Idiopathic male infertility revisited: can redox endophenotypes reframe the 'idiopathic' label?

Male infertility accounts for nearly half of all infertility cases worldwide, yet up to 30-40% of affected men remain categorized as 'idiopathic', reflecting limitations of conventional diagnostics such as semen analysis, hormonal profiling, karyotyping, and Y-chromosome microdeletion testing. These methods describe sperm quantity and morphology but fail to uncover underlying molecular dysfunctions. Increasing evidence suggests that oxidative stress plays a central role in driving sperm damage, encompassing lipid peroxidation, protein oxidation, mitochondrial dysfunction, DNA fragmentation, and epigenetic instability. Such diverse pathways highlight the inadequacy of a single idiopathic category and necessitate mechanistic stratification. This evidence-based study proposes redox endophenotypes, including hyper- and hypo-oxidative, DNA damage-dominant, mitochondrial dysfunction, epigenetic-redox, and inflammatory-redox phenotypes, as a framework for reclassifying idiopathic male infertility. Each phenotype integrates specific biomarkers, such as oxidation-reduction potential (ORP), isoprostanes, 8-hydroxy-2'-deoxyguanosine, or advanced oxidation protein products, with distinct functional impairments and clinical outcomes. Redox endophenotyping offers diagnostic refinement, guides personalized antioxidant or adjunctive therapy, and informs clinicians and embryologists for appropriate assisted reproductive technology (ART) protocols by counselling and treating the patient, and tailoring sperm selection and preparation strategies. Future directions include multi-center validation of redox assays, integration with omics and exposome data, and application of artificial intelligence for biomarker-driven algorithms. Recognizing redox endophenotypes not only reduces the reliance on exclusionary 'idiopathic' diagnoses but also advances precision andrology, improving patient diagnostics and care, reproductive outcomes and mitigating intergenerational health risks.