{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T05:41:00Z","timestamp":1792129260207,"version":"4.4.0"},"reference-count":86,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:00:00Z","timestamp":1733270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Varicoceles are a common contributor to male infertility, significantly impacting male-factor infertility cases. Traditional diagnostic methods often lack the sensitivity to detect the molecular and cellular disruptions caused by varicoceles, limiting the development of effective, personalized treatments. This narrative review aims to explore the advancements in proteomics and metabolomics as innovative, non-invasive diagnostic tools for varicocele-associated male infertility and their potential in guiding personalized therapeutic strategies. Methods: A comprehensive literature search was conducted using databases such as PubMed, Scopus, and Web of Science up to October 2024. Studies focusing on the application of proteomic and metabolomic analyses in varicocele-associated male infertility were selected. The findings were critically analyzed to synthesize current knowledge and identify future research directions. Results: Proteomic analyses revealed differentially expressed proteins in the sperm and seminal plasma of varicocele patients, revealing disruptions in pathways related to oxidative stress, mitochondrial dysfunction, apoptosis, and energy metabolism. Key proteins such as heat shock proteins, mitochondrial enzymes, and apoptotic regulators were notably altered. Metabolomic profiling uncovered specific metabolites in seminal plasma\u2014such as decreased levels of lysine, valine, and fructose\u2014that correlate with impaired sperm function and fertility potential. The integration of proteomic and metabolomic data provides a comprehensive molecular fingerprint of varicocele-induced infertility, facilitating the identification of novel biomarkers for early diagnosis and the development of personalized therapeutic interventions. Conclusions: Advances in proteomics and metabolomics have significantly enhanced our understanding of the molecular mechanisms underlying varicocele-associated male infertility. These \u201comics\u201d technologies hold great promise for improving diagnostic accuracy and personalizing treatment, ultimately leading to better outcomes for affected men. Future large-scale clinical trials and validations are essential to confirm these biomarkers and facilitate their integration into routine clinical practice.<\/jats:p>","DOI":"10.3390\/jcm13237390","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T06:38:25Z","timestamp":1733294305000},"page":"7390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Proteomics and Metabolomics in Varicocele-Associated Male Infertility: Advancing Precision Diagnostics and Therapy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4651-312X","authenticated-orcid":false,"given":"Aris","family":"Kaltsas","sequence":"first","affiliation":[{"name":"Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Zikopoulos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Royal Cornwall Hospital, Truro TR1 3LJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftheria","family":"Markou","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University Hospital of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5287-4450","authenticated-orcid":false,"given":"Athanasios","family":"Zachariou","sequence":"additional","affiliation":[{"name":"Laboratory of Spermatology, Department of Urology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marios","family":"Stavropoulos","sequence":"additional","affiliation":[{"name":"Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7281-3308","authenticated-orcid":false,"given":"Zisis","family":"Kratiras","sequence":"additional","affiliation":[{"name":"Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6360-0762","authenticated-orcid":false,"given":"Evangelos N.","family":"Symeonidis","sequence":"additional","affiliation":[{"name":"Department of Urology II, European Interbalkan Medical Center, 55535 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1198-9144","authenticated-orcid":false,"given":"Fotios","family":"Dimitriadis","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Sofikitis","sequence":"additional","affiliation":[{"name":"Laboratory of Spermatology, Department of Urology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1688-005X","authenticated-orcid":false,"given":"Michael","family":"Chrisofos","sequence":"additional","affiliation":[{"name":"Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.eursup.2014.07.002","article-title":"Mysteries, Facts, and Fiction in Varicocele Pathophysiology and Treatment","volume":"13","author":"Sofikitis","year":"2014","journal-title":"Eur. Urol. Suppl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.eururo.2016.06.044","article-title":"Varicocele Is Associated with Impaired Semen Quality and Reproductive Hormone Levels: A Study of 7035 Healthy Young Men from Six European Countries","volume":"70","author":"Damsgaard","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/0090-4295(93)90268-F","article-title":"Varicocele: A progressive or static lesion?","volume":"42","author":"Witt","year":"1993","journal-title":"Urology"},{"key":"ref_4","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_5","doi-asserted-by":"crossref","unstructured":"Kaltsas, A. (2023). Oxidative