Abstract
BackgroundThe lifesaving chemotherapy and radiation treatments that allow patients to survive cancer can also result in a lifetime of side-effects, including male infertility. Infertility in male cancer survivors is thought to primarily result from killing of the spermatogonial stem cells (SSCs) responsible for producing spermatozoa since SSCs turn over slowly and are thereby sensitive to antineoplastic therapies. We previously demonstrated that the cytokine granulocyte colony-stimulating factor (G-CSF) can preserve spermatogenesis after alkylating chemotherapy (busulfan).MethodsMale mice were treated with G-CSF or controls before and/or after sterilizing busulfan treatment and evaluated immediately or 10–19 weeks later for effects on spermatogenesis.ResultsWe demonstrated that the protective effect of G-CSF on spermatogenesis was stable for at least 19 weeks after chemotherapy, nearly twice as long as previously shown. Further, G-CSF treatment enhanced spermatogenic measures 10 weeks after treatment in the absence of a cytotoxic insult, suggesting G-CSF acts as a mitogen in steady-state spermatogenesis. In agreement with this conclusion, G-CSF treatment for 3 days before busulfan treatment exacerbated the loss of spermatogenesis observed with G-CSF alone. Reciprocally, spermatogenic recovery was modestly enhanced in mice treated with G-CSF for 4 days after busulfan. These results suggested that G-CSF promoted spermatogonial proliferation, leading to enhanced spermatogenic regeneration from surviving SSCs. Similarly, there was a significant increase in proportion of PLZF+ undifferentiated spermatogonia that were Ki67+ (proliferating) 1 day after G-CSF treatment.ConclusionsTogether, these results clarify that G-CSF protects spermatogenesis after alkylating chemotherapy by stimulating proliferation of surviving spermatogonia, and indicate it may be useful as a retrospective fertility-restoring treatment.
Highlights
The lifesaving chemotherapy and radiation treatments that allow patients to survive cancer can result in a lifetime of side-effects, including male infertility
We previously identified a completely non-invasive approach to preserving male fertility after cancer treatment, using injections of the cytokine granulocyte colony-stimulating factor (G-CSF), which would obviate the need for the invasive techniques currently under development
In our first experiment (Experiment 1, Fig. 1), male mice were separated into three groups, vehicle-treated “Control”, “Busulfan Only” (44 mg/kg), and “Busulfan + GCSF” animals which received G-CSF (50ug/kg/day) in addition to busulfan and all were allowed to recover until 19 weeks transpired (Fig. 1)
Summary
The lifesaving chemotherapy and radiation treatments that allow patients to survive cancer can result in a lifetime of side-effects, including male infertility. As a result of this clinical need for fertility preservation strategies in pre-pubertal cancer patients, a number of experimental approaches have been under intense development [10,11,12,13,14,15,16], and to preserve fertility of pre-pubertal boys Inherent to these strategies, are risks associated with invasive surgical testicular tissue retrieval, including anesthesia, infection and delays to primary disease therapy, which remain major concerns that drive the risk-benefit ratio in favor of no intervention and likelihood of permanent infertility. We previously identified a completely non-invasive approach to preserving male fertility after cancer treatment, using injections of the cytokine granulocyte colony-stimulating factor (G-CSF), which would obviate the need for the invasive techniques currently under development. GCSF treatment to protect spermatogenesis from cancer treatments has the potential to revolutionize male fertility preservation in a manner that can be rapidly translated to the clinic because various forms of G-CSF are already FDA-approved (e.g., filgrastim: Neupogen® Amgen, Granix® - Teva, Zarxio® - Novartis)
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