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-孕激素组合来抑制促性腺激素和精子发生。具有雄激素和孕激素活性的选择性雄激素受体调节剂（SARMs）是一种有吸引力的MHC治疗方法，正在由NICHD开发。我最近参与了NICHD支持的口服SARMs， 11β-甲基去甲睾酮十二烷基碳酸酯（11β-MNTDC）和十一酸二美雄龙（DMAU）的一期研究。在分析这些研究的数据时，我注意到体重增加和高密度脂蛋白的显著变化，类似于接受睾酮-黄体酮联合治疗的男性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性的新型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良影响。本研究的前提是全面评估SARMs和雄激素-黄体酮联合用药的代谢作用，以指导选择哪种化合物对长期健康最有益。该研究的目的是：目的1：比较SARMs和睾酮-黄体酮组合对健康男性体重、胰岛素抵抗和血脂的影响。这将使用先前试验的残留血清进行回顾性评估。我们假设，与单独的雄激素相比，某些孕激素会导致胰岛素抵抗和血脂异常。目的2：前瞻性比较口服左炔诺孕酮和不口服左炔诺孕酮对机体组成和代谢参数的影响。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会增加瘦肉和减少脂肪量。与单独使用DMAU相比，在DMAU中添加LNG（一种雄激素黄体酮）可以降低瘦体重，增加胰岛素抵抗和血脂异常。该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/串联质谱的实验室基础研究经验；2)利用生物电阻抗和DXA扫描测量人体成分；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；4)多试验数据的功率计算和统计分析。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极大地推进我在转化研究方面的职业生涯，并帮助我成为一名专注于代谢作用的男性避孕独立研究者的目标。

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.