Male fertility restoration: in vivo and in vitro stem cell-based strategies using cryopreserved testis tissue
Childhood cancer survival rates have increased substantially in the past few decades, with over 80% of survivors reaching adulthood thanks to modern treatment regimens. Many prepubertal patients with cancer are facing gonadotoxic treatments such as chemotherapy or gonadal radiation, which poses a significant threat to their future fertility. Prepubertal males have no option to preserve fertility by traditional sperm cryopreservation; for these patients, the only fertility preservation strategy is cryopreservation of immature testis tissue (ITT). Fertility restoration is increasingly becoming a concern, with the focus shifting toward continuation of care after successful cancer treatment and securing quality of life for childhood cancer survivors who wish to become biologic parents in adulthood. Some centers also offer testis tissue cryopreservation for selected young boys with cryptorchidism who have a high risk of infertility. A growing number of centers worldwide now offer routine cryopreservation of ITT with the aim of advancing spermatogonial stem cell (SSC)–based treatments to a clinical stage to provide opportunities for fertility restoration.
Fertility has a profound impact on our quality of life. Male fertility restoration is currently a dynamically evolving field including a broad range of strategies such as surgical and in vitro approaches to achieve restoration of fertility from prepubertally cryopreserved testis tissue. Meanwhile, the current evidence for fertility restoration strategies has not yet been systematically synthesized, leading to a potential lack of structured research cooperation across different disciplines. Thus, this topic lends itself to a scoping approach to map and assess the extent of the evolving heterogeneous literature and identify gaps in knowledge. This review aimed to examine the current evidence and clinical applicability of the different strategies for fertility restoration using ITT as well as identify future research questions that will accelerate the expected implementation of therapy options in clinical medicine. Furthermore, potential barriers in the development of clinically relevant therapies are identified.
The review was conducted after the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews criteria and previously published guidelines and examined 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.
In vivo strategies, such as testis tissue engraftment and spermatogonial stem cell 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 and embryonic stem cells. 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.
Male fertility restoration is a rapidly transforming field with new evolving technologies and a recent substantial advancement with the first proof-of-principle study of testis tissue engraftment in a human male. A broad range of studies on in vitro and in vivo stem cell–based strategies for male fertility restoration demonstrated significant advancements. However, lack of standardized outcomes and reporting tools, heterogeneous source tissue material, risk of reintroduction of malignant cells, and unresolved challenge of definite identification of SSCs in vitro are still challenging clinical implementation. After assessment of the currently available reports, autologous engraftment of cryopreserved and thawed testis tissue appears to be the most promising strategy for male fertility restoration and is likely close to the first human experimental clinical trials. Testis tissue has been cryopreserved from >3,000 boys aged <18 years worldwide, and it is now a collective task to team up, improve interdisciplinary efforts, and share knowledge across countries for establishing evidence-based robust guidelines for clinical male fertility preservation and restoration.
Source: Elena von Rohden, M.D.,a,b,h Christian Fuglesang S. Jensen, M.D., Ph.D.,a Claus Yding Andersen; Fertil Steril® Vol. 122, No. 5, November 2024 0015-0282 https://doi.org/10.1016/j.fertnstert.2024.07.010
