MOLECULAR SUBTYPING OF OBSTRUCTIVE VS. NON-OBSTRUCTIVE AZOOSPERMIA: DIAGNOSTIC PRECISION FOR SURGICAL OUTCOMES

Abstract

The most serious type of male infertility is azoospermia, which is mostly divided into obstructive and non-obstructive varieties with specific pathophysiological and prognostic implications. Conventional diagnostic methods are based on clinical, hormonal, and histologic evaluation but the techniques are not very precise in estimating the outcome of sperm retrieval in surgery. This narrative review summarizes recent developments in molecular subtyping of azoospermia with an emphasis on genetic, epigenetic, transcriptomic, proteomic, and multi-omics biomarker panels, which can be effectively used to increase diagnostic discrimination and prognostic validity. Etiological stratification with genetic markers like CFTR mutations and Y-chromosome microdeletions and next-generation sequencing has further enriched the spermatogenesis-related variants. New non-invasive overepigenetic and transcriptomic signatures -such as microRNAs, long non-coding RNAs and cell-free DNA fragmentomics- have potential to provide subtype differentiation and prediction of residual spermatogenesis. Proteomic biomarkers as TEX101 and LDHC, especially combined with the hormonal parameters and multi-omics models, enhance the stratification of risk in pre-operative. Predictive algorithms based on machine learning that uses both molecular and clinical data show improved prediction of the success of testicular sperm extraction (TESE). Together, molecular subtyping is a radical move toward accurate andrology, wherein individualized surgical advice, unnecessary interventions, and maximized assisted reproduction results are attained. To translate these advances into clinical practice, further validation and clinical integration of multi-omics panels is needed.