Stress and Male Infertility: The Protective Role of Antioxidants. Medicina, 59.","DOI":"10.3390\/medicina59101769"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.semcdb.2021.04.005","article-title":"Effect of varicoceles on spermatogenesis","volume":"121","author":"Kang","year":"2022","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","unstructured":"Kaltsas, A., Dimitriadis, F., Zachariou, D., Zikopoulos, A., Symeonidis, E.N., Markou, E., Tien, D.M.B., Takenaka, A., Sofikitis, N., and Zachariou, A. (2023). From Diagnosis to Treatment: Comprehensive Care by Reproductive Urologists in Assisted Reproductive Technology. Medicina, 59.","DOI":"10.3390\/medicina59101835"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1089\/ars.2019.7828","article-title":"Aberrant Upregulation of Compensatory Redox Molecular Machines May Contribute to Sperm Dysfunction in Infertile Men with Unilateral Varicocele: A Proteomic Insight","volume":"32","author":"Swain","year":"2020","journal-title":"Antioxid. Redox Signal"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Finelli, R., Darbandi, S., Pushparaj, P.N., Henkel, R., Ko, E., and Agarwal, A. (2021). In Silico Sperm Proteome Analysis to Investigate DNA Repair Mechanisms in Varicocele Patients. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.757592"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100074","DOI":"10.1016\/j.xfnr.2024.100074","article-title":"Biomarkers to predict improvement of sperm parameters and hypogonadism after varicocele repair","volume":"5","author":"Varnum","year":"2024","journal-title":"F&S Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4331\/wjbc.v12.i5.57","article-title":"Proteomics: Concepts and applications in human medicine","volume":"12","author":"Alshekaili","year":"2021","journal-title":"World J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/19396368.2024.2317804","article-title":"Insight into the complexity of male infertility: A multi-omics review","volume":"70","author":"Podgrajsek","year":"2024","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.fertnstert.2020.08.004","article-title":"Molecular characteristics of varicocele: Integration of whole-exome and transcriptome sequencing","volume":"115","author":"Yang","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Franco, A., Proietti, F., Palombi, V., Savarese, G., Guidotti, M., Leonardo, C., Ferro, F., Manna, C., and Franco, G. (2023). Varicocele: To Treat or Not to Treat?. J. Clin. Med., 12.","DOI":"10.3390\/jcm12124062"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.5534\/wjmh.210153","article-title":"Oxidative Stress: A Comprehensive Review of Biochemical, Molecular, and Genetic Aspects in the Pathogenesis and Management of Varicocele","volume":"40","author":"Finelli","year":"2022","journal-title":"World J. Mens Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s00441-015-2237-1","article-title":"The protein and transcript profiles of human semen","volume":"363","author":"Jodar","year":"2016","journal-title":"Cell Tissue Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/humupd\/dmt046","article-title":"The combined human sperm proteome: Cellular pathways and implications for basic and clinical science","volume":"20","author":"Amaral","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Samanta, L., Parida, R., Dias, T.R., and Agarwal, A. (2018). The enigmatic seminal plasma: A proteomics insight from ejaculation to fertilization. Reprod. Biol. Endocrinol., 16.","DOI":"10.1186\/s12958-018-0358-6"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.aju.2017.11.016","article-title":"Update on the proteomics of male infertility: A systematic review","volume":"16","author":"Agarwal","year":"2018","journal-title":"Arab. J. Urol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jprot.2016.08.018","article-title":"Semen proteomics and male infertility","volume":"162","author":"Jodar","year":"2017","journal-title":"J. Proteom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1093\/humrep\/des287","article-title":"Effect of smoking on the functional aspects of sperm and seminal plasma protein profiles in patients with varicocele","volume":"27","author":"Fariello","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1021\/pr100745u","article-title":"Proteomic analysis of seminal plasma from normal volunteers and post-vasectomy patients identifies over 2000 proteins and candidate biomarkers of the urogenital system","volume":"10","author":"Batruch","year":"2011","journal-title":"J. Proteome Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Candenas, L., and Chianese, R. (2020). Exosome Composition and Seminal Plasma Proteome: A Promising Source of Biomarkers of Male Infertility. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197022"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Panner Selvam, M.K., Agarwal, A., Pushparaj, P.N., Baskaran, S., and Bendou, H. (2019). Sperm Proteome Analysis and Identification of Fertility-Associated Biomarkers in Unexplained Male Infertility. Genes, 10.","DOI":"10.3390\/genes10070522"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1002\/pmic.200300493","article-title":"Development of narrow immobilized pH gradients covering one pH unit for human seminal plasma proteomic analysis","volume":"3","author":"Roux","year":"2003","journal-title":"Proteomics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1093\/molehr\/7.8.715","article-title":"Mapping of seminal plasma proteins by two-dimensional gel electrophoresis in men with normal and impaired spermatogenesis","volume":"7","author":"Poggioli","year":"2001","journal-title":"Mol. Hum. