Epigenomics in severe male infertility: sperm-derived cell-free DNA methylation for prediction of sperm retrieval.

PURPOSE OF REVIEW: Severe male factor infertility is increasingly managed with surgical sperm retrieval, yet current noninvasive predictors cannot reliably distinguish men with retrievable focal spermatogenesis from those with global spermatogenic failure. This review evaluates epigenomic approaches, with emphasis on seminal plasma cell-free DNA methylation, for prediction of sperm retrieval in nonobstructive azoospermia. RECENT FINDINGS: Recent literature reinforces a persistent clinical limitation: conventional markers and multivariable models can inform risk, but they do not reliably distinguish focal spermatogenesis from global failure before surgery. At the same time, DNA methylation-based tissue-of-origin analysis and seminal plasma cell-free DNA (cfDNA) studies have created a new opportunity to measure sperm-associated molecular signal directly from the reproductive tract. Preliminary multisite clinical data suggest that sperm-derived cfDNA is best understood as a conditional biomarker whose meaning depends on endocrine and etiologic context. SUMMARY: Epigenomic liquid biopsy analysis of cfDNA in seminal plasma may add a biologically direct, noninvasive layer to NOA counseling. The key insight is not simply that sperm-derived cfDNA can be measured, but that its interpretation changes with FSH, genetics, histology and the differential diagnosis of azoospermia. Prospective validation is needed to determine whether this approach improves treatment counseling and surgical planning.