{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T08:33:24Z","timestamp":1793003604383,"version":"4.5.0"},"reference-count":116,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":287,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Reprod Medicine &amp; Biology"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Varicocele is common in male infertility, yet many affected men retain conventional reproductive measures, and the anatomical grade is an imperfect proxy for phenotype. Established pathways explain injury more clearly than between\u2010person heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This structured, critical narrative review searched PubMed from 1 January 2015 to 26 August 2026, with targeted hand\u2010searching. There was no preregistered protocol, dual screening, or risk\u2010of\u2010bias assessment, and coverage is not exhaustive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Findings<\/jats:title>\n                    <jats:p>The threshold\u2010resilience framework is a hypothesis\u2010generating model separating lesion\u2010related exposure, candidate host response measures, and couple\u2010level variables. Human varicocele\u2010specific evidence supports hemodynamic, thermal, redox, and sperm DNA damage associations. No prospective human varicocele study was identified in which an independently measured antioxidant, DNA processing, heat response, or endocrine measure preserved fertility at a given exposure. Female age and ovarian reserve are couple\u2010level variables, and all candidate host response measures remain research\u2010only.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Intended for investigators in andrology and reproductive medicine, the framework is a research agenda rather than an explanatory mechanism or clinical algorithm. It maps evidence provenance, identifies measurement gaps, and specifies prospective tests of whether prespecified, outcome\u2010independent host response measures add prediction beyond anatomy, semen analysis, damage measures, and couple\u2010level factors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/rmb2.70102","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T16:41:32Z","timestamp":1792082492000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Male Reproductive Phenotype Heterogeneity in Varicocele: A Hypothesis\u2010Generating Threshold\u2010Resilience Framework and Research Agenda"],"prefix":"10.1002","volume":"25","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  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1528-4029","authenticated-orcid":false,"given":"Nikolaos","family":"Sofikitis","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, School of Health Sciences University of Ioannina  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  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_19_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/frph.2022.863695"},{"key":"e_1_2_19_3_1","doi-asserted-by":"publisher","DOI":"10.4103\/1008\u2010682X.172640"},{"key":"e_1_2_19_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.12637"},{"key":"e_1_2_19_5_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1464\u2010410x.2000.00735.x"},{"key":"e_1_2_19_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2017.98"},{"key":"e_1_2_19_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/8.1.53"},{"key":"e_1_2_19_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.04.005"},{"key":"e_1_2_19_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.13407"},{"key":"e_1_2_19_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0015\u20100282(16)55809\u20109"},{"key":"e_1_2_19_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u20105347(17)58387\u20101"},{"key":"e_1_2_19_12_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100029\u20101202306"},{"key":"e_1_2_19_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2026.156608"},{"key":"e_1_2_19_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41073\u2010019\u20100064\u20108"},{"key":"e_1_2_19_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/7.5.473"},{"key":"e_1_2_19_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/02841851221144427"},{"key":"e_1_2_19_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u20105347(17)38874\u20102"},{"key":"e_1_2_19_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10439\u2010010\u20100191\u20103"},{"key":"e_1_2_19_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dev057"},{"key":"e_1_2_19_20_1","doi-asserted-by":"publisher","DOI":"10.1039\/d2fo03423a"},{"key":"e_1_2_19_21_1","doi-asserted-by":"publisher","DOI":"10.1258\/phleb.2011.011051"},{"key":"e_1_2_19_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43032\u2010021\u201000696\u2010y"},{"key":"e_1_2_19_23_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2017.7253"},{"key":"e_1_2_19_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010019\u201003253\u20108"},{"key":"e_1_2_19_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/rmb2.12353"},{"key":"e_1_2_19_26_1","doi-asserted-by":"publisher","DOI":"10.4103\/aja202488"},{"key":"