{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T07:27:41Z","timestamp":1792740461190,"version":"4.5.0"},"reference-count":112,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,28]],"date-time":"2024-01-28T00:00:00Z","timestamp":1706400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Male-factor infertility is implicated in over half of the millions of cases of infertility worldwide, and varicoceles are the most common correctable cause of male-factor infertility. The pathophysiologic mechanism for varicoceles is complex and next-generation technologies offer promising insights into the molecular underpinnings of this condition. In this narrative review, we highlight historical and contemporary paradigms associated with varicoceles, with an emphasis on the biological underpinnings of this disease. Specifically, we review the literature describing the underlying causes of varicoceles, discuss the molecular and cellular mechanisms causing pathological changes in some (but not all) men, and highlight key articles regarding the next-generation analyses (e.g., transcriptome, epigenome, proteome, and microbiome) being applied to better understand the condition and its treatment. These data demonstrate an ongoing evolution of the knowledge of varicoceles and the potential for improved personalized care in the future for men with this condition.<\/jats:p>","DOI":"10.3390\/biology13020080","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T11:35:34Z","timestamp":1706614534000},"page":"80","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Evolving Landscape of Male Varicocele Pathophysiology in the Era of Multi-Omics: A Narrative Review of the Current Literature"],"prefix":"10.3390","volume":"13","author":[{"given":"Carlos","family":"Munoz-Lopez","sequence":"first","affiliation":[{"name":"Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Wong","sequence":"additional","affiliation":[{"name":"Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran","family":"Lewis","sequence":"additional","affiliation":[{"name":"Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5943-0185","authenticated-orcid":false,"given":"Raevti","family":"Bole","sequence":"additional","affiliation":[{"name":"Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah C.","family":"Vij","sequence":"additional","affiliation":[{"name":"Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0127-4295","authenticated-orcid":false,"given":"Scott D.","family":"Lundy","sequence":"additional","affiliation":[{"name":"Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0140-6736(20)32667-2","article-title":"Male Infertility","volume":"397","author":"Agarwal","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Agarwal, A., Mulgund, A., Hamada, A., and Chyatte, M.R. (2015). A Unique View on Male Infertility around the Globe. Reprod. Biol. Endocrinol. RBE, 13.","DOI":"10.1186\/s12958-015-0032-1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nrurol.2017.98","article-title":"Varicocele and Male Infertility","volume":"14","author":"Jensen","year":"2017","journal-title":"Nat. Rev. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.fertnstert.2017.06.036","article-title":"Varicoceles: Prevalence and Pathogenesis in Adult Men","volume":"108","author":"Clavijo","year":"2017","journal-title":"Fertil. Steril."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0015-0282(16)55809-9","article-title":"Loss of Fertility in Men with Varicocele","volume":"59","author":"Gorelick","year":"1993","journal-title":"Fertil. Steril."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0090-4295(99)80385-9","article-title":"Incidence of Varicoceles in Men with Primary and Secondary Infertility","volume":"47","author":"Jarow","year":"1996","journal-title":"Urology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e13629","DOI":"10.1111\/and.13629","article-title":"Conventional Semen Analysis and Advanced Sperm Function Tests in Diagnosis and Management of Varicocele","volume":"53","author":"Dave","year":"2021","journal-title":"Andrologia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.euf.2022.08.014","article-title":"The Effect of Varicocele Treatment on Fertility in Adults: A Systematic Review and Meta-Analysis of Published Prospective Trials","volume":"9","author":"Fallara","year":"2023","journal-title":"Eur. Urol. Focus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4","DOI":"10.5534\/wjmh.170010","article-title":"Varicocele and Testicular Pain: A Review","volume":"37","author":"Paick","year":"2019","journal-title":"World J. Mens Health"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.fertnstert.2011.10.034","article-title":"Current Management Principles for Adolescent Varicocele","volume":"96","author":"Diamond","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Esteves, S.C., Cho, C.