Objective: To study the optimized regimen and antifertility effect of oral administration of low-dose gossypol acetic acid (GA) combined with testosterone undecanoate (TU), desogestral (DSG) and ethinyl estradiol (EE) for contraception in males. Methods: Adult male Wistar rats were randomly divided into 6 groups. Rats in the combined treatment group (LGAH-GA) were administered daily with low-dose of GA (15 mg · kg-1 · d-1 ) plus TU, DSG and EE as loading dose for 7 weeks, followed by a single low-dose GA of 12.5 mg · kg-1 · d-1 from week 8 of treatment for another 17 weeks as a maintenance dose to sustain the infertility. Rat in the combined treatment group (LGAH) were treated with lower-dose of GA (12.5 mg · kg-1 · d-1 ) plus TU, DSG and EE for 7 weeks. Rats in the low-dose gossypol group (LGA) were treated with GA (15 mg · kg-1 · d-1 ) for 24 weeks. Rats in the high-dose gossypol group were treated with GA (30 mg · kg-1 · d-1 ) for 7 weeks. Rats in the hormone group were treated with TU (100 mg · kg-1 · day-1 ,EE and DSG for 14 weeks. Rats in the control group were treated daily with an equal volume of 1% methylcellulose for 24 weeks. Fertility test was used for determining infertility or restoration of fertility in treated rats. Histology examinations were used to examine the alteration on morphology of sperm, testis, epididymides of treated rats. Results: The rats from LGA-A group were completely infertile at week 6 after treatment, and the fulfilled infertility was maintained with single GA (12. 5 mg/kg) only daily after one more week of consolidation treatment with simultaneous administration of low-dose of GA and TU, DSG and EE. Eight weeks after cessation of treatment, all of the treated male rats regained their fertility. The low-dose of GA and TU combined dosage regimen could damage morphology, motility and density of mature sperm, induce infertility within 6 weeks in rats, and rendered treated male rats with spermiation failure within a period of 6-24 weeks of treatment. Conclusion : Oral administration of low dose GA (15 mg · kg-1 · d-1 ) combined with TU, DSG and micro-dose of EE as loading dose could successfully induce infertility in the short term (within 6 weeks). The efficacy could be maintained by a lower dose of GA (12.5 mg · kg 1 · d-1 ) alone in the long term after one extra week of consolidation treatment, and the fertility could recover within a short term after cessation of treatment. The optimized combined regimen provides a promising approach to the development of an effective, reversible, safe and rapid oral male contraceptive.%目的:探索低剂量醋酸棉酚(GA)联合十一酸睾丸酮(TU)、去氧孕烯( DSG)和微量炔雌醇(EE)可逆抗雄性生育作用效果和优化组方.方法:成年雄性Wistar大鼠分为联合用药7周+GA组、联合用药7周组、低剂量GA组、高剂量GA组、激素组和对照组.采用交配试验、组织学形态测定分析法、病理学等方法检测服药雄性大鼠生育能力、附睾精子和睾丸的组织学改变.结果:雄性大鼠联合用药7周+GA组服药6周,不育率达100%,大鼠附睾内长形精子数量减少,90%精子头尾断裂、活力丧失;第8周开始停用激素单独以低剂量GA(12.5 mg·kg-1·d-1)可继续维持抗生育效果17周;停药第8周雄鼠全部恢复生育.结论:口服低剂量GA(15mg· kg-1·d-1为起效剂量,12. 5mg· kg-1·d-1为维持剂量)联合TU (100 mg· kg-1·d-1)、DSG(0.125mg· kg-1·d-1)和微量EE(0. 025 mg·kg-1·d-1),通过严重损伤成熟精子、影响精子形成过程和诱导精子延迟释放发挥避孕效应,抗雄性生育作用起效时间短、效果好、可逆、安全,是优化的低剂量GA联合甾体激素男用避孕药实验用药方案.
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