Biological and clinical factors predicting sperm retrieval success in men with non-obstructive azoospermia

Abstract Non-obstructive azoospermia (NOA) represents the most severe form of male infertility, characterized by impaired spermatogenesis and consequent failure to produce sufficient sperm. Accordingly, the identification of reliable predictors of testicular sperm presence has become a central focus of contemporary research. In parallel, considerable effort has been directed toward the development of strategies to generate sperm cells. Accumulating evidence indicates that histopathological findings, physical examination parameters, and patient demographics may contribute to the prediction of sperm retrieval outcomes. In addition, circulating reproductive hormone levels, including testosterone, as well as proteomic and transcriptomic profiles derived from semen and testicular tissues, have demonstrated potential utility in predicting success during testicular sperm retrieval. Emerging approaches aimed at sperm generation-such as the application of spermatogonial stem cells, induced pluripotent stem cells, and pharmacological interventions including aromatase inhibitors, estrogen modulators, and hormonal therapies-have also been increasingly investigated. Collectively, these advances suggest that both the prediction of sperm retrieval and the development of sperm production strategies in NOA are evolving rapidly, with promising implications for future clinical practice. Lay Summary Non-obstructive azoospermia (NOA) is a severe form of male infertility in which the testes produce little to no sperm. Determining whether sperm can be retrieved from the testes and whether sperm production can be restored are therefore critical clinical challenges. Recent evidence indicates that testicular histopathology, physical examination findings, patient characteristics, and circulating hormone levels, together with advanced molecular analyses, can aid in predicting the likelihood of successful sperm retrieval. In parallel, emerging approaches including stem cell-based strategies and hormonal therapies are being investigated to promote sperm production. Overall, advances in both prediction and therapeutic development suggest that achieving sperm retrieval or generation in men with NOA may be more feasible than previously anticipated.