.118638","article-title":"Effect of Vaginal or Systemic Estrogen on Dynamics of Collagen Assembly in the Rat Vaginal Wall","volume":"92","author":"Montoya","year":"2015","journal-title":"Biol. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/lsm.22569","article-title":"Efficacy of Erbium: YAG laser treatment compared to topical estriol treatment for symptoms of genitourinary syndrome of menopause","volume":"49","author":"Gaspar","year":"2017","journal-title":"Lasers Surg. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S0015-0282(99)00113-2","article-title":"Estrogen receptor \u03b1 and \u03b2 expression in the vaginal walls and uterosacral ligaments of premenopausal and postmenopausal women","volume":"71","author":"Chen","year":"1999","journal-title":"Fertil. Steril."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s00192-003-1042-7","article-title":"Expression of estrogen receptor-\u03b1 and -\u03b2 in anterior vaginal walls of genuine stress incontinent women","volume":"14","author":"Fu","year":"2003","journal-title":"Int. Urogynecol. J. Pelvic Floor Dysfunct."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.maturitas.2008.01.004","article-title":"Estrogen receptor (ER) and ER-related receptor expression in normal and atrophic human vagina","volume":"59","author":"Cavallini","year":"2008","journal-title":"Maturitas"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1067\/mob.2001.119627","article-title":"Expression of estrogen receptor isoforms \u03b1 and \u03b2 messenger RNA in vaginal tissue of premenopausal and postmenopausal women","volume":"185","author":"Gebhart","year":"2001","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s10911-008-9098-0","article-title":"Crosstalk Between IGF1R and Estrogen Receptor Signaling in Breast Cancer","volume":"13","author":"Fagan","year":"2008","journal-title":"J. Mammary Gland. Biol. Neoplasia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3372","DOI":"10.1158\/0008-5472.CAN-12-0684","article-title":"Acquired Resistance to Tamoxifen Is Associated with Loss of the Type I Insulin-like Growth Factor Receptor: Implications for Breast Cancer Treatment","volume":"72","author":"Fagan","year":"2012","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1158\/0008-5472.CAN-06-1020","article-title":"Long-term Treatment with Tamoxifen Facilitates Translocation of Estrogen Receptor \u03b1 out of the Nucleus and Enhances its Interaction with EGFR in MCF-7 Breast Cancer Cells","volume":"67","author":"Fan","year":"2007","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.mce.2015.06.004","article-title":"The molecular, cellular and clinical consequences of targeting the estrogen receptor following estrogen deprivation therapy","volume":"418","author":"Fan","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1093\/jnci\/djh166","article-title":"Mechanisms of tamoxifen resistance: Increased estrogen receptor-HER2\/neu cross-talk in ER\/HER2-positive breast cancer","volume":"96","author":"Shou","year":"2004","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"pky035","DOI":"10.1093\/jncics\/pky035","article-title":"Potential Mechanisms of Age Acceleration Caused by Estrogen Deprivation: Do Endocrine Therapies Carry the Same Risks?","volume":"2","author":"Sehl","year":"2018","journal-title":"JNCI Cancer Spectr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1097\/01.gme.0000184423.88814.e6","article-title":"Effects of estrogen on proton secretion via the apical membrane in vaginal-ectocervical epithelial cells of postmenopausal women","volume":"12","author":"Gorodeski","year":"2005","journal-title":"Menopause"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1210\/jc.2004-1223","article-title":"Aging and Estrogen Effects on Transcervical-Transvaginal Epithelial Permeability","volume":"90","author":"Gorodeski","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1097\/gme.0b013e3180587eb5","article-title":"Estrogen modulation of epithelial permeability in cervical-vaginal cells of premenopausal and postmenopausal women","volume":"14","author":"Gorodeski","year":"2007","journal-title":"Menopause"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/j.1743-6109.2008.01122.x","article-title":"Endothelial Nitric Oxide Synthase Regulation in Female Genital Tract Structures","volume":"6","author":"Musicki","year":"2009","journal-title":"J. Sex. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1111\/jog.12425","article-title":"Decreased expression of elastin and lysyl oxidase family genes in urogenital tissues of aging mice: Elastin and LOX family genes decreased in aging","volume":"40","author":"Jiang","year":"2014","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1073\/pnas.1716016115","article-title":"Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation","volume":"115","author":"Yang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1038\/nchembio.1638","article-title":"Targeted protein destabilization reveals an estrogen-mediated ER stress response","volume":"10","author":"Raina","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref_46","first-page":"47","article-title":"Starzenie: Mechanizmy epigenetyczne i genetyczne. Aging: Epigenetic and genetic mechamisms","volume":"2","author":"Sawicki","year":"2015","journal-title":"Ginekol. Pol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3960\/jslrt.55.1","article-title":"Age-Dependent Decrease of DNA Hydroxymethylation in Human T Cells","volume":"55","author":"Truong","year":"2015","journal-title":"J. Clin. Exp. Hematop."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1159\/000438853","article-title":"TET Family of Dioxygenases: Crucial Roles and Underlying Mechanisms","volume":"146","author":"Li","year":"2015","journal-title":"Cytogenet. Genome Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.tcb.2018.10.002","article-title":"The Battle between TET Proteins and DNA Methylation for the Right Cell","volume":"28","author":"Li","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/emboj.2012.331","article-title":"Replication-coupled passive DNA demethylation for the erasure of genome imprints in mice","volume":"32","author":"Kagiwada","year":"2012","journal-title":"EMBO J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1021\/acs.biochem.8b01185","article-title":"Insights into the Biochemistry, Evolution, and Biotechnological Applications of the Ten-Eleven Translocation (TET) Enzymes","volume":"58","author":"Parker","year":"2019","journal-title":"Biochemistry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nature12052","article-title":"Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX","volume":"497","author":"Ko","year":"2013","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Huang, S., Litt, M.D., and Blakey, C.A. (2016). Structure, regulation, and function of TET family proteins. Epigenetic Gene Expression and Regulation, Academic Press.","DOI":"10.1016\/B978-0-12-799958-6.00017-2"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.4161\/epi.21464","article-title":"Metabolic, hormonal and immunological associations with global DNA methylation among postmenopausal women","volume":"7","author":"Ulrich","year":"2012","journal-title":"Epigenetics"}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/18\/9\/4935\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:57:28Z","timestamp":1760162248000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/18\/9\/4935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,6]]},"references-count":54,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijerph18094935"],"URL":"https:\/\/doi.org\/10.3390\/ijerph18094935","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,6]]}}}