Hormonal Suppression Restores Fertility in Irradiated Mice from both Endogenous and Donor-Derived Stem Spermatogonia

Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Toxicological Sciences (Impact Factor: 3.85). 09/2010; 117(1):225-37. DOI: 10.1093/toxsci/kfq191
Source: PubMed


Irradiation interrupts spermatogenesis and causes prolonged sterility in male mammals. Hormonal suppression treatment with gonadotropin-releasing hormone (GnRH) analogues has restored spermatogenesis in irradiated rats, but similar attempts were unsuccessful in irradiated mice, monkeys, and humans. In this study, we tested a stronger hormonal suppression regimen (the GnRH antagonist, acyline, and plus flutamide) for efficacy both in restoring endogenous spermatogenesis and in enhancing colonization of transplanted stem spermatogonia in mouse testes irradiated with a total doses between 10.5 and 13.5 Gy. A 4-week hormonal suppression treatment, given immediately after irradiation, increased endogenous spermatogenic recovery 1.5-fold, and 11-week hormonal suppression produced twofold increases compared with sham-treated irradiated controls. Furthermore, 10-week hormonal suppression restored fertility from endogenous surviving spermatogonial stem cells in 90% of 10.5-Gy irradiated mice, whereas only 10% were fertile without hormonal suppression. Four- and 11-week hormonal suppression also enhanced spermatogenic development from transplanted stem spermatogonia in irradiated recipient mice, by 3.1- and 4.8-fold, respectively, compared with those not given hormonal treatment. Moreover, the 10-week hormonal suppression regimen, but not a sham treatment, restored fertility of some 13.5-Gy irradiated recipient mice from donor-derived spermatogonial stem cells. This is the first report of hormonal suppression inducing recovery of endogenous spermatogenesis and fertility in a mouse model treated with anticancer agents. The combination of spermatogonial transplantation with hormonal suppression should be investigated as a treatment to restore fertility in young men after cytotoxic cancer therapy.

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    • "The suggestion that pre‐pubertal boys were less sensitive to the effects of chemotherapy (Schalet, 1981) led to the use of gonadotrophin releasing hormone (GnRH) analogues prior to chemotherapy. While this possible method for protecting the testis from the effects of both chemotherapy and irradiation is still used today (Wang et al., 2010), it remains controversial. GnRH analogues are also commonly used in the control of prostate cancer, often administered in depot form, with the side‐effect of azoospermia. "
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