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"212ra160","DOI":"10.1126\/scitranslmed.3006260","article-title":"Differential diagnosis of azoospermia with proteomic biomarkers ECM1 and TEX101 quantified in seminal plasma","volume":"5","author":"Drabovich","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5670","DOI":"10.1021\/pr500652y","article-title":"Identification of proteins involved in human sperm motility using high-throughput differential proteomics","volume":"13","author":"Amaral","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sharma, R., Agarwal, A., Mohanty, G., Du Plessis, S.S., Gopalan, B., Willard, B., Yadav, S.P., and Sabanegh, E. (2013). Proteomic analysis of seminal fluid from men exhibiting oxidative stress. Reprod. Biol. Endocrinol., 11.","DOI":"10.1186\/1477-7827-11-85"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.rbmo.2015.01.010","article-title":"Comparative analysis of the seminal plasma proteomes of oligoasthenozoospermic and normozoospermic men","volume":"30","author":"Giacomini","year":"2015","journal-title":"Reprod. Biomed. Online"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wood, G.J.A., Cardoso, J.P.G., Paluello, D.V., Nunes, T.F., and Cocuzza, M. (2021). Varicocele-Associated Infertility and the Role of Oxidative Stress on Sperm DNA Fragmentation. Front. Reprod. Health, 3.","DOI":"10.3389\/frph.2021.695992"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pavuluri, H., Bakhtiary, Z., Panner Selvam, M.K., and Hellstrom, W.J.G. (2024). Oxidative Stress-Associated Male Infertility: Current Diagnostic and Therapeutic Approaches. Medicina, 60.","DOI":"10.3390\/medicina60061008"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/bju.12233","article-title":"Sperm nuclear DNA fragmentation rate is associated with differential protein expression and enriched functions in human seminal plasma","volume":"112","author":"Intasqui","year":"2013","journal-title":"BJU Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1007\/s10815-013-0054-6","article-title":"Unraveling the sperm proteome and post-genomic pathways associated with sperm nuclear DNA fragmentation","volume":"30","author":"Intasqui","year":"2013","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.urology.2012.06.027","article-title":"Study of sperm protein profile in men with and without varicocele using two-dimensional gel electrophoresis","volume":"81","author":"Hosseinifar","year":"2013","journal-title":"Urology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s10815-014-0209-0","article-title":"Study of the effect of varicocelectomy on sperm proteins expression in patients with varicocele and poor sperm quality by using two-dimensional gel electrophoresis","volume":"31","author":"Hosseinifar","year":"2014","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Li, J., and Zhu, H.J. (2020). Liquid Chromatography-Tandem Mass Spectrometry (LC-MS\/MS)-Based Proteomics of Drug-Metabolizing Enzymes and Transporters. Molecules, 25.","DOI":"10.3390\/molecules25112718"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"282","DOI":"10.4103\/1008-682X.170445","article-title":"Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility","volume":"18","author":"Agarwal","year":"2016","journal-title":"Asian J. Androl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.juro.2018.03.009","article-title":"Proteomic Signatures of Sperm Mitochondria in Varicocele: Clinical Use as Biomarkers of Varicocele Associated Infertility","volume":"200","author":"Samanta","year":"2018","journal-title":"J. Urol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.eururo.2011.06.018","article-title":"Varicocele and male factor infertility treatment: A new meta-analysis and review of the role of varicocele repair","volume":"60","author":"Baazeem","year":"2011","journal-title":"Eur. Urol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.urology.2014.11.030","article-title":"Differential proteomic profiling of spermatozoal proteins of infertile men with unilateral or bilateral varicocele","volume":"85","author":"Agarwal","year":"2015","journal-title":"Urology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Agarwal, A., Sharma, R., Durairajanayagam, D., Ayaz, A., Cui, Z., Willard, B., Gopalan, B., and Sabanegh, E. (2015). Major protein alterations in spermatozoa from infertile men with unilateral varicocele. Reprod. Biol. Endocrinol., 13.","DOI":"10.1186\/s12958-015-0007-2"},{"key":"ref_44","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_45","doi-asserted-by":"crossref","unstructured":"Panner Selvam, M.K., Samanta, L., and Agarwal, A. (2020). Functional Analysis of Differentially Expressed Acetylated Spermatozoal Proteins in Infertile Men with Unilateral and Bilateral Varicocele. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093155"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"735","DOI":"10.2741\/4747","article-title":"Effects of sperm proteins on fertilization in the female reproductive tract","volume":"24","author":"Sun","year":"2019","journal-title":"Front. Biosci.