Dimethandrolone undecanoate

The drug works by targeting a component of the process that turns sperm stem cells into sperm. A drug with a past life as a potential anti-cancer agent might someday have a new job as "the pill" for men, new data in mice suggest.  In a journal article published Feb. 20 in Proceedings of the National Academy of Sciences, researchers at the Salk Institute explained how they discovered that an oral HDAC inhibitor called entinostat acts like an “off-on” switch for sperm creation that keeps male mice from reproducing without any effect on their libido. Within 60 to 90 days of stopping the pill, the mice were able to impregnate female animals again without any harm to the resulting offspring.  Effective male contraceptives are a long time coming, senior author Ronald Evans, Ph.D., told Fierce Biotech Research in an interview. Researchers have been trying for decades to develop a noninvasive, reversible, easily accessible drug candidate that is as effective as the birth control pill is for women, with no success so far.   “Our game-changing or transformative results are that it’s now possible to have a male equivalent of the pill that’s able to give men control as well, without having to rely on condoms,” Evans said. (Of course, this wouldn’t eliminate the need for condoms—they’re still necessary to protect against some types of sexually transmitted disease.) Sperm production is a complex process with many components, a limiting factor in coming up with drugs to block it. Hormonal candidates, such as the drug DMAU, have mainly focused on blocking testosterone—a route that varies in effectiveness depending on the patient population and can come with side effects. A non-hormonal injectable drug called RISUG is making its way through clinical trials in India, and a version called Vasalgel is in development in the U.S. However, both of these require either an injection or an in-office procedure.  One non-hormonal mechanism that scientists have long considered is blocking receptors for retinoic acid, a form of vitamin A that is critical to the process whereby sperm stem cells differentiate into fully functional sperm. But while this does stop sperm production in mice and rats, it comes at a cost: Retinoic acid is needed for a wide range of processes throughout the body, so inhibiting its activity systemically can lead to serious side effects, Evans explained. “You can kind of get it to work the way you want, but it’s not specific enough to be a useful way to address the challenge of controlling spermatogenesis,” he said. Researchers have largely abandoned the effort in favor of other approaches.  But in the new study, Evans’ lab—which was the first to clone the receptor for retinoic acid—learned that there’s another way to go about blocking its role in sperm production without systemic effects. While studying a gene regulatory factor called SMRT, one of the researchers in his lab pointed out that it was part of a complex of proteins that were involved in regulating retinoic acid receptors in sperm creation.  “He suggested that maybe we should actually not target the retinoic acid receptor itself, but target SMRT,” Evans recalled. Not only would doing so be easier than targeting the receptor directly, but it would also be safer because the target’s systemic effects are more limited, he added.  This led the team to see if blocking SMRT with entinostat, which Evans co-developed under his former company Syndax, would be a solution, as SMRT’s function is controlled by the same components that are interrupted by HDAC inhibitors. They gave male mice one of three different doses of the drug once a day for 60 days, then tested their ability to mate. They also tested whether taking mice off the drug would restore sperm production—and whether it would affect the health of their offspring.  To their surprise, the approach was a success.  “[The researcher] came back and said, ‘It really works.’ I said, ‘What do you mean it really works?’” Evans recalled. “He said, ‘It’s a total contraceptive. The mice’s libido is totally normal. And if you take it away, [their ability to reproduce] comes back.’” None of the mice that were on the drug sired offspring during the treatment period, compared to litters of around 10 pups each from control males. Sixty days after stopping the treatment, mice in the experimental groups were able to impregnate females again to the same degree as controls. All of the pups were born healthy.  During the treatment period, the researchers noticed that the animals’ testis size was “dose-dependently reduced” as their sperm production capacity fell. This was mostly recovered after 60 days off the drug, figures in the article showed. There were no other discernible side effects, such as weight loss that would indicate a change in testosterone levels, the researchers wrote in their paper. “As a proof of principle, our findings indicate that chronic, oral administration of MS-275 transiently blocks male fertility without permanently affecting reproductive capacity or the genomic integrity of sperm,” they wrote. Evans now hopes to test entinostat as a male contraceptive in larger animals and eventually in humans. The drug already has FDA breakthrough status for advanced breast cancer and has been studied in clinical trials for pancreatic cancer, brain cancer, melanoma and other cancers, so safety in humans has already been established, he said.  Given the results, Evans’ team has no plans to look at whether other HDAC inhibitors have birth control potential as well, he said, though they might look at other medical uses for entinostat. But for now, its use as a male contraceptive “is at the top of the list,” he said.  “That’s where we want to focus and see if there is a company that wants to actually develop this. Or do we have to start our own?” Evans, a serial biotech entrepreneur, said. “That’s kind of fun to think about.”

