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

男性激素避孕(MHC)的临床试验使用雄激素-孕激素联合抑制 促性腺激素与精子发生。选择性雄激素受体调节剂(SARM) 雄激素和孕激素活性是MHC的一种有吸引力的方法，NICHD正在开发这一方法。我 参与了新近的NICHD支持的口服SARM的第一阶段研究，11β-甲基去甲睾酮 十二烷基碳酸酯(11β-MNTDC)和十一酸二甲基雄酮(DMAU)。在分析这些数据时 研究中，我注意到体重增加和高密度脂蛋白的显著变化，类似于MHC试验中发生的变化 接受睾酮和孕激素联合治疗的男性。我们的长期目标是开发一种新型的SARM， 特定的特性，以最大限度地有益于代谢参数，并最大限度地减少对代谢参数的不利影响。这个 本研究的前提是全面评估SARMS和雄激素-孕激素的代谢效应 以指导选择选择哪种化合物(S)对长期健康最有利。这个 研究目标是：目标1：比较SARM和睾酮-孕激素组合对体重的影响， 胰岛素抵抗，以及健康男性的血脂。这将使用之前的残留血清进行回顾性评估 审判。我们假设某些孕激素会导致胰岛素抵抗和血脂紊乱。 单独的雄激素。目的2：前瞻性比较口服与不口服左炔诺孕酮(AN)对DMAU的影响 雄激素孕激素)对体成分和代谢参数的影响。在持续12周的安慰剂中- 对照研究，作为主要研究的推论，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会增加瘦肉和降低脂肪 质量。在DMAU中添加LNG(一种促雄激素的孕激素)可以减少瘦体重并增加胰岛素 与单独使用DMAU相比，耐药和血脂异常。 这项临床研究将直接提供以下方面的培训和经验：1)以实验室为基础的实践研究 使用免疫分析和液相色谱/串联质谱仪的经验；2)测量 使用生物电阻抗和DXA扫描的身体成分；3)临床研究培训，包括 监管审批流程、数据管理、IND修订和拨款撰写；以及4)权力 计算和统计分析多个试验的数据。这项研究将产生初步数据以 支持计划中的K23应用到NICHD。总的来说，这项研究和我提议的培训计划将 极大地促进了我在翻译研究方面的事业，并帮助我实现了成为独立人士的目标 男性避孕研究人员，重点研究代谢影响。

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.