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: 7318148
• 负责人: BARRY R ZIRKIN
• 金额: $ 20.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318148
• 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.

摘要-项目1 主要研究者：巴里R.齐金 睾酮（T）的管理可以可逆地抑制男性精子发生。然而，在这方面， 尽管大多数男性都有无精子症，但仍有相当数量的男性保持足够高的精子率， 精子的产生会有引发怀孕的风险。无精子症的患病率明显高于 在亚洲人身上比在高加索人身上更明显。个人或群体未能成为 无精子症减少了基于精子的避孕的希望。拟议的长期目标 研究的目的是确定生物学机制，解释为什么有些男人成为无精子症， 其他人则没有。我们将利用自然发生的种族差异，即 亚洲人和高加索人，以T为基础的避孕来解决这个生物学问题。三个具体目标是 提出了首先，我们假设亚洲人T代谢物的差异（例如，较低的DHT水平）， 这可能有助于解释亚洲人对基于T的避孕措施的反应性增加。到 为了解决这一假设，我们首先将量化未治疗的亚洲生育者睾丸中存在的T和DHT。 和白人男性，使用高灵敏度液相色谱串联质谱法 (LC/MS/MS）来实现。第二个目的是比较睾丸内总的生物活性雄激素 使用基于雄激素生物活性的高灵敏度测定， 刺激哺乳动物细胞中雄激素受体的转录活性。核心假设是 在亚洲人中，雄激素的结合百分比更高，因此没有生物利用度。 白种人如果这是真的，这将表明，减少T和DHT将需要实现 亚洲男性的无精子症比高加索男性多。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雄激素的生物活性和生物可利用性的差异 在接受避孕剂量的T.我们将要检验的中心假设是， 对避孕T剂量的反应，白种人男性;将有更大量的睾丸内生物活性 雄激素比亚洲男性多。在第三个目标中，我们将检验在特定的睾丸内总T 浓度，亚洲人睾丸中生物可利用的生物活性雄激素比高加索人少 男人这些研究的结果对于开发安全有效的基于 男性避孕药此外，比较两组对避孕药敏感性不同的人群， 剂量的T应该提供了重要的洞察男性的生理机制，通过T 调节精子发生。