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 spermatogonia in rats from procarbazine by pretreatment with steroid hormones were investigated. Male LBNF1 rats were treated for 6 weeks with Silastic implants containing testosterone plus 17 beta-estradiol. The hormone-treated rats and sham-treated controls were given a single injection of graded doses of procarbazine and the hormone implants were removed the next day. Spermatogonial stem cell survival and function, assessed by the repopulation indices and sperm head counts 10 weeks later, showed that stem spermatogonia were protected by testosterone plus 17 beta-estradiol treatment from the toxic effects of procarbazine with a dose-modifying protection factor of about 2.5. In contrast, there was no hormonal protection from the procarbazine-induced killing of differentiating spermatogonia, preleptotene spermatocytes, and spermatocytes in meiotic prophase or from the delay in maturation of round spermatids, assessed 9 days after procarbazine injection by histological or flow cytometric methods. In addition, there was no hormonal protection from the procarbazine-induced decline in body weights and lymphocyte counts, indicating that the gastrointestinal, neurological, and hematological systems were not protected. The specificity of protection indicates that the hormonal protection of the stem spermatogonia is not the result of a systemic or overall testicular decrease in drug delivery, decrease in bioactivation, nor increase in drug detoxification, except 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.