Examining the Androgenic and Progestational Effects of Novel Androgens for Male Contraception

检查新型雄激素对男性避孕的雄激素和孕激素作用

• 批准号: 10020186
• 负责人: Fiona N Yuen
• 金额: $ 8.62万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-04 至 2022-03-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020186
• 关键词: Adverse effects; Amendment; Androgens; Authorization documentation; Biolectric Impedance; Biological Markers; Biomedical Research; Body Composition; Cardiovascular system; Characteristics; Cholesterol; Clinical Research; Clinical Trials; Clinical Trials Network; Contraceptive Agents; Data; Data Analyses; Development; Dose; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Endocrine; Fasting; Fatty acid glycerol esters; Goals; Gonadotropins; Grant; Health; High Density Lipoproteins; Hormonal; Hormones; Immunoassay; Individual; Institutional Review Boards; Insulin Resistance; Knowledge; Laboratories; Laboratory Research; Lead; Leptin; Levonorgestrel; Lipids; Liquid Chromatography; Long-Term Effects; Low-Density Lipoproteins; Male Contraceptive Agents; Measurement; Measures; Mentors; Metabolic; Metabolic Diseases; Nandrolone; National Institute of Child Health and Human Development; Nestorone; Obesity; Oral; Outcome; Pharmaceutical Preparations; Placebos; Process; Progestins; Protocols documentation; Reporting; Research; Research Personnel; Research Training; Residual state; Route; Running; Scanning; Spermatogenesis; Statistical Data Interpretation; Testing; Testosterone; Therapeutic; Thinness; Training; Translational Research; Universities; Vasectomy; Washington; Weight; Weight Gain; Writing; adiponectin; androgenic; base; career; condoms; data management; experience; hormonal contraception; improved; male; men; metabolic abnormality assessment; muscle form; novel; oral form testosterone; phase 1 study; placebo controlled study; primary outcome; prospective; secondary outcome; selective androgen receptor modulator; tandem mass spectrometry

Clinical trials of male hormonal contraception (MHC) use an androgen-progestin combination to suppress gonadotropins and spermatogenesis. Selective androgen receptor modulators (SARMs) that possess both androgenic and progestational activity are an attractive approach to MHC and are being developed by NICHD. I participated in recent NICHD supported Phase 1 studies on the oral SARMs, 11β-methyl-nortestosterone dodecylcarbonate (11β-MNTDC) and dimethandrolone undecanoate (DMAU). While analyzing data from these studies, I noticed weight gain and significant changes in HDL, similar to changes that occurred in MHC trials of men receiving testosterone-progestin combinations. Our long-term objective is to develop a novel SARM with specific characteristics to maximize beneficial and minimize adverse effects on metabolic parameters. The premise of this study is to comprehensively assess metabolic effects of SARMs and androgen-progestin combinations in order to guide selection choice of which compound(s) is most beneficial to long-term health. The study aims are: AIM 1: Compare the impact of SARMs and testosterone-progestin combinations on weight, insulin resistance, and lipids in healthy men. This will be assessed retrospectively using residual sera from prior trials. We hypothesize that certain progestins will contribute to insulin resistance and dyslipidemia compared to androgens alone. AIM 2: Prospectively compare the effects of DMAU with and without oral levonorgestrel (an androgenic progestin) on body composition and metabolic parameters. In an ongoing 12-week placebo- controlled study, as a corollary to the main study we will compare the impact of DMAU alone or with levonorgestrel (LNG) on changes in lean mass. We hypothesize that DMAU will increase lean and decrease fat mass. Addition of LNG, an androgenic progestin, to DMAU could decrease lean mass and increase insulin resistance and dyslipidemia compared to DMAU alone. This clinical study will directly provide training on and experience with: 1) hands-on laboratory-based research experience using immunoassays and liquid chromatography/tandem mass spectrometry; 2) measurement of body composition using bioelectrical impedance and DXA scanning; 3) clinical research training including regulatory approval processes, data management, IND amendments, and grant writing; and 4) power calculations and statistical analysis of data across multiple trials. This study will produce preliminary data to support a planned K23 application to NICHD. Collectively, this study and my proposed training plan will significantly advance my career in translational research and assist in my goal of becoming an independent investigator in male contraception with a focus on metabolic effects.

男性激素避孕（MHC）的临床试验使用雄激素-孕酮组合来抑制促性腺激素和精子发生。选择性雄激素受体调节剂（SARMs）具有雄激素和孕激素活性是一种有吸引力的方法，MHC和正在开发的NICHD。我参加了最近NICHD支持的口服SARMs、11β-甲基-去甲睾酮十二烷基碳酸酯（11β-MNTDC）和二甲雄龙十一酸酯（DMAU）的I期研究。在分析这些研究的数据时，我注意到体重增加和HDL的显着变化，类似于接受睾酮-维生素B1组合的男性MHC试验中发生的变化。我们的长期目标是开发一种具有特定特征的新型SARM，以最大限度地提高对代谢参数的有益影响，并最大限度地减少对代谢参数的不利影响。本研究的前提是全面评估SARM和雄激素-孕酮组合的代谢作用，以指导选择哪种化合物对长期健康最有益。研究的目的是：目标1：比较SARMs和睾酮-孕酮组合对健康男性体重、胰岛素抵抗和血脂的影响。这将使用既往试验的残留血清进行回顾性评估。我们假设某些孕激素与单独的雄激素相比会导致胰岛素抵抗和血脂异常。目标2：普罗维登斯比较了DMAU与口服左炔诺孕酮（一种雄激素）对身体成分和代谢参数的影响。在一项正在进行的为期12周的安慰剂对照研究中，作为主要研究的必然结果，我们将比较DMAU单独或与左炔诺孕酮（LNG）对瘦体重变化的影响。我们假设DMAU会增加瘦肉和减少脂肪量。与单独使用DMAU相比，在DMAU中添加LNG（一种雄激素受体调节蛋白）可降低瘦体重，增加胰岛素抵抗和血脂异常。本临床研究将直接提供以下方面的培训和经验：1）使用免疫测定和液相色谱/串联质谱法的实验室研究实践经验; 2）使用生物电阻抗和DXA扫描测量身体成分; 3）临床研究培训，包括监管批准流程、数据管理、IND修订和批准书撰写;和4）功效计算和多个试验数据的统计分析。这项研究将产生初步数据，以支持计划中的K23应用于NICHD。总的来说，这项研究和我提出的培训计划将大大推进我在转化研究方面的职业生涯，并有助于我成为一名男性避孕独立研究者的目标，重点是代谢影响。