Ethnicity, Intratesticular Androgens and Spermatogenesis in Men

男性的种族、睾丸内雄激素和精子发生

• 批准号: 7670146
• 负责人: BARRY R ZIRKIN
• 金额: $ 24.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7670146
• 关键词: Address; Affect; Androgen Receptor; Androgens; Asians; Binding; Bioavailable; Biological; Biological Assay; Caucasians; Caucasoid Race; Contraceptive Agents; Contraceptive methods; Development; Dose; Ethnic Origin; Failure; Feedback; Goals; Gonadotropin Releasing Hormone Inhibitor; High Prevalence; Hormones; Human; Human Chorionic Gonadotropin; Individual; Liquid Chromatography; Maintenance; Male Contraceptive Agents; Mammalian Cell; Mass Spectrum Analysis; Metabolism; Methods; Numbers; Personal Satisfaction; Physiological; Pregnancy; Principal Investigator; Production; Progestins; Rattus; Reporting; Research; Risk; Serum; Spermatogenesis; Stanolone; Technology; Testing; Testis; Testosterone; Testosterone Enanthate; Two-Hybrid System Techniques; abstracting; base; ethnic difference; expectation; hormonal contraception; insight; men; men' s group; research study; response; sperm cell

ABSTRACT-PROJECT 1 Principal Investigator: Barry R. Zirkin The administration of testosterone (T) can reversibly suppress spermatogenesis in men. However, although azoospermia is achieved in a majority of men, significant numbers typically maintain high enough sperm production to pose a risk of initiating a pregnancy. A significantly higher prevalence of azoospermia has been noted in Asians than in Caucasians. The failure of individuals or groups of men to become azoospermic diminishes the promise of hormone-based contraception. The long-term goal of the proposed research is to determine the biological mechanisms that explain why some men become azoospermic while others do not. We will take advantage of the naturally occurring ethnic differences, namely the response of Asians and Caucasians, to T-based contraception to address this biological issue. Three specific aims are proposed. In the first, we hypothesjze that differences in T metabolites (e.g. lower DHT levels) in Asian than in Caucasian men might help explain the increased responsiveness of Asians to T-based contraception. To address this hypothesis, we first will quantify T and DHT present within the testes of untreated fertile Asian and Caucasian men, using a highly sensitive liquid chromatography tandem mass spectroscopy method (LC/MS/MS) to do so. A second objective will be to compare the total intratesticular bioactive androgen concentrations in Asian and Caucasian men, using a highly sensitive assay of androgen bioactivity based upon stimulation of androgen receptor transcriptional activity in mammalian cells. The central hypothesis to be tested is that a greater percentage of androgen is bound and therefore not bioavailable in Asian than in Caucasian men. If true, this would suggest that lesser reduction of T and DHT would be required to achieve azoospermia in Asian than in Caucasian men. In the second aim, we will determine whether there are differences in the bioactive, bioavailable pool of androgens within the testes'of Asians and Caucasians following the men receiving a contraceptive dose of T. The central hypothesis that we will test is that in response to a contraceptive T dose, the Caucasian men; will have greater amounts of intratesticular bioactive androgens than Asian men. In the third aim, we will test the hypothesis that at specific total intratesticular T concentrations, there will be less bioavailable, bioactive androgen in the testes of Asian than Caucasian men. The results of these studies should be invaluable to the development of a safe and effect hormonebased male contraceptive. Moreover, comparing two groups with different sensitivities to a contraceptive dose of T should provide significant insight into the physiological mechanisms in men through which T regulates spermatogenesis.

抽象项目1 首席研究员：巴里·齐尔金（Barry R. Zirkin） 睾丸激素（T）的给药可以可逆地抑制男性的精子发生。然而， 尽管大多数男性都可以实现Azoospermia，但大量数量通常保持足够高 精子产生有可能发起怀孕的风险。 Azoospermia的患病率明显更高 与高加索人相比，亚洲人已经注意到。个人或一群人的失败 Azoospermic减少了基于激素的避孕的希望。拟议的长期目标 研究是确定生物学机制，这些机制解释了为什么有些男人变成azoospermic而 其他人没有。我们将利用自然发生的种族差异，即 亚洲人和高加索人，基于T的避孕，以解决这个生物学问题。三个具体目标是 建议的。首先，我们假设亚洲的T代谢产物（例如DHT水平较低）的差异而不是 在高加索人中，可能有助于解释亚洲人对基于T的避孕的反应能力。到 解决这个假设，我们首先将量化未经治疗的亚洲睾丸中存在的T和DHT 和高加索男性，使用高灵敏的液相色谱串联质谱法 （LC/MS/MS）要这样做。第二个目标是比较全死肠生物活性雄激素 使用高度敏感的基于雄激素生物活性的测定，亚洲和高加索男性的浓度 刺激雄激素受体转录活性在哺乳动物细胞中。中心假设 接受测试是，雄激素的比例更大，因此在亚洲人中不可生物利用 高加索人。如果是真的，这表明将需要减少T和DHT才能实现 亚洲的Azoospermia比白人男人。在第二个目标中，我们将确定是否有 亚洲人和高加索人睾丸中生物活性，可生物可利用的雄激素的差异 在接受T避孕剂量T的男性之后。我们将测试的中心假设是 对避孕药的反应，高加索人；将具有大量的肠内生物活性 雄激素比亚洲男人。在第三个目标中，我们将检验以下假设： 浓度，亚洲睾丸中的生物活性雄激素比白种人的生物活性雄激素要少。 男人。这些研究的结果对于基于安全和效应激素的发展应该是无价的 男性避孕。此外，将两个具有不同灵敏度的组与避孕 T剂量应为男性的生理机制提供重大见解 调节精子发生。