Antisperm antibodies and autoimmunity in the era of assisted reproduction

Male factor infertility acts as a contributing or sole cause in approximately half of all infertility cases, with autoimmunity against spermatozoa-manifested as antisperm antibodies (ASA)-affecting 5%-12% of infertile men. The ASA formation typically results from a disruption of the blood-testis barrier because of trauma, obstruction, or inflammation, leading to the exposure of immunogenic sperm antigens to the systemic immune system. These antibodies, predominantly of the immunoglobulin G and immunoglobulin A classes, impair fertility by hindering sperm motility, preventing cervical mucus penetration, and blocking gamete interaction. Diagnostic evaluation primarily relies on direct assays such as the mixed antiglobulin reaction and immunobead test; however, in the era of intracytoplasmic sperm injection, the utility of ASA testing has evolved from routine screening to a targeted triage tool. Contemporary guidelines discourage universal testing, reserving it for ‟gray zone" clinical scenarios, such as unexplained infertility or isolated asthenozoospermia, where results directly influence the decision between intrauterine insemination (IUI) and in vitro fertilization. Therapeutically, historical reliance on systemic immunosuppression has been largely abandoned because of inefficacy and adverse effects. Instead, management is now stratified by the degree of autoimmunity: although IUI remains a viable option for lower levels of antibody binding, high levels of sperm autoimmunization (>80%) render IUI ineffective, necessitating intracytoplasmic sperm injection to mechanically bypass the immune barrier. This views and reviews article summarizes current evidence on pathophysiology and diagnostic methodologies, providing a pragmatic, management-oriented algorithm to guide urologists and reproductive specialists in optimizing outcomes for couples with immunologic infertility.