Why a universal sperm DNA fragmentation cut-off is scientifically unsound: a context-dependent clinical framework

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Abstract Sperm DNA fragmentation (SDF) has gained increasing recognition as a biologically relevant biomarker in the evaluation of male infertility, reflecting genomic instability within the paternal gamete and its potential consequences for fertilization, embryo development, and pregnancy outcomes. Despite its growing clinical adoption, a persistent question in reproductive medicine concerns the existence of a single, universally applicable SDF cut-off that can reliably define male infertility. The present correspondence critically examines this assumption considering current evidence. Available data indicate that the concept of a universal numerical threshold is scientifically problematic because SDF measurements vary substantially across analytical platforms, including sperm chromatin structure assay (SCSA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), sperm chromatin dispersion (SCD), and Comet assays. Evidence suggests that values around ~ 20% may distinguish fertile from infertile men at a population level. However, this represents a population-level diagnostic estimate rather than a clinical decision threshold. In contrast, thresholds near 25–30%, derived primarily from SCSA-based studies, represent an assay-specific prognostic range associated with reduced natural conception or intrauterine insemination success. However, these thresholds are assay-dependent and influenced by methodological variability, clinical context, and couple-related factors. Consequently, SDF should not be interpreted as a binary diagnostic marker but rather as a probabilistic indicator of male reproductive competence. Future efforts should prioritize assay standardization, laboratory-specific validation, and outcome-oriented interpretation rather than the pursuit of a single universal cut-off.

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