-L., Majzoub, A., and Agarwal, A. (2019). Varicocele and Male Infertility: A Complete Guide, Springer International Publishing.","DOI":"10.1007\/978-3-319-79102-9"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e14539","DOI":"10.1111\/and.14539","article-title":"Varicocele Is Underdiagnosed in Men Evaluated for Infertility: Examination of Multi-Center Large-Scale Electronic Health Record Data","volume":"54","author":"Carto","year":"2022","journal-title":"Andrologia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1097\/MOU.0000000000001052","article-title":"The \u201c-Ics\u201d of Male Reproduction: Genomics, Epigenetics, Proteomics, Metabolomics, and Microbiomics","volume":"33","author":"Kang","year":"2023","journal-title":"Curr. Opin. Urol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"472","DOI":"10.5534\/wjmh.190018","article-title":"Sperm and Seminal Plasma Proteomics: Molecular Changes Associated with Varicocele-Mediated Male Infertility","volume":"38","author":"Agarwal","year":"2020","journal-title":"World J. Men\u2019s Health"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1002\/pros.24051","article-title":"Paying the Price for Standing Tall: Fluid Mechanics of Prostate Pathology","volume":"80","author":"Gat","year":"2020","journal-title":"Prostate"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s12262-010-0155-8","article-title":"Principles of Physics in Surgery: The Laws of Mechanics and Vectors Physics for Surgeons\u2014Part 2","volume":"72","author":"Srivastava","year":"2010","journal-title":"Indian J. Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"533","DOI":"10.4111\/kju.2014.55.8.533","article-title":"Adolescent Varicocele: Are Somatometric Parameters a Cause?","volume":"55","author":"Bae","year":"2014","journal-title":"Korean J. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/j.1365-2605.2008.00926.x","article-title":"The Relationship between Varicoceles and Obesity in a Young Adult Population","volume":"32","author":"Tsao","year":"2009","journal-title":"Int. J. Androl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"659","DOI":"10.4103\/1008-682X.153539","article-title":"Varicocele and Testicular Function","volume":"17","author":"Pastuszak","year":"2015","journal-title":"Asian J. Androl."},{"key":"ref_20","first-page":"972","article-title":"Varicocele Is Associated with Varicose Veins: A Population-Based Case-Control Study","volume":"22","author":"Lai","year":"2015","journal-title":"Int. J. Urol. Off. J. Jpn. Urol. Assoc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"850114","DOI":"10.3389\/fgene.2022.850114","article-title":"Role of Oxidative Stress in Varicocele","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1111\/j.1464-410X.2008.07517.x","article-title":"The Assessment of Oxidative Stress in Infertile Patients with Varicocele","volume":"101","author":"Sakamoto","year":"2008","journal-title":"BJU Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3109\/01485018908986765","article-title":"Biochemical Changes in Testicular Varicocele","volume":"22","author":"Fujisawa","year":"1989","journal-title":"Arch. Androl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"43","DOI":"10.4103\/1008-682X.153848","article-title":"Spermatozoa Protein Alterations in Infertile Men with Bilateral Varicocele","volume":"18","author":"Agarwal","year":"2016","journal-title":"Asian J. Androl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1016\/j.fertnstert.2014.10.020","article-title":"Male Infertility Testing: Reactive Oxygen Species and Antioxidant Capacity","volume":"102","author":"Ko","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_26","first-page":"323","article-title":"Negative Effect of Varicocele on Sperm Mitochondrial Dysfunction: A Cross-Sectional Study","volume":"21","author":"Elahi","year":"2023","journal-title":"Int. J. Reprod. Biomed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.2147\/TCRM.S161641","article-title":"A Preliminary Evaluation of Serum Level of Testosterone, LH, and FSH in Patients with Varicocele after Varicocelectomy as a Kidney-Related Disease","volume":"14","author":"Alizadeh","year":"2018","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1159\/000081595","article-title":"Varicocele and Retrograde Adrenal Metabolites Flow. An Experimental Study on Rats","volume":"73","author":"Camoglio","year":"2004","journal-title":"Urol. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S0015-0282(16)40159-7","article-title":"Varicocele Sterility: Cortisol and Catecholamines","volume":"25","author":"Comhaire","year":"1974","journal-title":"Fertil. Steril."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/S0015-0282(16)41541-4","article-title":"The Role of Internal Spermatic Vein Plasma Catecholamine Determinations in Subfertile Men with Varicoceles","volume":"26","author":"Cohen","year":"1975","journal-title":"Fertil. Steril."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e12993","DOI":"10.1111\/and.12993","article-title":"Significant Alterations of 6-Keto Prostaglandin F1a and NO Levels in Spermatic Vein Plexus Patients with Varicocele","volume":"50","author":"Tian","year":"2018","journal-title":"Andrologia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0022-5347(17)56091-7","article-title":"The Varicocele: Elevated Serotonin and Infertility","volume":"123","author":"Caldamone","year":"1980","journal-title":"J. Urol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e13576","DOI":"10.1111\/and.13576","article-title":"Pathophysiology and Treatment Options of Varicocele: An Overview","volume":"53","author":"Su","year":"2021","journal-title":"Andrologia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.aju.2017.11.003","article-title":"Varicocele Management for Infertility and Pain: A Systematic Review","volume":"16","author":"Lundy","year":"2018","journal-title":"Arab J. Urol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.urology.2012.07.017","article-title":"Effects of Angiogenesis Inhibition by Spironolactone on Isolated Vas Deferens Contractility in an Experimental Varicocele Model in Rats","volume":"80","author":"Erdem","year":"2012","journal-title":"Urology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1007\/s43032-021-00696-y","article-title":"Expression of Hypoxia-Inducible Factor1-\u03b1 in Varicocele Disease: A Comprehensive Systematic Review","volume":"29","author":"Babaei","year":"2022","journal-title":"Reprod. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e13189","DOI":"10.1111\/and.13189","article-title":"Hypoxia Pathway Has More Impact than Inflammation Pathway on Etiology of Infertile Men with Varicocele","volume":"51","author":"Tavalaee","year":"2019","journal-title":"Andrologia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/S0022-5347(05)00417-9","article-title":"Increased Expression of Hypoxia-Inducible Factor-1\u03b1 in the Internal Spermatic Vein of Patients With Varicocele","volume":"175","author":"Lee","year":"2006","journal-title":"J. Urol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5471","DOI":"10.3892\/mmr.2017.7253","article-title":"Autophagy May Play an Important Role in Varicocele","volume":"16","author":"Zhu","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e12614","DOI":"10.1111\/and.12614","article-title":"Effects of Experimental Left Varicocele Repair on Hypoxia-Inducible Factor-1\u03b1 and Vascular Endothelial Growth Factor Expressions and Angiogenesis in Rat Testis","volume":"49","author":"Goren","year":"2017","journal-title":"Andrologia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1097\/01.ju.0000135455.97627.15","article-title":"Experimental Varicocele Induces Hypoxia Inducible Factor-1alpha, Vascular Endothelial Growth Factor Expression and Angiogenesis in the Rat Testis","volume":"172","author":"Kayaselcuk","year":"2004","journal-title":"J. Urol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s00441-019-03064-0","article-title":"Effect of Silencing HIF-1\u03b1 Gene on Testicle Spermatogenesis Function in Varicocele Rats","volume":"378","author":"Zhao","year":"2019","journal-title":"Cell Tissue Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"205","DOI":"10.4103\/1008-682X.172642","article-title":"Specialized Sperm Function Tests in Varicocele and the Future of Andrology Laboratory","volume":"18","author":"Majzoub","year":"2016","journal-title":"Asian J. Androl."