Testicular tissue transplantation: from animal models to clinical application

Abstract BACKGROUND Every year, approximately 14,000 new cases of childhood cancer are diagnosed in Europe. Chemo- and radiotherapy have improved significantly, leading to survival rates of up to 81% in children. The growing number of childhood cancer survivors has brought increased attention to the long-term gonadotoxic effects of these treatments, with lifelong infertility being one of the most frequent side effects. Consequently, fertility preservation and restoration strategies are actively under investigation. Since spermatogenesis starts only at puberty, pre-pubertal boys cannot benefit from sperm banking. However, as spermatogonial stem cells are present from birth, the surgical retrieval and cryopreservation of pre-pubertal testicular tissue represent a promising strategy to preserve fertility in boys before undergoing gonadotoxic treatment. Pre-pubertal testicular tissue has been cryopreserved for more than 3,000 boys worldwide. At adulthood, the cryopreserved testicular tissue may be used to restore fertility, either through testicular tissue transplantation or spermatogonial stem cell transplantation (SSCT), or through in vitro spermatogenesis (IVS). Reviews are already available for SSCT and IVS, but an updated cross-species comparative overview of testicular tissue transplantation with emphasis on recent clinical translation is needed. OBJECTIVE AND RATIONALE The aim of this review is to provide an overview of pre-clinical research on testicular tissue transplantation in animal models, and to highlight the initial steps of the clinical application of autologous testicular tissue transplantation. SEARCH METHODS A comprehensive review of peer-reviewed publications on testicular tissue transplantation was performed using PubMed and Google Scholar databases. The literature search was limited to English-language studies published between 2002 (the first study on testicular tissue transplantation) and December 2025. The search was conducted using the following search terms: testicular tissue grafting, allotransplantation of testicular tissue, xenotransplantation of testicular tissue, and autotransplantation of testicular tissue. Titles and abstracts were screened for relevance. Articles not subjected to peer review were excluded. Studies were included if they involved testicular tissue grafting and reported graft outcomes, such as the most advanced germ cell stage. OUTCOMES Animal studies have demonstrated that donor age and graft site play a crucial role in the outcome of testicular tissue transplantation. For instance, transplantation of adult testicular tissue usually led to degeneration of the seminiferous tubules, while allo-, xeno-, and autotransplantation of pre-pubertal testicular tissue successfully restores complete spermatogenesis in most of the species. In addition, homotopic engraftment generally provides the best support to restore spermatogenesis. LIMITATIONS, REASONS FOR CAUTION As a narrative review, the risk of bias in the interpretation of findings cannot be completely eliminated. WIDER IMPLICATIONS These findings support the clinical translation of autologous pre-pubertal testicular tissue transplantation, highlighting the potential to restore fertility and improve quality of life in men who underwent gonadotoxic treatment during childhood. Pre-pubertal testicular tissue transplantation can be considered following thorough risk assessment for patients suffering from a non-malignant disease, as well as for cancer patients with solid and non-metastatic malignancies. STUDY FUNDING/COMPETING INTEREST(S) The authors acknowledge financial support from the Vrije Universiteit Brussel (Strategic Research Program 89). The authors declare no competing interests.