Effect of hormone modulations on donor-derived spermatogenesis or colonization after syngeneic and xenotransplantation in mice.

Abstract

Cytotoxic cancer treatments, such as irradiation, can cause permanent sterility in male mammals owing to the loss of spermatogonial stem cells. In animal models, spermatogenesis could be restored from transplanted spermatogonial stem cells. Previously, we showed that transient suppression of FSH, LH, and testosterone in the recipient with a gonadotropin-releasing hormone antagonist (GnRH-ant), given immediately after irradiation, enhanced spermatogenesis from transplanted spermatogonial stem cells in mice and monkeys. To explore improvements in the preparation of the recipient for efficient and reliable spermatogenic recovery from spermatogonial stem cell transplantation, so that it can be used effectively in clinical practice. In mouse recipients, we evaluated the effects of hormone suppression given after germ cell depletion was complete, which is a more clinically relevant model, and also the importance of total androgen ablation and maintenance of FSH levels. Three regimens, GnRH-ant, GnRH-ant plus flutamide (androgen receptor antagonist), and GnRH-ant plus FSH, were administered prior to and around the time of transplantation of testis cells from immature mice or from prepubertal monkeys. Treatment with GnRH-ant resulted in a fourfold increase in spermatogenic recovery from GFP-marked transplanted mouse cells. Total androgen ablation with the addition of flutamide, started two weeks before transplantation, did not further enhance recovery. Surprisingly, FSH supplementation, started around the time of transplantation, actually reduced spermatogenic recovery from transplanted spermatogonial stem cells in GnRH-ant-treated mice. When prepubertal monkey testicular cells were transplanted into nude mice that were given the same hormone treatments, the numbers of donor-derived colonies were independent of hormone treatment. The enhancements in spermatogenic recovery may only occur when syngeneic or closely related donor-recipient pairs are used. These results are useful in further investigations in choosing a hormone suppression regimen in combination with spermatogonial transplantation as a treatment to restore fertility in primates after cytotoxic therapy.