ETHNICITY, INTRATESTICULAR ANDROGENS AND SPERMAGOGENESIS IN MEN

男性的种族、睾丸内雄激素和精子发生

• 批准号: 8127153
• 负责人: BARRY R ZIRKIN
• 金额: $ 25.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127153
• 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; Physiological; Pregnancy; Production; Progestins; Rattus; Reporting; Research; Risk; Serum; Spermatogenesis; Stanolone; Technology; Testing; Testis; Testosterone; Testosterone Enanthate; Two-Hybrid System Techniques; base; ethnic difference; expectation; hormonal contraception; insight; men; men' s group; research study; response; sperm cell

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.

服用睾酮(T)可以可逆地抑制男性的精子生成。然而， 虽然无精子症在大多数男性中都会发生，但相当多的人通常会保持足够高的水平。 精子的产生会带来引发怀孕的风险。无精子症的患病率明显更高 在亚洲人中比在高加索人中发现的更多。个人或一群男人未能成为 无精子症削弱了以激素为基础的避孕的前景。建议的长期目标 这项研究是为了确定解释为什么有些人会变得无精子症 其他人则不这么认为。我们将利用自然产生的种族差异，即对 亚洲人和高加索人，以T为基础的避孕措施，以解决这一生物学问题。三个具体目标是 建议。在第一种情况下，我们假设亚洲人的T代谢物的差异(例如较低的DHT水平)比 在高加索人中，男性可能有助于解释亚洲人对以T为基础的避孕措施的反应增加。至 为了解决这一假设，我们首先将量化T和DHT存在于未经治疗的有生育能力的亚洲人的睾丸中 和高加索男性，使用高灵敏的液相色谱串联质谱仪方法 (LC/MS/MS)。第二个目标将是比较睾丸内总的生物活性雄激素 使用一种基于雄激素生物活性的高灵敏分析方法，在亚洲和高加索男性中的浓度 在哺乳动物细胞中雄激素受体转录活性的刺激下。核心假设是 需要测试的是，与亚洲人相比，更大比例的雄激素被结合在一起，因此在亚洲无法生物利用 高加索男人。如果是真的，这将表明需要较少的T和DHT的减少才能实现 亚洲人的无精子症比高加索人的男性更严重。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内生物活性、生物可利用型雄激素池的差异 在男性接受避孕药T.之后，我们将检验的中心假设是，在 对避孕药T剂量的反应，高加索男性；将有更多的睾丸内生物活性 比亚洲男人更多的雄激素。在第三个目标中，我们将检验假设，在特定的总睾丸内T 浓度，亚洲人睾丸中生物可利用的生物活性雄激素将比高加索人少。 男人。这些研究的结果对于开发安全有效的荷尔蒙应该是非常有价值的。 男性避孕药。此外，比较两组对避孕药不同敏感的人 T的剂量应该对男性的生理机制提供重要的洞察，通过T 调节精子发生。