e_1_2_19_27_1","doi-asserted-by":"publisher","DOI":"10.1071\/RD14276"},{"key":"e_1_2_19_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022\u20105347(05)68818\u20100"},{"key":"e_1_2_19_29_1","doi-asserted-by":"publisher","DOI":"10.1590\/S1677\u20105538.IBJU.2024.9917"},{"key":"e_1_2_19_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2005.08.032"},{"key":"e_1_2_19_31_1","doi-asserted-by":"publisher","DOI":"10.23736\/S0031\u20100808.18.03529\u20102"},{"key":"e_1_2_19_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox15030293"},{"key":"e_1_2_19_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ju.0000138344.56941.b1"},{"key":"e_1_2_19_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464\u2010410X.2007.07008.x"},{"key":"e_1_2_19_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ucl.2016.01.009"},{"key":"e_1_2_19_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743\u20106109.2010.01974.x"},{"key":"e_1_2_19_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2016.06.044"},{"key":"e_1_2_19_38_1","doi-asserted-by":"publisher","DOI":"10.1177\/03000605211061045"},{"key":"e_1_2_19_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2007.08.061"},{"key":"e_1_2_19_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1439\u20100272.2010.01103.x"},{"key":"e_1_2_19_41_1","doi-asserted-by":"publisher","DOI":"10.4238\/2015.December.28.34"},{"key":"e_1_2_19_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.13007"},{"key":"e_1_2_19_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2020.04.045"},{"key":"e_1_2_19_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmae034"},{"key":"e_1_2_19_45_1","doi-asserted-by":"publisher","DOI":"10.22074\/cellj.2023.2000170.1284"},{"key":"e_1_2_19_46_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1464\u2010410x.2002.02746.x"},{"key":"e_1_2_19_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s003450050149"},{"key":"e_1_2_19_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2009.12.039"},{"key":"e_1_2_19_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1472\u20106483(10)60004\u20101"},{"key":"e_1_2_19_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1939\u20104640.2004.tb02757.x"},{"key":"e_1_2_19_51_1","doi-asserted-by":"publisher","DOI":"10.22037\/uj.v0i0.4653"},{"key":"e_1_2_19_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2020.08.013"},{"key":"e_1_2_19_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10071067"},{"key":"e_1_2_19_54_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2019.7828"},{"key":"e_1_2_19_55_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes10020105"},{"key":"e_1_2_19_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2006.05.030"},{"key":"e_1_2_19_57_1","doi-asserted-by":"crossref","unstructured":"A.Natsume Y.Ozaki Y.Kitadate et\u00a0al. \u201cRole of Dynamic Changes in Human Sperm Heat Shock Protein A2 in Male Infertility \u201dJournal of Reproduction and Development(2026) https:\/\/doi.org\/10.1262\/jrd.2026\u2010023.","DOI":"10.1262\/jrd.2026-023"},{"key":"e_1_2_19_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/frph.2022.811487"},{"key":"e_1_2_19_59_1","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.240109"},{"key":"e_1_2_19_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2025.03.007"},{"key":"e_1_2_19_61_1","doi-asserted-by":"publisher","DOI":"10.4103\/aja.aja_83_18"},{"key":"e_1_2_19_62_1","doi-asserted-by":"publisher","DOI":"10.1515\/med\u20102016\u20100039"},{"key":"e_1_2_19_63_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1439\u20100272.2003.00546.x"},{"key":"e_1_2_19_64_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP\u201016\u20100077"},{"key":"e_1_2_19_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1097\u2010010x(19991101)284:6<696::aid\u2010jez11>3.0.co;2\u2010e"},{"key":"e_1_2_19_66_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deu228"},{"key":"e_1_2_19_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2014.10.018"},{"key":"e_1_2_19_68_1","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12700"},{"key":"e_1_2_19_69_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.14180"},{"key":"e_1_2_19_70_1","doi-asserted-by":"publisher","DOI":"10.1177\/15579883251334561"},{"key":"e_1_2_19_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2006.10.013"},{"key":"e_1_2_19_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u20105347(17)32710\u20106"},{"key":"e_1_2_19_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43032\u2010023\u201001237\u20105"},{"key":"e_1_2_19_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2007.07.1377"},{"key":"e_1_2_19_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2007.01.016"},{"key":"e_1_2_19_76_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.13885"},{"key":"e_1_2_19_77_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464\u2010410X.2008.07517.x"},{"key":"e_1_2_19_78_1","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.230235"},{"key":"e_1_2_19_79_1","doi-asserted-by":"publisher","DOI":"10.1177\/15579883241285670"},{"key":"e_1_2_19_80_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