HORMONAL PROTECTION FROM CYCLOPHOSPHAMIDE-INDUCED INACTIVATION OF RATSTEM SPERMATOGONIA

Studies of protection of testicular function from cyclephosphamide wit h hormonal pretreatment have been limited by the lack of a convenient model for cyclophosphamide-induced inactivation of stem spermatogonia. In the rat, the mortality from cyclephosphamide had prevented the adm inistration of sufficient dosages to produce detectible damage to stem spermatogonia. To overcome this problem, we used bone marrow transpla ntation and sodium 2-mercaptoethanesulfonate (Mesna) treatment to rais e the lethal dose for 50% of the animals (LD(50)) for cyclophosphamide from 275 to > 400 mg/kg body weight. In addition we used irradiation, 2 weeks prior to injection of cyclophosphamide, to greatly enhance th e measured toxicity of cyclophosphamide towards stem spermatogonia. Wh ereas sperm counts at 9 weeks after a 300 mg/kg cyclophosphamide dose were reduced by only a factor of 1.6 without prior irradiation, they w ere reduced by a factor of 60 when 2.5 Gy of irradiation had been give n, Dramatic protection against this toxicity was produced by hormone t reatment with a gonadotropin-releasing hormone (GnRH) antagonist (Nal- Glu) and an antiandrogen (flutamide) following the radiation but prior to cyclophosphamide. This hormone treatment did not modify the stem c ell toxicity of the radiation and it therefore must be protecting stem cells against cyclophosphamide-induced damage. Because GnRH antagonis t-antiandrogen treatment can protect stem spermatogonial survival and/ or function in the rat from cyclophosphamide-induced damage, if the sa me principles are applicable in human, hormonal pretreatment should be useful for preventing the prolonged azoospermia caused by chemotherap y with cyclophosphamide-containing protocols.