Future developments in fertility preservation in males

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Although the cryopreservation of ejaculated (or surgically recovered) mature spermatozoa remains the mainstay of fertility preservation in males, there are a number of areas of current research which, if successful, could revolutionize fertility preservation.

The first is based on an approach to try and actually prevent the death or damage to the population of stem (sperm-producing) cells in the testis that typically occurs following exposure to radiation or alkylating agents (see above). Following a number of experimental observations in rats, it has been suggested that this might be possible by altering the endocrine environment (essentially suppressing the production of testosterone and follicle stimulating hormone or FSH) of the patient either before or after the onset of treatment (Meistrich and Shetty 2003). However, although this strategy can restore some sperm production in the rat, it is not yet known whether it can be adapted for human clinical application. Encouraging results from a small study of 15 patients with nephritic syndrome3 (being treated with the chemotherapy drug cyclophosphamide) have been obtained (Masala et al. 1997). More recent experiments in non-human primates (Boekelheide etal. 2005) have, however, been unable to reproduce the experimental results obtained in rats, raising the possibility that there are important species-specific differences in the testicular response either to the treatment (in this case radiotherapy) or the endocrine rescue protocol, or both. As an approach, therefore, the use of endocrine manipulation to protect the testis from damage (or salvage them from it) is still very much experimental.

A second area of research activity is in the area of spermatogonial transplantation. Unlike the current approach of freezing mature ejaculated sperm, many authors have commented on the desirability of being able to remove (before treatment) and potentially replace (after treatment) a population of the stem (sperm-producing) cells (called spermatogonia) within the testis that ultimately give rise to sperm. The advantage of being able to do this is that, unlike frozen sperm that are a finite resource, stem cells in the testis are 'self-renewing'. As such, if they could be successfully transplanted back into the patient, then they could continue to produce sperm for the rest of his life. Even if this was only moderately successful, then it could potentially provide sufficient (freshly ejaculated) sperm for use in repeated cycles of assisted conception. If very successful, and ejaculates were near normal in terms of quality, then it is possible to envisage some patients being able to father a child quite normally and without further assistance.

Although the concept of spermatogonial transplantation remained theoretical for many years, major progress was made when Brinster and Zimmermann (1994) published details of experiments in mice where they had successfully removed spermatogonia from one individual and transplanted it back into the testes ofanother animal. This provided proofofconcept that the technique was feasible, and, in subsequent years, the underlying technology for retrieval, storage, genetic manipulation (important for animal breeding purposes) and transplantation were developed (see Johnson, Russell and Griswold 2000). In progressing to human clinical trials scientists have been notably cautious. Although some small-scale trials have been attempted (Radford, Shalet and Lieberman 1999), at the time ofwriting the results have not yet been published.

A major concern with this approach, however, is the fear that in oncology patients in particular, the process of transplantation could lead to the re-introduction of malignant cells into the patient who was otherwise cured of his original disease. It has been suggested that this is particularly pertinent for lymphoma and leukaemia patients as in these diseases the testis is a likely organ for the settlement of metastasizing cells (Schlatt 2002) as has been shown experimentally in leukaemic rats (Jahnukainen et al. 2001). This could be potentially avoided if it were possible to develop suitable technologies by which the process of spermatogenesis could occur in vitro.

The prospects for spermatogenesis in vitro have recently been reviewed by Parks etal. (2003) who outline the technical complexity of cell culture systems that would be required to maintain the development of spermatozoa in vitro. Although some progress in animal models has been made (in as much as presumptive spermatids [i.e. early sperm cells] expressing appropriate genetic markers have been identified and have been injected into eggs to produce viable embryos), it is far from the stage of being clinically useful for human applications. However, an area with perhaps more technical promise is in the development of techniques to transplant pieces of testicular material (termed explants) into 'host' animals that then act to support the sperm production process. Proof that this can work has come from a number of experimental approaches (reviewed in Parks etal. 2003) dating back to the 1970s and interestingly it seems as though spermatogenesis can be supported even when testicular explants are transplanted to various extra-testicular sites. More recently Honaramooz etal. (2002) were able to show that this technique could be used to initiate spermatogenesis in pre-pubertal testicular tissue, which could give hope for fertility preservation in pre-pubertal boys where sperm banking is not possible (see above). However, it should be recognized that this type of xenotransplantation may raise many ethical issues in some individuals, and there are obvious safety concerns to address about the potential for non-human DNA (or animal viruses) being transferred to the fertilized egg during the assisted conception procedure. Much work is therefore needed until the safety and acceptability of this approach can be demonstrated.

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