Extended intervention time and evaluation of sperm suppression by dienogest plus testosterone undecanoate in male rat

摘要

Background: The potential of using dienogest [DNG, 40 mg/kg body weight (bw)] plus testosterone undecanoate (TU, 25 mg/kg bw) in rats for development of a once-a-month male hormonal contraceptive has been reported earlier in our laboratories. Study Design: In the present study, we report a separate efficacy evaluation of the same combination, DNG (40 mg/kg bw) and TU (25 mg/kg bw) in which interval of drug administration has been extended further to 45 and 60 days instead of every 30 days. Results: Complete sperm suppression was observed in rats sacrificed either 60 or 90 days after DNG+TU administration, for two injections at 45-day interval. The neutral α-glucosidase activity in these treated rats remained in the normal range. Germ cell loss due to apoptosis was frequently observed both after 60 or 90 days of combination treatment. Significant decline in serum gonadotropin and testosterone, both serum and intratesticular levels, were observed in the treated rats. Following stoppage of treatment (given at 45-day interval) after two (0 and 45 days) or three injections (0, 45 and 90 days), complete restoration of spermatogenesis was observed by 120 and 165 days, respectively. The sperm suppression, however, could not be sustained when the period of combined drug administration was extended from every 45 to 60 days. Conclusions: Dienogest plus testosterone undecanoate in the above doses retained contraceptive effectiveness when administered every 45 days but not 60 days. The spermatogenic arrest was completely reversible once drug treatment is stopped. The dose and the frequency of intervention can be extrapolated in future clinical trials.