{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T05:19:09Z","timestamp":1787548749859,"version":"build-2736575974"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Urol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sperm DNA fragmentation (SDF) is associated with impaired fertility, adverse reproductive outcomes, and an increased risk of miscarriage. Although oxidative stress is considered the predominant contributor to SDF, accumulating evidence suggests that abnormalities arising during spermatogenesis may also influence sperm DNA integrity. However, whether relative Sertoli-cell FSH hyporesponsiveness contributes to SDF has not been directly investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To evaluate the biological plausibility that relative Sertoli-cell FSH hyporesponsiveness may contribute to SDF and to propose a multidimensional research framework for future biological investigation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A hypothesis-driven narrative review was conducted using experimental, translational, and clinical evidence addressing FSH signaling, Sertoli-cell biology, spermatogenesis, SDF, pharmacogenetics, and FSH-based therapeutic interventions. Relevant literature was identified through structured searches of PubMed, Scopus, and Embase up to June 1, 2026.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Available evidence suggests that circulating FSH concentrations may not accurately reflect effective intratesticular FSH action. Human associative studies, pharmacogenetic findings, and mechanistic experimental evidence collectively support the biological plausibility that inter-individual variation in effective FSH signaling may influence Sertoli-cell support of germ-cell maturation, chromatin remodeling, and cellular quality-control mechanisms. Although direct clinical evidence remains limited, these observations suggest that relative Sertoli-cell FSH\u00a0hyporesponsiveness could contribute to defective chromatin packaging, persistence of DNA damage, and increased susceptibility to SDF in selected men. To facilitate future investigation of this hypothesis, the FERTILE framework is proposed as a seven-domain conceptual model integrating FSH and effective intratesticular signaling, endocrine markers, receptor and ligand genetics, testicular structure, inflammation and oxidative stress, lifestyle and environmental factors, and evaluation of DNA integrity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Relative Sertoli-cell FSH hyporesponsiveness represents a biologically plausible but currently unproven contributor to elevated SDF. The\u00a0proposed FERTILE framework is intended as a conceptual research tool for\u00a0biological stratification and hypothesis generation rather than a clinical decision-making instrument. Prospective studies incorporating endocrine profiling, pharmacogenetic characterization, standardized SDF assessment, and\u00a0direct or\u00a0validated surrogate measures of Sertoli-cell responsiveness are\u00a0required to\u00a0determine whether relative Sertoli-cell FSH hyporesponsiveness has independent clinical relevance for sperm DNA integrity and reproductive outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fruro.2026.1915445","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T04:24:40Z","timestamp":1787545480000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Relative Sertoli-cell FSH hyporesponsiveness as a potential contributor to sperm DNA fragmentation: a hypothesis-driven narrative review and proposal of the FERTILE framework"],"prefix":"10.3389","volume":"6","author":[{"given":"Hussein","family":"Kandil","sequence":"first","affiliation":[{"name":"Male Reproductive Unit, Fakih IVF Fertility Center","place":["Abu Dhabi, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/genes10020105","article-title":"Single and double strand sperm DNA damage: Different reproductive effects on male fertility","volume":"10","author":"Ribas-Maynou","year":"2019","journal-title":"Genes (Basel)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.200128","article-title":"Sperm DNA fragmentation: A new guideline for clinicians","volume":"38","author":"Agarwal","year":"2020","journal-title":"World J Mens Health"},{"key":"B3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/B978-0-323-85687-4.00018-X","article-title":"Sperm DNA fragmentation and male infertility","volume-title":"Handbook of Current and Novel Protocols for the Treatment of Infertility","author":"Kandil","year":"2024"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.21037\/tau-22-149","article-title":"Sperm DNA integrity and male infertility: A narrative review and guide for the reproductive physicians","volume":"11","author":"Farkouh","year":"2022","journal-title":"Transl Androl Urol"},{"key":"B5","volume-title":"WHO Laboratory Manual for the Examination and Processing of Human Semen","year":"2021"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.210074","article-title":"Editorial commentary on draft of World Health Organization sixth edition laboratory manual for the examination and processing of human semen","volume":"39","author":"Kandil","year":"2021","journal-title":"World J Mens Health"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12700","article-title":"Clinical implications of sperm DNA damage in IVF and ICSI: Updated systematic review and meta-analysis","volume":"96","author":"Ribas-Maynou","year":"2021","journal-title":"Biol Rev Camb Philos Soc"},{"key":"B8","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4103\/1008-682X.182822","article-title":"A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome","volume":"19","author":"Simon","year":"2017","journal-title":"Asian J Androl"},{"key":"B9","volume-title":"EAU Guidelines on Sexual and Reproductive Health. 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