Fertility preservation in boys: recent developments and new insights †

Abstract

BACKGROUND Infertility is an important side effect of treatments used for cancer and other non-malignant conditions in males. This may be due to the loss of spermatogonial stem cells (SSCs) and/or altered functionality of testicular somatic cells (e.g. Sertoli cells, Leydig cells). Whereas sperm cryopreservation is the first-line procedure to preserve fertility in post-pubertal males, this option does not exist for prepubertal boys. For patients unable to produce sperm and at high risk of losing their fertility, testicular tissue freezing is now proposed as an alternative experimental option to safeguard their fertility. OBJECTIVE AND RATIONALE With this review, we aim to provide an update on clinical practices and experimental methods, as well as to describe patient management inclusion strategies used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss. SEARCH METHODS Based on the expertise of the participating centres and a literature search of the progress in clinical practices, patient management strategies and experimental methods used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss were identified. In addition, a survey was conducted amongst European and North American centres/networks that have published papers on their testicular tissue banking activity. OUTCOMES Since the first publication on murine SSC transplantation in 1994, remarkable progress has been made towards clinical application: cryopreservation protocols for testicular tissue have been developed in animal models and are now offered to patients in clinics as a still experimental procedure. Transplantation methods have been adapted for human testis, and the efficiency and safety of the technique are being evaluated in mouse and primate models. However, important practical, medical and ethical issues must be resolved before fertility restoration can be applied in the clinic.Since the previous survey conducted in 2012, the implementation of testicular tissue cryopreservation as a means to preserve the fertility of prepubertal boys has increased. Data have been collected from 24 co-ordinating centres worldwide, which are actively offering testis tissue cryobanking to safeguard the future fertility of boys. More than 1033 young patients (age range 3 months to 18 years) have already undergone testicular tissue retrieval and storage for fertility preservation. LIMITATIONS, REASONS FOR CAUTION The review does not include the data of all reproductive centres worldwide. Other centres might be offering testicular tissue cryopreservation. Therefore, the numbers might be not representative for the entire field in reproductive medicine and biology worldwide. The key ethical issue regarding fertility preservation in prepubertal boys remains the experimental nature of the intervention. WIDER IMPLICATIONS The revised procedures can be implemented by the multi-disciplinary teams offering and/or developing treatment strategies to preserve the fertility of prepubertal boys who have a high risk of fertility loss. STUDY FUNDING/COMPETING INTEREST(S) The work was funded by ESHRE. None of the authors has a conflict of interest.

Fertility Preservation for Prepubertal Patients at Risk of Infertility: Present Status and Future Perspectives

“…Thus, cryopreservation of sperm should be considered when testicular volume is above 10-12 mL. Current strategies to preserve fertility in prepubertal boys center around the cryopreservation of testicular material [72]. However, the success of this approach to restore subsequent fertility is dependent on the preservation of germ cells with stem cell capability within the cryopreserved tissue.…”

“…As such, continued stratification of fertility risks based on underlying diagnoses and treatment is necessary to validate and, if necessary, adapt patient selection criteria to avoid unnecessary surgery in those who would subsequently retain natural fertility. This could be achieved through multicenter follow-up studies employing standardized protocols [72]. Despite an increasing number of centers worldwide offering storage of testis tissue, strategies for the subsequent generation of viable sperm, including autologous testicular tissue grafting, spermatogonial stem cells (SSC) transplantation, and in vitro spermatogenesis, remain experimental.…”

Unique metabolic phenotype and its transition during maturation of juvenile male germ cells

“…The isolation, expansion, and transplantation of spermatogonia could present an option to restore fertility. 9,10,[17][18][19][20][21][22] Preservation of fertility will require large numbers of matured stem cells for efficient neospermatogenesis. Therefore, a thorough understanding of immature germ cell maturational processes is essential to facilitate the in vitro maintenance and propagation of functional stem cells.…”

ITGA6+ Human Testicular Cell Populations Acquire a Mesenchymal Rather than Germ Cell Transcriptional Signature during Long-Term Culture

“…Although mature sperm cells are absent in young patients, a functional pool of SSCs is present from birth. Autotransplantation of SSCs into the testis has been suggested as a novel fertility restoration approach to restore sperm production in sterile male survivors of cancer or hematological diseases during childhood [ 5 , 6 , 7 , 8 ]. More specifically, this technique involves isolation of SSCs from a cryopreserved testicular biopsy that was taken prior to treatment, expansion of SSCs in vitro and autotransplantation of SSCs (SSCT) after successful treatment when sterility has manifested in the patient [ 9 ].…”