Multifactorial pathophysiology of varicocele: Integrating hemodynamic, oxidative, and endocrine mechanisms

Varicocele is the most frequent surgically correctable cause of male factor infertility and the mechanisms underlying the detrimental impact of varicocele on testicular function are not fully understood. The current evidence suggests that varicocele is accompanied by significant changes of the microenvironment of the testicles, not only are the veins dilated, but there are also deep changes. Venous drainage defects and abnormal testicular hemodynamic can favour the development of hyperthermia, hypoxia, oxidative stress, inflammation and hormonal disturbances, which can affect cellular homeostasis, impairing spermatogenesis and steroidogenesis. A growing body of evidence also indicates that there is considerable variation in the clinical presentation and reproductive outcomes of affected men, which may be attributable to genetic susceptibility, epigenetic dysregulation, and molecular alterations. The above changes have been associated with sperm DNA damage, dysfunction of sperm, Leydig cell dysfunction and progressive loss of testicular architecture. While varicocele surgery can enhance semen quality and reproductive outcomes in the right patients, there is great variability in response to surgery. The use of molecular profiling and multi-omics technologies has now enhanced the understanding of the molecular pathways involved in varicocele-associated infertility and may enable the development of predictive biomarkers and more personalized treatment plans. This review synthesises current evidence regarding the pathophysiological, genetic, and molecular mechanisms underlying varicocele associated male infertility and examines their clinical implications for diagnosis, treatment, and future precision-based approaches.