导语：根据2022年美国内分泌学会年会（Endocrine Society，ENDO）上公布的一项新研究显示，两款男性口服避孕药已经通过了Ⅰ期临床，显示出一定程度的睾酮抑制，足以达到避孕效果，同时不会产生症状性性腺功能减退症等副作用。ENDO于2022年6月11日-14日在亚特兰大召开，是国际内分泌领域的重要学术会议。“避孕”是当下社会不可避免的话题，至今在全球范围内约2/3的避孕节育任务主要由女性来承担，要想实现“男女平等”，“避孕平等”也理所应当，即男性应当与女性承担一样的“避孕”责任。目前,男性避孕技术还仅仅只是停留在避孕套以及结扎手术上，临床上至今仍然没有一种有效的男性避孕药。对『男用避孕药』的临床需求对于很多年轻夫妻来说，并没有做好为人父母的准备，因此，采取安全有效的避孕措施很有必要。我国是全球避孕方法使用率较高的国家之一，20世纪90年代以来，我国综合避孕率一直稳定在85%-90%之间，其中绝大部分的避孕责任都是由女性承担。女性拥有各种避孕措施，而在男性避孕层面，则一直停留在避孕套和结扎手术上，当“男女平等”来到避孕层面，两性天平更是显著失衡。女性不仅承担着生育的痛苦，同时也肩负着避孕的压力。从社会层面来说，抛开“避孕平等”谈“男女平等”，这本身就是谬论。另外，目前来说，主流的避孕方式包括避孕套和紧急避孕药，前者由男性承担，后者由女性承担，但是由于担心体验不佳，很多男性并不情愿戴上避孕套，这样一来，避孕的重担就完全落在了女性肩上。而服用事后紧急避孕药对于女性身体来说是一个很大的负担，尽管某些层面上，避孕药解放了女性，让女性得以从生育中解脱，但同时，也对其身体造成了很大影响。综上，研发安全有效的男用避孕药是当下阶段的要紧事。男性避孕药Ⅰ期临床试验结果公布，安全有效激素性男用避孕药是一类将促雄性激素和促孕激素活性结合在一个单一分子内的双功能前药物。尤尼斯·肯尼迪·施莱佛国家研究所避孕药开发项目研究员Tamar Jacobsohn表示，目前有两种男用避孕药正在开发中，包括十一酸二甲雄酮（Dimethandrolone Undecanoate，DMAU）和11-β-甲基-19-去甲睾酮十二烷基碳酸酯（11β-methyl-19-nortestosterone 17β-dodecylcarbonate，11β-MNTDC），这两种药物都是具有雄激素和孕激素作用的双功能前药。前药被设计成在摄入后被切割，以便活性激素在24小时内释放，每天给药一次[1]。在2022年美国内分泌学会年会上，研究团队介绍了这两款药物的Ⅰ期临床结果。两项Ⅰ期临床试验共纳入96名健康男性受试者，这些受试者被随机分配到每天用药2片组、每天用药4片组或安慰剂组，持续服用28天。结果显示，持续服药7天后，用药组所有受试者的睾酮水平下降至安全范围以内，均低于100ng/dL，从第7天至第28天，用药组受试者睾酮水平都维持在这一范围内。并且，用药组受试者均没有发生严重不良事件。注：睾酮是一种类固醇激素，是人体内活性最强，也是最重要的雄性激素。对于男性来说，睾酮水平是男性生育力的重要衡量因素，其对精子的生成及发育至关重要。医生通常认为正常的睾酮水平在300ng/dL-1000ng/dL之间。因此，上述这两种药物能够通过降低男性体内睾酮水平，以有效抑制精子生成，最终达到避孕效果。研究人员Jacobsohn表示，“作为强效雄激素，这些类固醇抑制促性腺激素分泌，导致血清睾酮产生显著下降”[1]。全球男性避孕药研究进展如何？尽管目前尚无男用避孕药上市，但是相关研究进展并没有停滞。就在今年3月份，美国明尼苏达大学的研究人员在American Chemical Society(ACS)春季会议上报告了一项最新研究成果，题为“A non-hormonal pill could soon expand men’s birth control options”（图1），他们通过小鼠实验证实了一种非激素类男性口服避孕药（YCT529）的有效性和安全性。图1 研究成果（图源：[2]）YCT529是一款非激素类男性口服避药，当雄性小鼠服下此药物4周后精子数量显著减少，避孕有效率高达99%，而且没有任何可观察到的副作用。