Exposure of men to gonadotoxic cancer therapeutic agents can severely impair spermatogenesis. Many of the radiotherapeutic and chemotherapeutic regimens may result in complete killing of the stem spermatogonia without a chance for endogenous restoration of spermatogenesis. In such cases cryopreservation of spermatogonia and autologous transplantation is the only a potential method for restoring spermatogenesis and possibly rescuing fertility. Although one study indicated that autologous germ cells transplantation might be successful in monkeys, the frequency was low and results did not confirm that the spermatogenic recovery was from transplanted spermatogonia. Improvement of this technique is required to facilitate spermatogenic recovery from the transplanted stem spermatogonia, especially considering the potential adverse effects of cytotoxicants on testis. Previously we demonstrated that in rats testicular irradiation damages the somatic environment resulting in a block in the differentiation of radio-resistant stem spermatogonia, which can be ameliorated by suppression of testosterone and FSH. However, in monkeys such hormone suppression treatment after irradiation was not successful in enhancing differentiation of the few surviving, more radiosensitive endogenous spermatogonia. Nonetheless, we also observed that hormone suppression restores the ability of somatic compartment to facilitate the colonization and differentiation of transplanted normal stem spermatogonia in irradiated recipient rat and mouse testis. Thus spermatogonial transplantation in combination with hormone suppression gives a new option for the preservation of the spermatogonia and restoration of the somatic environment of irradiated testes, which can be combined in monkeys in our approach to fertility preservation. We propose that hormonal suppression in combination with spermatogonial transplantation can be a method to restore fertility in patients who are exposed to high doses of gonadotoxicants that could kill all the germ cells. Using the monkey as a primate model, we will test our hypothesis that testosterone and FSH suppression can facilitate colonization and differentiation of autologously transplanted stem spermatogonia in irradiated monkeys. We will autologously transplant the green fluorescent protein (GFP)--marked cryopreserved germ cells back to the respective monkeys after depletion of endogenous germ cells by testicular irradiation. We will then test whether GnRH-antagonist treatment in some of these monkeys given before the transplantation, starting immediately after irradiation, enhances the colonization/differentiation of transplanted spermatogonia. If our hypothesis is correct, it will suggest the feasibility of similar procedures for the restoration of fertility in young men and childhood cancer survivors.
A significant number of childhood cancer survivors and young men are at risk of sterility due to the loss of spermatogenic cells after cancer treatment. At present there are no options to preserve fertility that can be offered to prepubertal boys who have an enriched population of stem spermatogonia, but cannot have chance for preserving their sperm for later use. Cryopreservation of spermatogonial stem cells before start of the cancer therapy followed by autologous intratesticular transplantation of these stem cells after cure is a hypothetical option that has been demonstrated in rodent models. If our hypothesis that pretreatment with GnRH antagonist stimulates differentiation of autologously derived transplanted spermatogonia in the irradiated monkey testis is correct, it will suggest the feasibility of similar procedures for the restoration of spermatogenesis and fertility in male childhood and young cancer survivors.
| Shetty, G; Uthamanthil, R K; Zhou, W et al. (2013) Hormone suppression with GnRH antagonist promotes spermatogenic recovery from transplanted spermatogonial stem cells in irradiated cynomolgus monkeys. Andrology 1:886-98 |
