Sperm DNA fragmentation (SDF) represents strand breaks that may compromise embryo development, reproductive outcomes, and offspring health, particularly when the oocyte's repair capacity is limited. This mini-review provides a clinically pragmatic framework addressing how to test, when to test, and whom to test for SDF, translating biological and laboratory insights into actionable andrology practice. The mechanistic basis of SDF is summarized, including the two-step hypothesis linking defective chromatin packaging to oxidative stress, and the combined influence of paternal and maternal aging on the creation and repair of DNA lesions. Contemporary methods for detecting both single- and double-strand breaks (DSBs), as well as DSB-specific platforms, are reviewed with emphasis on assay-specific cut-offs and clinical indications. Management strategies are outlined, prioritizing andrological optimization through lifestyle modification, antioxidant supplementation, treatment of genital tract infection, varicocele repair, and selected hormonal therapy, followed by retesting after one spermatogenic cycle. For persistently high SDF, selective use of testicular sperm for ICSI (Testi-ICSI) and laboratory adjuncts is discussed, supported by evidence of lower miscarriage and higher live-birth rates in defined high-SDF phenotypes. The limitations of the existing observational evidence base-particularly the paucity of phenotype-targeted randomized controlled trials-are highlighted. The review also underscores the value of embedding SDF testing within quality-managed programs and incorporating systematic audits of indications, treatment effects, and ART outcomes. Beyond ART, SDF assessment is positioned within preconception care, recognizing sperm chromatin integrity as a determinant of reproductive and intergenerational health. Future priorities include randomized trials comparing testicular and ejaculated sperm for ICSI in high-SDF cohorts, validation of DSB-specific assays, and longitudinal offspring follow-up to clarify intergenerational effects. This integrative approach promotes precision rather than proliferation of testing, aligning molecular insight with clinical prudence to improve reproductive and generational outcomes.
Human reproduction (Oxford, England). 2026 Apr 28 [Epub ahead of print]
Sandro C Esteves, Peter Humaidan
ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, SP, Brazil., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.