这些服药小鼠在停用药物4-6周后就可恢复生育能力,并生下幼崽[2]，这说明这些药物不会破坏雄性小鼠的生育能力。除了口服避孕药，2019年，来自印度医学研究理事会的研究人员曾经开发出全球首款注射式男性避孕药，可有效控制男性生育力。这款名为RISUG的注射式避孕药，可实现1次注射有效避孕13年。RISUG由「苯乙烯马来酸酐」化合物制成，通过使精子在输卵管中破裂而防止怀孕，在小鼠临床研究中被证明是可靠的避孕方式，可实现98%的有效避孕率，且暂未发现任何重大副作用[3]。图2 RISUG相关报道（图源：《印度时报》）在Ⅲ期临床试验中，研究团队共招募303名参与者，RISUG的避孕成功率为97.3%[3]。据研究人员所说，这种药物并不会影响男性性功能，RISUG所用的生物材料会产生电荷，通过SMA聚合电解质效应，导致经过注射处的精子细胞分裂，破坏精子头部构成，无法与卵子有效结合。RISUG的有效期可长达13年，但是需要注意的是，这种避孕方式是可逆的，即可以根据自己的生育意愿选择是否恢复生育能力。从这方面来说，RISUG会是广大情侣及夫妻避孕的良好选择。此外，2021年2月，美国伦奎斯特研究所资深研究员、加州大学洛杉矶分校闫威教授课题组与广东省计划生育科学技术研究所唐运革课题组在Nature Communications上联合发表了题为“Triptonide is a reversible non-hormonal male contraceptive agent in male mice and non-human primates”（图2）的研究成果，介绍了一款可逆的非激素男用避孕药。图3 研究成果（图源：Nature Communciations）研究指出，口服雷公藤内酯酮可诱导雄鼠和雄性食蟹猴精子畸形，使精子失去活力，从而达到避孕目的。试验显示这种避孕药物的避孕有效率可达100%，且无明显副作用，雄性生育力可在停药之后实现完全恢复[4]。因此，雷公藤内酯酮或可作为一种有效的男性避孕候选药物。纵览多项男用避孕药相关研究表明，开发一种有效的、可逆的男性避孕方法将改善男性和女性的生育选择，并使男性在计划生育中发挥越来越积极的作用。但是我们还需要知道，以上药物仅仅只是停留在动物研究阶段或临床试验阶段，离产品上市恐怕还有一段距离。对于男用避孕药能否顺利上市，我们拭目以待！题图来源：Power of Positivity，仅用于学术交流。撰文|木子久排版|木子久 End 参考资料：[1]https://www.medscape.com/viewarticle/975435[2]https://www.acs.org/content/acs/en/pressroom/newsreleases/2022/march/non-hormonal-pill-could-soon-expand-mens-birth-control-options.html[3]https://www.hindustantimes.com/india-news/india-closer-to-world-s-first-male-contraceptive-injection/story-o3lTFLnCkKHpuEDNNqrEnO.html[4]Chang Z, Qin W, Zheng H, et al. Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates. Nat Commun. 2021 Feb 23;12(1):1253. doi: 10.1038/s41467-021-21517-5. PMID: 33623031; PMCID: PMC7902613. 本文系生物探索原创，欢迎个人转发分享。 其他任何媒体、网站如需转载，须在正文前注明来源生物探索。 往期精选 围观 牛奶喝多易致癌！男性前列腺癌风险增加27%，女性乳腺癌风险增加17% 热文 强悍的生育能力，靠你的精子『生理学』年龄而非『身份证』年龄 热文 到底几点睡觉算熬夜？补觉能补回来吗？Nature & Cell子刊为您解答 热文 用数据揭示重症率！首次披露上海奥密克戎数据，哪些结论值得关注？ 热文 灭癌率极高！这一途径可让癌细胞高效“自杀” 点击“阅读原文”，了解更多~