Misro Man M, Chaki Shankar P, Kaushik Mahesh C, Nandan Deoki
Department of Reproductive Biomedicine, National Institute of Health and Family Welfare, New Delhi, India.
Contraception. 2009 Jun;79(6):488-97. doi: 10.1016/j.contraception.2009.01.003. Epub 2009 Feb 28.
The study was conducted to test the potential of using dienogest (DNG) plus testosterone undecanoate (TU) in rats for development of a once-a-month injectable male hormonal contraceptive.
Dose selection studies were initiated with administration of DNG in three different doses of 20, 30 and 40 mg/kg body weight (bw) per week plus TU 25 mg/kg bw once in every 6 weeks. Status of spermatogenesis and sperm count in epididymis was evaluated. The frequency of DNG intervention was later extended to every 2- and 4-week intervals. Mating studies, toxicity and reversibility of spermatogenesis following stoppage of treatment were carried out with DNG 40 mg/kg bw at 4-week intervals.
Complete arrest of spermatogenesis was observed after 60 days of treatment at all doses of DNG (20, 30 and 40 mg/kg bw per week)+TU. However, weights of testis and accessory sex organs (epididymis, prostate and seminal vesicle) declined significantly 60 days post treatment compared to vehicle-treated controls. Epididymis in the treated animals was completely devoid of sperm. When the frequency of DNG injection (20 mg/kg bw) was extended to once every 15 days, a few immotile and decapitated sperm were observed in the epididymis. With TU treatment unchanged, animals receiving DNG (40 mg/kg bw) once either every 2- or 4-week intervals demonstrated good and uniform arrest of spermatogenesis. DNG 40 mg/kg per 4 weeks+TU also demonstrated a significant rise in germ cell apoptosis in the seminiferous epithelium. There was no significant increase in the serum high-density lipoprotein and low-density lipoprotein levels at the end of 120 days of treatment. Following withdrawal of treatment after 60 or 120 days, qualitative restoration of spermatogenesis was rapid in the former compared to the latter.
Dienogest plus TU has the potential for development as a monthly injectable showing reversible hormonal male contraception with good efficacy.
本研究旨在测试在大鼠中使用地诺孕素（DNG）加十一酸睾酮（TU）开发每月注射一次的男性激素避孕药的潜力。
开始进行剂量选择研究，每周给予三种不同剂量（20、30和40毫克/千克体重）的DNG加每6周一次25毫克/千克体重的TU。评估精子发生状态和附睾中的精子数量。随后将DNG干预频率延长至每2周和4周一次。以4周的间隔对40毫克/千克体重的DNG进行交配研究、毒性研究以及治疗停止后精子发生的可逆性研究。
在所有剂量的DNG（每周20、30和40毫克/千克体重）加TU治疗60天后，观察到精子发生完全停滞。然而，与赋形剂处理的对照组相比，治疗后60天睾丸和附属生殖器官（附睾、前列腺和精囊）的重量显著下降。治疗动物的附睾中完全没有精子。当DNG注射频率（20毫克/千克体重）延长至每15天一次时，在附睾中观察到一些不动和断头的精子。在TU治疗不变的情况下，每2周或4周接受一次DNG（40毫克/千克体重）的动物表现出良好且一致的精子发生停滞。每4周40毫克/千克的DNG加TU也显示生精上皮中的生殖细胞凋亡显著增加。治疗120天后血清高密度脂蛋白和低密度脂蛋白水平没有显著增加。在60天或120天后停止治疗后，前者的精子发生定性恢复比后者更快。
地诺孕素加TU有潜力开发成为一种每月注射一次的可逆性高效男性激素避孕药。
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