Relative Sertoli-cell FSH hyporesponsiveness as a potential contributor to sperm DNA fragmentation: a hypothesis-driven narrative review and proposal of the FERTILE framework.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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 hyporesponsiveness 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. CONCLUSIONS: Relative Sertoli-cell FSH hyporesponsiveness represents a biologically plausible but currently unproven contributor to elevated SDF. The proposed FERTILE framework is intended as a conceptual research tool for biological stratification and hypothesis generation rather than a clinical decision-making instrument. Prospective studies incorporating endocrine profiling, pharmacogenetic characterization, standardized SDF assessment, and direct or validated surrogate measures of Sertoli-cell responsiveness are required to determine whether relative Sertoli-cell FSH hyporesponsiveness has independent clinical relevance for sperm DNA integrity and reproductive outcomes.