{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:30:41Z","timestamp":1791419441711,"version":"4.3.3"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T00:00:00Z","timestamp":1681344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This systematic review and meta-analysis summarize the difference in the methylation of the H19 gene in patients with abnormal versus normal conventional sperm parameters. It also evaluates the effects of age and sperm concentration on H19 methylation in spermatozoa using meta-regression analysis. It was performed according to the MOOSE guidelines for meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The quality of the evidence reported in the studies included was assessed using the Cambridge Quality Checklists. A total of 11 articles met our inclusion criteria. Quantitative analysis showed that H19 methylation levels were significantly lower in the group of infertile patients than in fertile controls. The reduction in methylation was much more pronounced in patients with oligozoospermia (alone or associated with other sperm parameter abnormalities) and in those with recurrent pregnancy loss. Meta-regression analysis showed the results to be independent of both patient age and sperm concentration. Therefore, the H19 methylation pattern should be evaluated among couples accessing assisted reproductive techniques (ART), in order to gain prognostic information on ART outcome and offspring health.<\/jats:p>","DOI":"10.3390\/ijms24087224","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T02:28:12Z","timestamp":1681439292000},"page":"7224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["H19 Sperm Methylation in Male Infertility: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4599-8487","authenticated-orcid":false,"given":"Rossella","family":"Cannarella","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH 44125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Crafa","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Barbagallo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Lundy","sequence":"additional","affiliation":[{"name":"Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH 44125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7113-2372","authenticated-orcid":false,"given":"Sandro","family":"La Vignera","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5217-9343","authenticated-orcid":false,"given":"Rosita A.","family":"Condorelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6950-335X","authenticated-orcid":false,"given":"Aldo E.","family":"Calogero","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,13]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2018). International Classification of Diseases, 11th Revision (ICD-11), World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"694325","DOI":"10.3389\/fendo.2021.694325","article-title":"The Burden of Hormonal Disorders: A Worldwide Overview with a Particular Look in Italy","volume":"12","author":"Crafa","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_3","first-page":"18","article-title":"Causes of male infertility: A 9-year prospective monocentre study on 1737 patients with reduced total sperm counts","volume":"32","author":"Punab","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e13586","DOI":"10.1111\/and.13586","article-title":"Role of genetics and epigenetics in male infertility","volume":"53","author":"Gunes","year":"2021","journal-title":"Andrologia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"689624","DOI":"10.3389\/fcell.2021.689624","article-title":"Epigenetics of Male Infertility: The Role of DNA Methylation","volume":"9","author":"Rotondo","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.fertnstert.2019.05.006","article-title":"Impact of male factor infertility on offspring health and development","volume":"111","author":"Rumbold","year":"2019","journal-title":"Fertil. Steril."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1093\/oxfordjournals.jbchem.a022661","article-title":"Mechanisms of Igf2\/H19 imprinting: DNA methylation, chromatin and long-distance gene regulation","volume":"127","author":"Sasaki","year":"2000","journal-title":"J. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cannarella, R., Crafa, A., Mongio\u00ec, L.M., Leggio, L., Iraci, N., La Vignera, S., Condorelli, R.A., and Calogero, A.E. (2022). DNA Methylation in Offspring Conceived after Assisted Reproductive Techniques: A Systematic Review and Meta-Analysis. J. Clin. Med., 11.","DOI":"10.3390\/jcm11175056"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/andr.12379","article-title":"Impairment of sperm DNA methylation in male infertility: A meta-analytic study","volume":"5","author":"Santi","year":"2017","journal-title":"Andrology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1080\/19396368.2021.1909667","article-title":"Relevance of sperm imprinted gene methylation on assisted reproductive technique outcomes and pregnancy loss: A systematic review","volume":"67","author":"Cannarella","year":"2021","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.arr.2014.10.007","article-title":"Consistent age-dependent declines in human semen quality: A systematic review and