},{"key":"ref_44","first-page":"444","article-title":"Scrotal temperature in 258 healthy men, randomly selected from a population of men aged 18 to 23 years old. Statistical analysis, epidemiologic observations, and measurement of the testicular diameters","volume":"3","author":"Valeri","year":"1993","journal-title":"Prog. En Urol. J. De L\u2019association Fr. D\u2019urologie Et De La Soc. Fr. D\u2019urologie"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0890-6238(02)00025-4","article-title":"Impact of Diurnal Scrotal Temperature on Semen Quality","volume":"16","author":"Hjollund","year":"2002","journal-title":"Reprod. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.juro.2016.08.085","article-title":"Predictive Factors for Sperm Recovery after Varicocelectomy in Men with Nonobstructive Azoospermia","volume":"197","author":"Shiraishi","year":"2017","journal-title":"J. Urol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/S0015-0282(16)38223-1","article-title":"Scrotal and Testicular Temperature: Its Relation to Sperm Count before and after Operation for Varicocele*","volume":"22","author":"Agger","year":"1971","journal-title":"Fertil. Steril."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0015-0282(16)35885-X","article-title":"Varicocele and Testicular Temperature","volume":"17","author":"Tessler","year":"1966","journal-title":"Fertil. Steril."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/S0022-5347(17)50874-5","article-title":"Varicocele: Reversal of the Testicular Blood Flow and Temperature Effects by Varicocele Repair","volume":"131","author":"Green","year":"1984","journal-title":"J. Urol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.fertnstert.2011.01.002","article-title":"The Great Debate: Varicocele Treatment and Impact on Fertility","volume":"95","author":"Will","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1093\/humrep\/dev057","article-title":"Twenty-Four-Hour Monitoring of Scrotal Temperature in Obese Men and Men with a Varicocele as a Mirror of Spermatogenic Function","volume":"30","author":"Garolla","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/S0015-0282(16)42620-8","article-title":"Bilateral Testicular Biopsy in Men with Varicocele","volume":"28","author":"Ibrahim","year":"1977","journal-title":"Fertil. Steril."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Ustuner, M., Yilmaz, H., Yavuz, U., Ciftci, S., Saribacak, A., Aynur, B.S., Yasar, H., and Culha, M.M. (2015). Varicocele Repair Improves Testicular Histology in Men with Nonobstructive Azoospermia. BioMed Res. Int., 2015.","DOI":"10.1155\/2015\/709452"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1046\/j.1439-0272.2000.00355.x","article-title":"Sperm Ultramorphology as a Pathophysiological Indicator of Spermatogenesis in Males Suffering from Varicocele","volume":"32","author":"Reichart","year":"2000","journal-title":"Andrologia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S0015-0282(00)00703-2","article-title":"Varicocele Is Associated with Abnormal Retention of Cytoplasmic Droplets by Human Spermatozoa","volume":"74","author":"Zini","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"94","DOI":"10.2164\/jandrol.05081","article-title":"Studies on Varicocele III: Ultrastructural Sperm Evaluation and 18, X and Y Aneuploidies","volume":"27","author":"Baccetti","year":"2006","journal-title":"J. Androl."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/andr.12940","article-title":"Varicocoele and Oxidative Stress: New Perspectives from Animal and Human Studies","volume":"9","author":"Razi","year":"2021","journal-title":"Andrology"},{"key":"ref_58","first-page":"209","article-title":"Testicular Biohistochemical Alterations Following Experimental Varicocele in Rats","volume":"10","author":"Razi","year":"2012","journal-title":"Iran. J. Reprod. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"270","DOI":"10.3109\/19396368.2013.794253","article-title":"Silymarin Protects from Varicocele-Induced Damages in Testis and Improves Sperm Quality: Evidence for E2f1 Involvement","volume":"59","author":"Moshtaghion","year":"2013","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1002\/mrd.23263","article-title":"Immune Regulatory Molecules as Modifiers of Semen and Fertility: A Review","volume":"86","author":"Archana","year":"2019","journal-title":"Mol. Reprod. Dev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"729539","DOI":"10.3389\/fimmu.2021.729539","article-title":"Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation","volume":"12","author":"Fang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.eururo.2021.08.014","article-title":"European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 Update on Male Infertility","volume":"80","author":"Minhas","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1097\/JU.0000000000001521","article-title":"Diagnosis and Treatment of Infertility in Men: AUA\/ASRM Guideline Part I","volume":"205","author":"Schlegel","year":"2021","journal-title":"J. Urol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1111\/andr.13472","article-title":"Epidemiology of Sperm DNA Fragmentation in a Retrospective Cohort of 1191 Men","volume":"11","author":"Ghaleno","year":"2023","journal-title":"Andrology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e13874","DOI":"10.1111\/and.13874","article-title":"Sperm DNA Fragmentation Testing: Summary Evidence and Clinical Practice Recommendations","volume":"53","author":"Esteves","year":"2021","journal-title":"Andrologia"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e14275","DOI":"10.1111\/and.14275","article-title":"Effect of Varicocele on Sperm DNA Damage: A Systematic Review and Meta-Analysis","volume":"54","author":"Zhang","year":"2022","journal-title":"Andrologia"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.fertnstert.2023.06.001","article-title":"Sperm DNA Fragmentation and Its Interaction with Female Factors","volume":"120","author":"Marinaro","year":"2023","journal-title":"Fertil. Steril."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/978-3-030-21664-1_6","article-title":"Sperm DNA Fragmentation: Consequences for Reproduction","volume":"1166","author":"Simon","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1007\/s10815-018-1304-4","article-title":"Paternal Factors Contributing to Embryo Quality","volume":"35","author":"Colaco","year":"2018","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12610-020-00112-6","article-title":"The effects of varicocelectomy on the DNA fragmentation index and other sperm parameters: A meta-analysis","volume":"30","author":"Birowo","year":"2020","journal-title":"Basic Clin. Androl."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1056\/NEJM199702203360802","article-title":"Microdeletions in the Y Chromosome of Infertile Men","volume":"336","author":"Pryor","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/j.1939-4640.2004.tb02770.x","article-title":"Chromosomal Abnormalities and y Chromosome Microdeletions in Infertile Men with Varicocele and Idiopathic Infertility of South Indian Origin","volume":"25","author":"Rao","year":"2004","journal-title":"J. Androl."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1093\/humrep\/17.3.718","article-title":"Polymorphisms of Glutathione S-Transferase M1 and Male Infertility in Taiwanese Patients with Varicocele","volume":"17","author":"Chen","year":"2002","journal-title":"Hum. Reprod."},{"key":"ref_74","first-page":"739","article-title":"The POLG Gene Polymorphism in Iranian Varicocele-Associated Infertility Patients","volume":"15","author":"Heidari","year":"2012","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s10815-017-0931-5","article-title":"Genetics and Epigenetics of Varicocele Pathophysiology: An Overview","volume":"34","author":"Santana","year":"2017","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/and.12229","article-title":"Is Methylenetetrahydrofolate Reductase (MTHFR) Gene A1298C Polymorphism Related with Varicocele Risk?","volume":"47","author":"Ucar","year":"2015","journal-title":"Andrologia"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S0090-4295(99)80270-2","article-title":"Defective Mitochondrial Oxidative Phosphorylation in Varicocele-Bearing Testicles","volume":"46","author":"Hsu","year":"1995","journal-title":"Urology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e14542","DOI":"10.1111\/and.14542","article-title":"Transcriptome and Genome Sequencing Investigating the Molecular Characteristics of Patients with Varicocele Infertility","volume":"54","author":"Zhang","year":"2022","journal-title":"Andrologia"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/j.juro.2016.05.004","article-title":"Changes in Inflammatory Cytokines Accompany Deregulation of Claudin-11, Resulting in Inter-Sertoli Tight Junctions in Varicocele Rat Testes","volume":"196","author":"Oh","year":"2016","journal-title":"J. Urol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"183","DOI":"10.29252\/ijrm.16.3.183","article-title":"Alteration in CatSper1 and 2 Genes Expression, Sperm Parameters and Testis Histology in Varicocelized Rats","volume":"16","author":"Soleimani","year":"2018","journal-title":"Int. J. Reprod. Biomed."