Aris Kaltsas, Eleftheria Markou, Athanasios Zachariou, Fotios Dimitriadis, Nikolaos Sofikitis
Non-coding RNAs (ncRNAs) are biologically plausible biomarkers in male infertility, but no assay is ready for routine use. This narrative review organizes human evidence by intended clinical decision and defines clinical actionability as a test's ability to inform a specified decision through analytical reliability, clinical validity, incremental value, decision-level benefit, and feasible implementation. Evidence is most developed for obstructive versus non-obstructive azoospermia (NOA) classification and sperm-retrieval prognosis. Most reports, however, use selected case-control samples, single-center development cohorts, or same-program evaluations. Mixed biospecimens, incompletely specified RNA isoforms and normalization, uncertain cohort independence, imperfect diagnostic references, and protocol-dependent retrieval outcomes limit transportability. No independent geographic validation of a locked ncRNA assay or prospective evaluation of ncRNA-guided management was identified within the retrieved sources. Current guidelines do not recommend routine ncRNA testing. Progress requires prespecified intended uses, locked assays, representative multicenter validation, same-patient comparison with contemporary care, calibrated risk estimates, decision-curve analysis, and patient-important, couple-centered outcomes.