Biomarkers to predict improvement of sperm parameters and hypogonadism after varicocele repair

Approximately 15% of couples in the US are affected by infertility, with male factor infertility acting as the sole or contributing factor in 20% and 40% of cases, respectively. Of the numerous potential causes of male infertility, varicocele is the most common and correctable. Although there are several hypotheses for the mechanism by which varicocele may cause symptoms such as infertility, pain, or hypogonadism, many patients with varicocele remain asymptomatic, and it remains unclear why only a subset of men with varicocele develop symptomatic pathology. Biomarkers are measurable indicators of disease presence or progression and have been proposed for use in the diagnosis and management of men with various reproductive conditions, including varicocele. This study examines a range of markers, including proteins, ribonucleic acid, deoxyribonucleic acid, and metabolites. Proteins implicated in heat shock reactions, oxidative stress, and mitochondrial function, including heat shock protein family A member 2, apolipoprotein A2, and TOM22, have been investigated within the context of varicocele when compared with their expression in healthy men. Additionally, potential biomarkers associated with sperm motility and spermatogenesis, such as serpin family A member 5 and adenosine triphosphate synthase delta domain protein, have been identified with studies showing improvement in concentrations post varicocelectomy. The pursuit of noninvasive biomarkers has gained significance for predicting improvement in fertility and assessing responses to varicocelectomy, offering opportunities for early intervention, minimizing unnecessary surgeries, and optimizing patient outcomes. This review consolidates current knowledge, underscores existing gaps, and outlines future research directions refining diagnostic and therapeutic strategies for varicocele-related infertility.