},{"key":"ref_81","first-page":"5647","article-title":"Expression of Claudin-11 in a Rat Model of Varicocele and Its Effects on the Blood-testis Barrier","volume":"18","author":"Pan","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3109\/19396368.2015.1020116","article-title":"DNA Hypomethylation Predisposes Sperm to DNA Damage in Individuals with Varicocele","volume":"61","author":"Bahreinian","year":"2015","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.fertnstert.2020.04.045","article-title":"Differential DNA Methylation Pattern and Sperm Quality in Men with Varicocele","volume":"114","author":"Santana","year":"2020","journal-title":"Fertil. Steril."},{"key":"ref_84","first-page":"389","article-title":"Increased de Novo DNA Methylation Enzymes in Sperm of Individuals with Varicocele","volume":"23","author":"Rashidi","year":"2021","journal-title":"Cell J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"257","DOI":"10.2164\/jandrol.110.012468","article-title":"Genetic Polymorphisms of glutathione S-transferase M1, T1, and P1, and the assessment of oxidative damage in infertile men with varicoceles from northwestern china","volume":"2","author":"Tang","year":"2012","journal-title":"J Androl."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1262\/jrd.2016-093","article-title":"Is Transcription in Sperm Stationary or Dynamic?","volume":"63","author":"Ren","year":"2017","journal-title":"J. Reprod. Dev."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.juro.2014.02.046","article-title":"Sperm Protamine mRNA Ratio and DNA Fragmentation Index Represent Reliable Clinical Biomarkers for Men with Varicocele after Microsurgical Varicocele Ligation","volume":"192","author":"Ni","year":"2014","journal-title":"J. Urol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s10930-021-10013-w","article-title":"Proteomic Profile of Sperm in Infertile Males Reveals Changes in Metabolic Pathways","volume":"40","author":"Liang","year":"2021","journal-title":"Protein J."},{"key":"ref_89","first-page":"323","article-title":"Expression of TRPV1 as A Heat Sensitive Voltage-Dependent Ion Channel and Oxidative Stress in Sperm Samples of Infertile Men with Varicocele: A Case-Control Study","volume":"24","author":"Salahshouri","year":"2022","journal-title":"Cell J."},{"key":"ref_90","first-page":"100370","article-title":"Resveratrol Ameliorates Spermatogenesis by Increasing Protamine 1, 2 and HSPA2 Expression in Experimental Varicocele Rat Model","volume":"21","author":"Baazm","year":"2023","journal-title":"Rev. Int. Androl."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.fertnstert.2013.04.036","article-title":"Changes in the Seminal Plasma Proteome of Adolescents before and after Varicocelectomy","volume":"100","author":"Fraietta","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e13562","DOI":"10.1111\/and.13562","article-title":"Seminal Plasma Protein Networks and Enriched Functions in Varicocele: Effect of Smoking","volume":"52","author":"Antoniassi","year":"2020","journal-title":"Andrologia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"757592","DOI":"10.3389\/fendo.2021.757592","article-title":"In Silico Sperm Proteome Analysis to Investigate DNA Repair Mechanisms in Varicocele Patients","volume":"12","author":"Finelli","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e12873","DOI":"10.1111\/and.12873","article-title":"Impact of Varicocelectomy on the Proteome Profile of Testicular Tissues of Rats with Varicocele","volume":"50","author":"Xu","year":"2018","journal-title":"Andrologia"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jprot.2019.01.019","article-title":"Molecular Pathways of Varicocele and Its Repair\u2014A Paired Labelled Shotgun Proteomics Approach","volume":"196","author":"Camargo","year":"2019","journal-title":"J. Proteom."