Intracytoplasmic spermatid injection in non-obstructive azoospermia: a review of current evidence and future directions

Non-obstructive azoospermia (NOA) represents one of the most severe forms of male infertility, with spermatozoa retrieval only possible in about half of the cases. Spermatids can be identified in up to 30% of men with negative spermatozoa during testicular sperm extraction (TESE) procedure. Intracytoplasmic spermatid injection has been proposed for TESE-negative patients desiring biological parenthood. However, significant limitations jeopardize the clinical implementation of this technique. Key challenges include the accurate identification of viable spermatids and the need for artificial oocyte activation. These limitations contribute to lower fertilization, pregnancy, and live birth rates compared to conventional intracytoplasmic sperm injection using mature sperm. Additionally, the absence of rigorous randomized controlled trials and the predominance of low-quality and outdated underpinning studies have significantly jeopardized its clinical implementation. These concerns have led the Practice Committee of the American Society for Reproductive Medicine to consider the technique experimental. Recent advances in microscopy, improved tissue processing, and refined activation techniques have enhanced outcomes. Furthermore, while initial safety concerns about epigenetic modifications persist, follow-up studies of spermatid injection offspring have shown normal development. This review comprehensively explores current evidence regarding intracytoplasmic spermatid injection techniques, focusing on their utilization, efficacy, and safety in men with NOA. We also evaluate spermatid identification and retrieval methods, ethical considerations, technical limitations, and emerging technologies that could enhance outcomes.