-Landmark"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1093\/humrep\/des357","article-title":"Unbiased label-free quantitative proteomic profiling and enriched proteomic pathways in seminal plasma of adult men before and after varicocelectomy","volume":"28","author":"Camargo","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e53","DOI":"10.1542\/peds.2007-0340","article-title":"Adolescent varicocele: Who is at risk?","volume":"121","author":"Kumanov","year":"2008","journal-title":"Pediatrics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3109\/00365597109133569","article-title":"Varicocele in children and adolescents. An investigation of the incidence among Danish school children","volume":"5","author":"Oster","year":"1971","journal-title":"Scand. J. Urol. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.fertnstert.2012.08.048","article-title":"Proteomic analysis of seminal plasma in adolescents with and without varicocele","volume":"99","author":"Zylbersztejn","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1007\/s10815-016-0808-z","article-title":"Alterations in the proliferative\/apoptotic equilibrium in semen of adolescents with varicocele","volume":"33","author":"Belardin","year":"2016","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1111\/andr.12174","article-title":"Determination of testicular function in adolescents with varicocoele\u2014A proteomics approach","volume":"4","author":"Belardin","year":"2016","journal-title":"Andrology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.urology.2014.05.016","article-title":"Seminal BAX and BCL2 gene and protein expressions in infertile men with varicocele","volume":"84","author":"Mostafa","year":"2014","journal-title":"Urology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1080\/004982599238047","article-title":"\u2018Metabonomics\u2019: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data","volume":"29","author":"Nicholson","year":"1999","journal-title":"Xenobiotica"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.drudis.2010.06.012","article-title":"Cell culture metabolomics: Applications and future directions","volume":"15","author":"Barnett","year":"2010","journal-title":"Drug Discov. Today"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1530\/REP-12-0168","article-title":"Prediction of embryo implantation potential by mass spectrometry fingerprinting of the culture medium","volume":"145","author":"Cortezzi","year":"2013","journal-title":"Reproduction"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1039\/C5CS00585J","article-title":"Developing and understanding biofluid vibrational spectroscopy: A critical review","volume":"45","author":"Baker","year":"2016","journal-title":"Chem. Soc. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.cca.2015.09.001","article-title":"Metabolic characterization of asthenozoospermia using nontargeted seminal plasma metabolomics","volume":"450","author":"Zhang","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Qiao, S., Wu, W., Chen, M., Tang, Q., Xia, Y., Jia, W., and Wang, X. (2017). Seminal plasma metabolomics approach for the diagnosis of unexplained male infertility. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181115"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1586\/14737159.7.4.351","article-title":"Role of metabolomic analysis of biomarkers in the management of male infertility","volume":"7","author":"Deepinder","year":"2007","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.talanta.2015.09.040","article-title":"A potential tool for diagnosis of male infertility: Plasma metabolomics based on GC-MS","volume":"147","author":"Zhou","year":"2016","journal-title":"Talanta"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1007\/s10815-014-0282-4","article-title":"Identification of biochemical differences between different forms of male infertility by nuclear magnetic resonance (NMR) spectroscopy","volume":"31","author":"Jayaraman","year":"2014","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3109\/19396368.2015.1054003","article-title":"Discrimination of human semen specimens by NMR data, sperm parameters, and statistical analysis","volume":"61","author":"Bonechi","year":"2015","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/mrd.22284","article-title":"Metabolomics fingerprinting of the human seminal plasma of asthenozoospermic patients","volume":"81","author":"Gilany","year":"2014","journal-title":"Mol. Reprod. Dev."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Correnti, S., Preiano, M., Fregola, A., Gamboni, F., Stephenson, D., Savino, R., D\u2019Alessandro, A., and Terracciano, R. (2023). Seminal plasma untargeted metabolomic and lipidomic profiling for the identification of a novel panel of biomarkers and therapeutic targets related to male infertility. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1275832"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/mrd.22457","article-title":"Metabolomics fingerprinting of seminal plasma from unexplained infertile men: A need for novel diagnostic biomarkers","volume":"82","author":"Jafarzadeh","year":"2015","journal-title":"Mol. Reprod. Dev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/and.12496","article-title":"Metabolomics: A state-of-the-art technology for better understanding of male infertility","volume":"48","author":"Jafarzadeh","year":"2016","journal-title":"Andrologia"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"S233","DOI":"10.1016\/j.fertnstert.2011.07.893","article-title":"Metabolomics of male infertility: Characterization of seminal plasma lipid fingerprints in men with spinal cord injury","volume":"96","author":"Silva","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_69","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_70","doi-asserted-by":"crossref","unstructured":"Agarwal, A., Panner Selvam, M.K., and Baskaran, S. (2020). Proteomic Analyses of Human Sperm Cells: Understanding the Role of Proteins and Molecular Pathways Affecting Male Reproductive Health. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051621"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Panner Selvam, M.K., and Agarwal, A. (2019). Proteomic and Metabolomic Profile of Semen and Seminal Plasma in Varicocele. Varicocele and Male Infertility, Springer.","DOI":"10.1007\/978-3-319-79102-9_6"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"324","DOI":"10.5534\/wjmh.180108","article-title":"Protein Fingerprinting of Seminal Plasma Reveals Dysregulation of Exosome-Associated Proteins in Infertile Men with Unilateral Varicocele","volume":"39","author":"Agarwal","year":"2021","journal-title":"World J. Mens Health"},{"key":"ref_73","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_74","doi-asserted-by":"crossref","unstructured":"Kaltsas, A., Stavros, S., Kratiras, Z., Zikopoulos, A., Machairiotis, N., Potiris, A., Dimitriadis, F., Sofikitis, N., Chrisofos, M., and Zachariou, A. (2024). Predictors of Successful Testicular Sperm Extraction: A New Era for Men with Non-Obstructive Azoospermia. Biomedicines, 12.","DOI":"10.3390\/biomedicines12122679"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1007\/s10815-020-01896-2","article-title":"1H NMR-based metabonomics for infertility diagnosis in men with varicocele","volume":"37","author":"Neto","year":"2020","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Serrano, R., Garcia-Marin, L.J., and Bragado, M.J. (2022). Sperm Phosphoproteome: Unraveling Male Infertility. Biology, 11.","DOI":"10.3390\/biology11050659"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/aja.2010.71","article-title":"Proteomics of spermatogenesis: From protein lists to understanding the regulation of male fertility and infertility","volume":"13","author":"Huang","year":"2011","journal-title":"Asian J. Androl."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"272","DOI":"10.5534\/wjmh.220186","article-title":"Towards a Multi-Omics of Male Infertility","volume":"41","author":"Wagner","year":"2023","journal-title":"World J. Mens Health"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"McShane, L.M., Cavenagh, M.M., Lively, T.G., Eberhard, D.A., Bigbee, W.L., Williams, P.M., Mesirov, J.P., Polley, M.Y., Kim, K.Y., and Tricoli, J.V. (2013). Criteria for the use of omics-based predictors in clinical trials: Explanation and elaboration. BMC Med., 11.","DOI":"10.1186\/1741-7015-11-220"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"302","DOI":"10.5534\/wjmh.180114","article-title":"An In-Depth Bibliometric Analysis and Current Perspective on Male infertility Research","volume":"39","author":"Baskaran","year":"2021","journal-title":"World J. Men\u2019s Health"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Preiano, M., Correnti, S., Butt, T.A., Viglietto, G., Savino, R., and Terracciano, R. (2023). Mass Spectrometry-Based Untargeted Approaches to Reveal Diagnostic Signatures of Male Infertility in Seminal Plasma: A New Laboratory Perspective for the Clinical Management of Infertility?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054429"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Omolaoye, T.S., Omolaoye, V.A., Kandasamy, R.K., Hachim, M.Y., and Du Plessis, S.S. (2022). Omics and Male Infertility: Highlighting the Application of Transcriptomic Data. Life, 12.","DOI":"10.1038\/s41598-022-06476-1"},{"key":"ref_83","first-page":"38","article-title":"High-throughput sequencing of the testicular microbiome in patients with non-obstructive azoospermia and varicocele","volume":"16","author":"Faniev","year":"2023","journal-title":"Exp. Clinical Urol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Kaltsas, A., Zachariou, A., Markou, E., Dimitriadis, F., Sofikitis, N., and Pournaras, S. (2023). Microbial Dysbiosis and Male Infertility: Understanding the Impact and Exploring Therapeutic Interventions. J. Pers. Med., 13.","DOI":"10.3390\/jpm13101491"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Kaltsas, A., Markou, E., Zachariou, A., Dimitriadis, F., Mamoulakis, C., Andreadakis, S., Giannakis, I., Tsounapi, P., Takenaka, A., and Sofikitis, N. (2022). Varicoceles in Men with Non-obstructive Azoospermia: The Dilemma to Operate or Not. Front. Reprod. Health, 4.","DOI":"10.3389\/frph.2022.811487"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.fertnstert.2013.01.111","article-title":"The use of genomics, proteomics, and metabolomics in identifying biomarkers of male infertility","volume":"99","author":"Kovac","year":"2013","journal-title":"Fertil. Steril."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/23\/7390\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:46:45Z","timestamp":1760114805000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/23\/7390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,4]]},"references-count":86,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["jcm13237390"],"URL":"https:\/\/doi.org\/10.3390\/jcm13237390","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,4]]}}}