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"R163","DOI":"10.1530\/REP-13-0178","article-title":"Mitochondria Functionality and Sperm Quality","volume":"146","author":"Amaral","year":"2013","journal-title":"Reproduction"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1159\/000473620","article-title":"Testicular Function after Unilateral Bacterial Epididymo-Orchitis","volume":"19","author":"Osegbe","year":"1991","journal-title":"Eur. Urol."},{"key":"ref_98","first-page":"339","article-title":"Urogenital Infection as a Risk Factor for Male Infertility","volume":"114","author":"Schuppe","year":"2017","journal-title":"Dtsch. \u00c4rztebl. Int."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1258\/ijsa.2008.008334","article-title":"Prevalence of Ureaplasma Urealyticum and Ureaplasma Parvum in Semen of Infertile and Healthy Men","volume":"20","author":"Zeighami","year":"2009","journal-title":"Int. J. STD AIDS"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.jmii.2016.09.004","article-title":"Ureaplasma Spp. in Male Infertility and Its Relationship with Semen Quality and Seminal Plasma Components","volume":"51","author":"Zhou","year":"2018","journal-title":"J. Microbiol. Immunol. Infect. Wei Mian Yu Gan Ran Za Zhi"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3855\/T2.2.116","article-title":"Association of Ureaplasma Urealyticum Infection with Varicocele-Related Infertility","volume":"2","author":"Peerayeh","year":"2008","journal-title":"J. Infect. Dev. Ctries."},{"key":"ref_102","first-page":"865","article-title":"Genital Ureaplasma Urealyticum Infection in Varicocele-Related Infertility","volume":"110","author":"Li","year":"1997","journal-title":"Chin. Med. J."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1136\/gutjnl-2021-326789","article-title":"Gut Microbiome and Health: Mechanistic Insights","volume":"71","author":"Tilg","year":"2022","journal-title":"Gut"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Hills, R.D., Pontefract, B.A., Mishcon, H.R., Black, C.A., Sutton, S.C., and Theberge, C.R. (2019). Gut Microbiome: Profound Implications for Diet and Disease. Nutrients, 11.","DOI":"10.3390\/nu11071613"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5029","DOI":"10.1038\/s41467-019-13036-1","article-title":"Evaluation of 16S rRNA Gene Sequencing for Species and Strain-Level Microbiome Analysis","volume":"10","author":"Johnson","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.fertnstert.2013.07.1991","article-title":"Microbiota of the Seminal Fluid from Healthy and Infertile Men","volume":"100","author":"Hou","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Weng, S.-L., Chiu, C.-M., Lin, F.-M., Huang, W.-C., Liang, C., Yang, T., Yang, T.-L., Liu, C.-Y., Wu, W.-Y., and Chang, Y.-A. (2014). Bacterial Communities in Semen from Men of Infertile Couples: Metagenomic Sequencing Reveals Relationships of Seminal Microbiota to Semen Quality. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110152"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Baud, D., Pattaroni, C., Vulliemoz, N., Castella, V., Marsland, B.J., and Stojanov, M. (2019). Sperm Microbiota and Its Impact on Semen Parameters. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.00234"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.eururo.2021.01.014","article-title":"Functional and Taxonomic Dysbiosis of the Gut, Urine, and Semen Microbiomes in Male Infertility","volume":"79","author":"Lundy","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1124\/pr.110.002790","article-title":"The Blood-Testis Barrier and Its Implications for Male Contraception","volume":"64","author":"Cheng","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"289","DOI":"10.5534\/wjmh.220142","article-title":"Impact of Varicocele Repair on Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis","volume":"41","author":"Agarwal","year":"2023","journal-title":"World J. Men\u2019s Health"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.juro.2011.09.041","article-title":"Time for Improvement in Semen Parameters after Varicocelectomy","volume":"187","author":"Lo","year":"2012","journal-title":"J. Urol."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/2\/80\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:50:38Z","timestamp":1760104238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/2\/80"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,28]]},"references-count":112,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["biology13020080"],"URL":"https:\/\/doi.org\/10.3390\/biology13020080","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,28]]}}}