IMPORTANCE: Advances in the treatment of childhood cancer have significantly improved survival rates, with more than 80% of survivors reaching adulthood. However, gonadotoxic cancer treatments endanger future fertility and prepubertal males have no option to preserve fertility by sperm cryopreservation. Also, boys with cryptorchidism are at risk of compromised fertility in adulthood.

OBJECTIVE: This scoping review focuses on male fertility restoration, particularly relevant for prepubertal male cancer survivors and boys with cryptorchidism. The aim was to investigate current evidence for fertility restoration strategies, explore barriers to clinical implementation, and outline potential steps to overcome these barriers.

EVIDENCE REVIEW: The review was conducted following the PRISMA-ScR criteria and previously published guidelines and examines studies using human testis tissue of prepubertal boys or healthy male adults. A literature search in PubMed was conducted and 72 relevant studies were identified, including in vivo and in vitro approaches.

FINDINGS: In vivo strategies, such as testis tissue engraftment and spermatogonial stem cell (SSC) transplantation, hold promise for promoting cell survival and differentiation. Yet complete spermatogenesis has not been achieved. In vitro approaches focus on the generation of male germ cells from direct germ cell maturation in various culture systems, alongside human induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs). These approaches mark significant advancements in understanding and promoting spermatogenesis but achieving fully functional spermatozoa in vitro remains a challenge. Barriers to clinical implementation include the risk of reintroducing malignant cells and introduction of epigenetic changes.

CONCLUSION: Male fertility restoration is an area in rapid development. Based on the reviewed studies the most promising and advanced strategy for restoring male fertility using cryopreserved testis tissue is direct testis tissue transplantation.

RELEVANCE: This review identifies persistent barriers to the clinical implementation of male fertility restoration. However, direct transplantation of frozen-thawed testis tissue remains a promising strategy that is on the verge of clinical application.