Recovery of Spermatogenesis after Irradiation or Chemotherapy.

Cytotoxic damage to the testis by radiation and chemotherapy primarily kills the most sensitive cells, the rapidly proliferating differentiating spermatogonia, but stem spermatogonia are also damaged and undergo either immediate or delayed cell loss. The surviving stem cells then change from their steady-state self-renewal pattern to enhance recovery processes, likely in response to altered signaling from the somatic environment constituting the niche. At this point the stem cells increase proliferation and self-renewal and their differentiation and cell loss processes are altered. Although the kinetics of recovery varies greatly between mice, rats, macaques, and humans, it is gradual in all species. Recovery kinetics in a given species often seem to occur in parallel after irradiation or treatment with gonadotoxic chemotherapy drugs. Three aspects of the recovery process need to be considered for tissue homeostasis; (1) the recovery of surviving stem cell numbers, (2) the initiation of their differentiation process, and (3) their ability to produce mature germ cells including the spermatozoa. In mice and rats the stem spermatogonia initiate self-renewal within 2 weeks after cytotoxic injury and their number gradually recovers to a maximum level over a 5-month period. In contrast in monkeys and humans, after irradiation there is a progressive decline in the numbers of putative stem cells, the type A spermatogonia, over a period of 2-4 months, then followed by subsequent increases in numbers. Complete recovery of stem cell numbers may be possible after low doses of cytotoxicants but not after higher doses. The species markedly differ with respect to the reinitiation of spermatogonial differentiation. In mice, differentiating cells are observed as soon as 1 week after cytotoxic treatment, but in rats this appears to be more delayed, and in some strains there is an absolute and permanent block in spermatogonial differentiation even at modest doses radiation. In humans, but not monkeys, there is a transient suppression of spermatogonial differentiation, lasting about 4 months, but then it proceeds. Finally in rodents and monkeys where quantitative and histological studies have been performed, higher doses of cytotoxic injury result in a decreased ability of the tissue to support complete differentiation of developing germ cells to post-meiotic stages and result in a permanent decrease in sperm counts. In humans however, many patients, who do recover sperm counts after cancer therapy, recover to their pretreatment range but occasional patients remain severely oligospermic. Failure of recovery appears to be due at least in part to damage to the somatic environment, as we have demonstrated with reciprocal transplantation experiments that irradiated rat testes were not capable of supporting differentiation of normal spermatogonia but the spermatogonia from these irradiated rats normally colonized and differentiated in nude mouse testes. This highlights the importance of assessing somatically derived factors known to influence the self-renewal of spermatogonial stem cells (e.g. GDNF, FGF2, CSF1, IGF-I) and the differentiation of spermatogonia (Neuregulin 1, BMP4, activin A, retinoids) in these models attempting recovery of stem cell number and maintaining spermatogenic cell differentiation to achieve homeostasis of the seminiferous epithelium after cytotoxic injury. (Research supported by NIH ES008075 to MLM and HD061301to GS)