meta-analysis","volume":"19","author":"Johnson","year":"2015","journal-title":"Ageing Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.urology.2022.07.043","article-title":"Impact of Age and Fertility Status on the Consistency of Repeat Measurements of Sperm DNA Damage: A Single-center, Prospective, Dual Visit Study","volume":"169","author":"Petrella","year":"2022","journal-title":"Urology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e1600584","DOI":"10.1126\/sciadv.1600584","article-title":"Epigenetics and aging","volume":"2","author":"Pal","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"509","DOI":"10.18632\/aging.100476","article-title":"Space\/population and time\/age in DNA methylation variability in humans: A study on IGF2\/H19 locus in different Italian populations and in mono- and di-zygotic twins of different age","volume":"4","author":"Pirazzini","year":"2012","journal-title":"Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1093\/hmg\/ddm010","article-title":"Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2\/H19 locus","volume":"16","author":"Heijmans","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1001\/jama.283.15.2008","article-title":"Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group","volume":"283","author":"Stroup","year":"2000","journal-title":"JAMA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"g7647","DOI":"10.1136\/bmj.g7647","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation","volume":"350","author":"Shamseer","year":"2015","journal-title":"BMJ"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Methley, A.M., Campbell, S., Chew-Graham, C., McNally, R., and Cheraghi-Sohi, S. (2014). PICO, PICOS and SPIDER: A comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv. Res., 14.","DOI":"10.1186\/s12913-014-0579-0"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11292-008-9066-0","article-title":"Drawing conclusions about causes from systematic reviews of risk factors: The Cambridge Quality Checklists","volume":"5","author":"Murray","year":"2009","journal-title":"J. Exp. Criminol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1530\/REP-11-0008","article-title":"Aberrant DNA methylation at imprinted genes in testicular sperm retrieved from men with obstructive azoospermia and undergoing vasectomy reversal","volume":"141","author":"Minor","year":"2011","journal-title":"Reproduction"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1177\/1933719116650755","article-title":"Abnormal Methylation of Imprinted Genes and Cigarette Smoking: Assessment of Their Association with the Risk of Male Infertility","volume":"24","author":"Dong","year":"2017","journal-title":"Reprod. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, B., Li, J.B., Xiao, X.F., Ma, Y.F., Wang, J., Liang, X.X., Zhao, H.X., Jiang, F., Yao, Y.Q., and Wang, X.H. (2013). Altered DNA methylation patterns of the H19 differentially methylated region and the DAZL gene promoter are associated with defective human sperm. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071215"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3892\/etm.2016.3314","article-title":"H19 gene methylation status is associated with male infertility","volume":"12","author":"Li","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1089\/omi.2018.0019","article-title":"Novel Epigenomic Biomarkers of Male Infertility Identified by Methylation Patterns of CpG Sites within Imprinting Control Regions of H19 and SNRPN Genes","volume":"22","author":"Peng","year":"2018","journal-title":"OMICS"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1111\/and.12535","article-title":"DNA methylation levels of imprinted and nonimprinted genes DMRs associated with defective human spermatozoa","volume":"48","author":"Xu","year":"2016","journal-title":"Andrologia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1016\/j.fertnstert.2012.07.1143","article-title":"Methylation analysis of idiopathic recurrent spontaneous miscarriage cases reveals aberrant imprinting at H19 ICR in normozoospermic individuals","volume":"98","author":"Ankolkar","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.4161\/epi.21743","article-title":"Semen samples showing an increased rate of spermatozoa with imprinting errors have a negligible effect in the outcome of assisted reproduction techniques","volume":"7","author":"Pladevall","year":"2012","journal-title":"Epigenetics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1159\/000323806","article-title":"Methylation status of imprinted genes and repetitive elements in sperm DNA from infertile males","volume":"5","author":"Zechner","year":"2011","journal-title":"Sex. Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1093\/hmg\/ddu540","article-title":"Epigenetic germline mosaicism in infertile men","volume":"24","author":"Laurentino","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/andr.12001","article-title":"Sperm global DNA methylation level: Association with semen parameters and genome integrity","volume":"3","author":"Montjean","year":"2015","journal-title":"Andrology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/S0140-6736(04)16256-9","article-title":"Genomic imprinting in disruptive spermatogenesis","volume":"363","author":"Marques","year":"2004","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/molehr\/gam093","article-title":"Abnormal methylation of imprinted genes in human sperm is associated with oligozoospermia","volume":"14","author":"Marques","year":"2008","journal-title":"Mol. Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1095\/biolreprod.114.122465","article-title":"Association of DNA methylation and mitochondrial DNA copy number with human semen quality","volume":"91","author":"Tian","year":"2014","journal-title":"Biol. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/ejhg.2009.117","article-title":"Specific epigenetic alterations of IGF2-H19 locus in spermatozoa from infertile men","volume":"18","author":"Boissonnas","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/j.fertnstert.2009.09.010","article-title":"Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility","volume":"94","author":"Hammoud","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_36","first-page":"48","article-title":"DNA methylation defects in spermatozoa of male partners from couples experiencing recurrent pregnancy loss","volume":"36","author":"Khambata","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1111\/j.2047-2927.2013.00118.x","article-title":"DNA methylation in spermatozoa as a prospective marker in andrology","volume":"1","author":"Bleiziffer","year":"2013","journal-title":"Andrology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1111\/j.1365-2605.2009.01000.x","article-title":"Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2\/H19 ICR1","volume":"33","author":"Poplinski","year":"2010","journal-title":"Int. J. Androl."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1159\/000090831","article-title":"The H19 gene: Regulation and function of a non-coding RNA","volume":"113","author":"Gabory","year":"2006","journal-title":"Cytogenet. Genome. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0168-9525(02)00004-5","article-title":"H19 and Igf2\u2014Enhancing the confusion?","volume":"19","author":"Arney","year":"2003","journal-title":"Trends Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1093\/hmg\/9.14.2183","article-title":"Establishment of the paternal methylation imprint of the human H19 and MEST\/PEG1 genes during spermatogenesis","volume":"9","author":"Kerjean","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"545","DOI":"10.5534\/wjmh.190070","article-title":"IGF2 and IGF1R mRNAs Are Detectable in Human Spermatozoa","volume":"38","author":"Cannarella","year":"2020","journal-title":"World J. Men\u2019s Health"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/andr.12444","article-title":"Effects of the insulin-like growth factor system on testicular differentiation and function: A review of the literature","volume":"6","author":"Cannarella","year":"2018","journal-title":"Andrology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/jcp.26920","article-title":"H19 regulates the proliferation of bovine male germline stem cells via IGF-1 signaling pathway","volume":"234","author":"Lei","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.bbrc.2017.05.125","article-title":"The effects of IGF-1 on mouse spermatogenesis using an organ culture method","volume":"491","author":"Yao","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s10815-018-1350-y","article-title":"Reactive oxygen species-induced alterations in H19-Igf2 methylation patterns, seminal plasma metabolites, and semen quality","volume":"36","author":"Darbandi","year":"2019","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.fertnstert.2019.03.003","article-title":"Sperm DNA fragmentation and recurrent pregnancy loss: A systematic review and meta-analysis","volume":"112","author":"McQueen","year":"2019","journal-title":"Fertil. Steril."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1093\/humupd\/dmac033","article-title":"Age-associated epigenetic changes in mammalian sperm: Implications for offspring health and development","volume":"29","author":"Ashapkin","year":"2023","journal-title":"Hum. Reprod. Update"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/j.fertnstert.2013.06.047","article-title":"Methylation changes in mature sperm deoxyribonucleic acid from oligozoospermic men: Assessment of genetic variants and assisted reproductive technology outcome","volume":"100","author":"Montjean","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1093\/humupd\/dmac010","article-title":"DNA methylation profiles after ART during human lifespan: A systematic review and meta-analysis","volume":"28","author":"Barberet","year":"2022","journal-title":"Hum. Reprod. Update"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Hor\u00e1nszky, A., Becker, J.L., Zana, M., Ferguson-Smith, A.C., and Dinny\u00e9s, A. (2021). Epigenetic Mechanisms of ART-Related Imprinting Disorders: Lessons From iPSC and Mouse Models. Genes, 12.","DOI":"10.3390\/genes12111704"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7224\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:15:44Z","timestamp":1760123744000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,13]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24087224"],"URL":"https:\/\/doi.org\/10.3390\/ijms24087224","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,13]]}}}