010025\u201093267\u2010z"},{"key":"e_1_2_19_81_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm15041524"},{"key":"e_1_2_19_82_1","doi-asserted-by":"publisher","DOI":"10.18502\/jri.v23i2.8992"},{"key":"e_1_2_19_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2015.01.015"},{"key":"e_1_2_19_84_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11934\u2010018\u20100798\u20108"},{"key":"e_1_2_19_85_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.77477"},{"key":"e_1_2_19_86_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12174"},{"key":"e_1_2_19_87_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/4302754"},{"key":"e_1_2_19_88_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1682362"},{"key":"e_1_2_19_89_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.13462"},{"key":"e_1_2_19_90_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11255\u2010017\u20101749\u2010x"},{"key":"e_1_2_19_91_1","doi-asserted-by":"publisher","DOI":"10.4103\/aja2021125"},{"key":"e_1_2_19_92_1","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.250025"},{"key":"e_1_2_19_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2016.10.008"},{"key":"e_1_2_19_94_1","doi-asserted-by":"publisher","DOI":"10.4103\/aja.aja_5_19"},{"key":"e_1_2_19_95_1","doi-asserted-by":"publisher","DOI":"10.1530\/RAF\u201021\u20100005"},{"key":"e_1_2_19_96_1","volume-title":"EAU Guidelines on Sexual and Reproductive Health","author":"European Association of Urology","year":"2026"},{"key":"e_1_2_19_97_1","doi-asserted-by":"publisher","DOI":"10.1111\/bju.70194"},{"key":"e_1_2_19_98_1","volume-title":"American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men: AUA\/ASRM Guideline (2024 Amendment)","author":"American Urological Association","year":"2024"},{"key":"e_1_2_19_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2010.12.008"},{"key":"e_1_2_19_100_1","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.220048"},{"key":"e_1_2_19_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2025.11.014"},{"key":"e_1_2_19_102_1","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.250004"},{"key":"e_1_2_19_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2014.03.046"},{"key":"e_1_2_19_104_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.13809"},{"key":"e_1_2_19_105_1","doi-asserted-by":"publisher","DOI":"10.3390\/medicina60122056"},{"key":"e_1_2_19_106_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00345\u2010025\u201005702\u20105"},{"key":"e_1_2_19_107_1","doi-asserted-by":"publisher","DOI":"10.1080\/20905998.2025.2494180"},{"key":"e_1_2_19_108_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13278"},{"key":"e_1_2_19_109_1","doi-asserted-by":"publisher","DOI":"10.4103\/1008\u2010682X.170445"},{"key":"e_1_2_19_110_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13237390"},{"key":"e_1_2_19_111_1","doi-asserted-by":"crossref","unstructured":"J.Zhang J.Yang Y.Liang et\u00a0al. \u201cSystemic Signatures Differentiating Varicocele\u2010Associated Semen Quality Heterogeneity: An Exploratory Multi\u2010Omics Pilot Study \u201dAndrology(2026) https:\/\/doi.org\/10.1111\/andr.70372.","DOI":"10.1111\/andr.70372"},{"key":"e_1_2_19_112_1","doi-asserted-by":"publisher","DOI":"10.4103\/aja202568"},{"key":"e_1_2_19_113_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618\u2010026\u201002844\u20100"},{"key":"e_1_2_19_114_1","doi-asserted-by":"publisher","DOI":"10.1080\/17520363.2026.2686307"},{"key":"e_1_2_19_115_1","doi-asserted-by":"crossref","unstructured":"G. M.Busetto G.Barbieri P.Fischetti et\u00a0al. \u201cMultifunctional Automated Semen Analysis System of Global SDF and DSBs Provides New Insights Into Varicocele Diagnosis \u201dAsian Journal of Andrology(2026) https:\/\/doi.org\/10.4103\/aja202633.","DOI":"10.4103\/aja202633"},{"key":"e_1_2_19_116_1","doi-asserted-by":"crossref","unstructured":"K.Chen L.Pan J.Cai et\u00a0al. \u201cDifferential Effects of Sperm DNA Fragmentation Index on Cumulative Live Birth Rate Per Complete Cycle Following IVF and ICSI Treatment in Patients Without Severe Male Infertility \u201dAndrology(2026) https:\/\/doi.org\/10.1111\/andr.70338.","DOI":"10.1111\/andr.70338"},{"key":"e_1_2_19_117_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2026.1881113"}],"container-title":["Reproductive Medicine and Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rmb2.70102","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/rmb2.70102","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rmb2.70102","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T07:50:08Z","timestamp":1793001008000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/rmb2.70102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":116,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/rmb2.70102"],"URL":"https:\/\/doi.org\/10.1002\/rmb2.70102","archive":["Portico"],"relation":{},"ISSN":["1445-5781","1447-0578"],"issn-type":[{"value":"1445-5781","type":"print"},{"value":"1447-0578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2026-07-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70102"}}