Rapid protection of rat spermatogenic stem cells against procarbazine by treatment with a gonadotropin-releasing hormone antagonist (Nal-Glu) and an antiandrogen (flutamide)

Abstract

GnRH antagonist (Nal-Glu) treatment combined with the antiandrogen flutamide was used to suppress rat spermatogenesis to achieve protection of spermatogonial stem cells against the anticancer drug procarbazine. Daily injections with Nal-Glu alone suppressed spermatogenesis in a dose-responsive manner. However, it was necessary to combine Nal-Glu (600 micrograms/kg.day) with flutamide at 20 mg/kg.day to decrease testicular weight in 2 weeks to less than 0.6 g, a level previously demonstrated sufficient to protect stem cells in our model system. The Nal-Glu-flutamide pretreatment suppressed serum gonadotropin levels and intratesticular testosterone levels (6% of control) and action, resulting in a reversible decrease in the number of late spermatids to 1% of control levels. When rats were given Nal-Glu-flutamide for 2 weeks before a 250 mg/kg dose of procarbazine, recovery of spermatogenesis, as measured by testis weight, testicular sperm head counts, and repopulation indexes, was significantly better than in control rats (no hormonal pretreatment). The protection achieved with Nal-Glu-flutamide was better than that achieved with 2 weeks of testosterone and estradiol treatment. The present results show that Nal-Glu-flutamide protects spermatogonial stem cells against procarbazine and suggest a method of hormonal pretreatment to achieve rapid and efficient protection of spermatogenesis in humans.