Cytoprotection

Infertility arising from cancer treatment involving serious bystander damage to the testis from cytotoxic drugs and/or irradiation is distinctive since the timing, dose and nature of the testicular damage are clearly defined. This creates unique possibilities for prevention of male infertility through elective sperm cryostorage, germ cell autotransplantation (Schlatt 2002) and cytoprotective strategies to minimise bystander damage to non-target organs such as the testis. Such cytoprotective strategies might be based on physical measures such as temporary tissue cooling or restricting blood flow during drug exposure or on chemicals such as radioresistance drugs (Adams et al. 1976) or hormones that protect against unintended cytotoxic effects.

One of the first approaches proposed to protect the testis was hormonal manipulation to render the testis "quiescent" before and during the administration of the testicular toxin (Morris 1993). The seminal study was the claim that pretreatment with a GnRH analogue reduces cyclophosphamide induced spermatogenic damage in the mouse testis (Glode et al. 1981) together with the belief that prepubertal gonads seemed relatively less damaged by chemotherapy treatment for leukaemia compared with their post-pubertal counterparts. However, infancy is not a quiescent period for the testis (Chemes 2001), the clinical impression of prepubertal protection is illusory (Shalet etal. 1978) and the initial experimental findings were not reproducible (da Cunha etal. 1987), the latter reflecting the known resistance of mice to the GnRH analogue employed (Bex et al. 1982). Nevertheless this concept has prompted many better defined and validated experimental animal models showing promise (Meistrich 1993; Morris 1993) and limitations (Crawford et al. 1998) as well as several clinical studies to test this hypothesis.

However, the available clinical studies (Brennemann et al. 1994; Johnson et al. 1985;Kreusser etal. 1990;Waxman etal. 1987) have not demonstrated that adjuvant GnRH superactive agonists treatment during cancer therapy can promote recovery of spermatogenesis. Nonetheless, these studies were an inadequate test of the hypothesis since (a) superactive GnRH agonists feature an initial boost in, rather than immediate and thorough cessation of, gonadotrophin secretion during the start of cytotoxin exposure which vitiate the hypothesis, (b) only one study was randomised (Waxman etal. 1987) while another was uncontrolled (Johnson etal. 1985) and (c) the follow-up duration was insufficient to define an improvement given the likely timescale of gonadal recovery. Better designed studies of pure GnRH antagonists would be of interest.

Androgens cause feedback suppression of gonadotrophins and are relatively inexpensive, but are considered impractical as a cytoprotective strategy since their onset of action is too slow to be effective given the imperatives of life-saving cancer treatment which cannot be delayed. Nevertheless, a recent randomised controlled pilot study reported that androgen administration commencing well before and continuing during cyclophosphamide therapy for nephrotic syndrome could speed recovery of spermatogenesis (Masala et al. 1997). However, this potentially important finding warrants cautious interpretation since it was a small study of a single agent cytotoxic drug treatment, which could be delayed. Whether an androgen-based cytoprotective regimen is feasible or effective for the more frequent and intensive combination chemotherapy used for cancer treatment remains unclear.

Meistrich has recently developed an important novel hypothesis regarding the mechanism of the often very slow rate of recovery of spermatogenesis following cytotoxic damage. Noting that stem cells often survive but their differentiation is blocked, he has shown experimentally that high intratesticular testosterone inhibits spermatogonial replication and differentiation. This suggests that a new approach to enhancing recovery from cancer treatment-related spermatogenic damage may be to temporarily depress intratesticular testosterone by the use of GnRH analogs (Shetty etal. 2000) or other methods. This interesting but paradoxical claim could provide the basis for a novel and feasible treatment to accelerate recovery of spermatogenesis, although a recent small uncontrolled clinical trial has failed to demonstrate faster recovery (Thomson et al. 2002). Evaluation of this hypothesis in well controlled trials is warranted.

Ultimately long-term studies comparing cytoprotection regimens for efficacy, safety and cost-effectiveness compared with standard sperm cryopreservation (Kelleher et al. 2001) with or without artificial reproductive technologies will be needed. Potential cytoprotective regimens based on pure GnRH antagonists, with their immediate and complete gonadotrophin suppression, warrant clinical trials. The development of experimental germ cell transplantation to re-establish sper-matogenesis in rodents (Brinster and Zimmermann 1994) allowing the restoration of genetic paternity (Brinster and Avarbock 1994) introduces a new and potentially important method of preserving fertility by germ cell autotransplantation in these men (Schlatt 2002). Nuclear transfer cloning may have an unusually acceptable niche if developed for germ cell autotransplantation if the appropriate methodologies are developed.

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