Development of a Hormonal Male Contraceptive With Health Benefits: Safety, Effic

项目总结(见说明)： 专有的雄激素，7a-甲基-19-去甲睾酮(ment�)与DMPA孕激素联合使用，正在进行男性避孕研究。他汀类药物在抑制促性腺激素和维持肌肉质量方面比睾酮(T)有效10倍。因此，通过硅胶植入物可以有效地抑制促性腺激素和精子发生。此外, 根据体外和动物研究的结果，Mment将对前列腺、骨骼和肌肉质量以及髓鞘再生具有潜在的健康益处。例如，(1)它抵抗5a-还原，因此在相同的替代剂量下，它对前列腺的刺激作用较小；(2)它被芳香化成一种有效的雌激素，从而维持动物和男人的性行为；(3)它不与性激素结合。 结合球蛋白(SHBG)，并具有与T相似的药代动力学；以及(4)最近被证明可增加神经细胞的再髓鞘形成(M.Schumacher，未发表)。因此，男性长期服用长效避孕药预期优于服用避孕药，对健康有额外的益处。第一代外源性治疗方案 在男性避孕临床试验中，使用睾酮注射剂、凝胶或可生物降解颗粒或醋酸酯硅橡胶植入物的效果有限。第二代方案使用雄激素与孕激素联合使用，如左旋诺孕酮、雌酮雌激素或DMPA，显示出更高的抑制精子发生的效果。在这项研究项目中，我们将使用三种植入物(释放~1500pg/天的植入物)的方案，结合开始时单次注射DMPA或每隔3个月多次注射。AC植入物将被制造出来，临床试验将在下一个资金周期内开始(等待批准)。此外，还将进行药理学和机械学研究，以确定使用甲硝唑和二甲基苯丙胺的安全和健康益处。乙二醇乙酯是乙酸甲酯的乙酰化衍生物，用于植入物制造以获得最佳释放率。由于从植入物中释放出的Ac迅速被分解为活性At，因此Ac和Ac可以交替使用。Depo Provera(DMPA，辉瑞)注射剂是一种获得批准的女性避孕药，目前正在进行男性避孕研究。Depo Provera释放一种活性孕激素，即醋酸甲羟孕酮(MPA)。甲孕酮将用于动物和体外研究。

PROJECT SUMMARY (See instructions): The proprietary androgen, 7a-methyl-19-nortestosterone (MENT�) in combination with DMPA progestin is being investigated for male contraception. MENT is 10 fold more effective than testosterone (T) in suppressing gonadotropins and maintaining muscle mass. Therefore, it is possible to deliver a dose of MENT via silastic implants that will be effective in suppressing gonadotropins and spermatogenesis. In addition, MENT will have potential health benefits on prostate, bone and muscle mass and myelin regeneration based on the results of in vitro and animal studies. For example, (1) MENT is resistant to 5a-reduction, therefore, it is less stimulatory on the prostate at a comparable replacement dose; (2) MENT is aromatized to a potent estrogen, thereby, maintains sexual behavior in animals and men; (3) MENT does not bind to sex hormone binding globulin (SHBG) and has similar pharmacokinetics as T; and (4) MENT was recently shown to increase remyelination of neuronal cells (M. Schumacher, unpublished). Hence the long-term use of MENT in men is expected to be superior to T with added health benefits. First generation exogenous treatment regimens using testosterone injection, gel or biodegradable pellet or MENT acetate (MENT Ac) silastic implant showed limited efficacy in male contraceptive clinical trials. Second generation regimens using androgen in combination with a progestin such as levonorgestrel, etonogestrel or DMPA showed higher efficacy in suppressing spermatogenesis. In this research project, we will use a regimen of three MENT Ac implants (releasing ~ 1500 pg/day of MENT Ac) in combination with either a single DMPA injection at the start or multiple injections at 3 month intervals. MENT Ac implants will be manufactured, and the clinical trial will commence during the next funding cycle (pending approval). In addition, pharmacological and mechanistic studies will be conducted to determine the safety and health benefits of MENT and DMPA use. MENT Ac is an acetylated derivative of MENT and is used in implant manufacturing for optimal release rates. MENT and MENT Ac are used interchangeably since MENT Ac released from implants is rapidly hydrolyzed to the active MENT. Depo Provera (DMPA, Pfizer) injectable is an approved female contraceptive and is being investigated for male contraception. Depo provera releases an active progestin, medroxyprogesterone acetate (MPA). MPA will be used in animal and in vitro studies.