HORMONAL PROTECTION FROM PROCARBAZINE-INDUCED TESTICULAR DAMAGE IS SELECTIVE FOR SURVIVAL AND RECOVERY OF STEM SPERMATOGONIA

Procarbazine produces long-term sterility in the male by killing stem spermatogonia. The degree and selectivity of protection of stem sperma togonia in rats from procarbazine by pretreatment with steroid hormone s were investigated. Male LBNF(1) rats were treated for 6 weeks with S ilastic implants containing testosterone plus 17 beta-estradiol. The h ormone-treated rats and sham-treated controls were given a single inje ction of graded doses of procarbazine and the hormone implants were re moved the next day. Spermatogonial stem cell survival and function, as sessed by the repopulation indices and sperm head counts 10 weeks late r, showed that stem spermatogonia were protected by testosterone plus 17 beta-estradiol treatment from tile toxic effects of procarbazine wi th a dose-modifying protection factor of about 2.5. In contrast, there was no hormonal protection from the procarbazine-induced killing of d ifferentiating spermatogonia, preleptotene spermatocytes, and spermato cytes in meiotic prophase or from the delay in maturation of round spe rmatids, assessed 9 days after procarbazine injection by histological or flow cytometric methods. In addition, there was no hormonal protect ion from the procarbazine-induced decline in body weights and lymphocy te counts, indicating that the gastrointestinal, neurological, and hem atological systems were not protected. The specificity of protection i ndicates that the hormonal protection of the stem spermatogonia is not the result of a systemic or overall testicular decrease in drug deliv ery, decrease in bioactivation, nor increase in drug detoxification, e xcept possibly within the stem cells themselves. We conclude that the degree of hormonal protection and its specificity would be appropriate for clinical application provided that the mechanism of protection is elucidated and appears applicable to humans.