Dose-response relationship between circulating and prostatic androgens in men

描述（由申请人提供）：睾酮（T）和双氢睾酮（DHT）是人类前列腺中的主要雄激素，是正常前列腺发育和体内平衡所必需的。在男性中，衰老与血清T水平的逐渐下降有关。尽管血清T浓度下降，但前列腺疾病的发病率随年龄增长而显著增加。雄激素替代疗法在老年男性与年龄相关的“雄激素缺乏症”的结果是有益的肌肉和骨骼的合成代谢作用，并可以改善性功能和力量，但显着的关注存在的可能性，增强前列腺疾病。因此，治疗性雄激素治疗的目标是最大化合成代谢作用，同时最小化对前列腺的影响。先前的研究已经证明，T的合成代谢益处表现出线性剂量反应效应，但表明前列腺对血清雄激素的增加没有表现出类似的剂量反应。我们假设外源性雄激素在前列腺内的剂量-反应效应不是线性的，因为前列腺在面对血清雄激素的变化时保持着独特的雄激素环境。在目标1的拟议研究中，我们将确定是否增加血清T浓度改变前列腺内雄激素环境，并在腺体内下游细胞的后果。在前列腺内，酶51-还原酶（51 R）高度表达，导致前列腺内高浓度的DHT，这与前列腺疾病的发展有关。在目标2中，我们将确定在前列腺内存在51 R抑制剂的情况下低剂量和高剂量T的激素和分子效应，以更好地表征这种“保留前列腺”的雄激素替代策略。在目标3中，我们将调查是否健康的人前列腺有能力合成DHT和T原位从肾上腺前体，一种机制，这可能有助于稳定intraprostate雄激素浓度时，血清水平波动。我们将在具有前列腺组织分析经验的人类中进行干预，包括激素定量和细胞特异性基因表达分析作为雄激素作用的标志物。这些研究将提供对前列腺微环境中与前列腺增生相关的变化的理解，并将有助于为老年男性雄激素替代疗法的未来研究提供信息。 公共卫生相关性：在过去十年中，男性中的特氟沙星使用量大幅增加，部分原因是它有望增加力量和性功能。然而，人们相当担心服用睾酮的男性患前列腺疾病的风险会增加，包括前列腺癌，这已经是男性中最常见的癌症。在拟议的研究中，我们将确定增加剂量的睾酮对健康男性前列腺组织的影响。更好地了解睾酮对前列腺的影响将有助于告知老年男性睾酮治疗的风险：收益比。

DESCRIPTION (provided by applicant): Testosterone (T) and dihydrotestosterone (DHT) are the major androgens in the human prostate and are required for normal prostate development and homeostasis. In men, aging is associated with a gradual decline in serum T levels. Despite declining serum T concentrations, the incidence of prostate diseases increases markedly with age. Androgen replacement therapy in older men with age-associated "androgen deficiency" results in beneficial anabolic effects on muscle and bone, and can improve sexual function and strength, yet significant concern exists regarding the possibility of potentiating prostate disease. The goal of therapeutic androgen therapy is thus to maximize anabolic effects while minimizing effects on the prostate. Previous studies have demonstrated that the anabolic benefits of T exhibit linear dose-response effects but suggest that the prostate does not exhibit similar dose-responses to increases in serum androgens. We hypothesize that the dose-response effects of exogenous androgens within the prostate are not linear because the prostate maintains a unique androgenic milieu in the face of changes in serum androgens. In Aim 1 of the proposed studies, we will determine whether increasing concentrations of serum T alter the intraprostatic androgen environment and have downstream cellular consequences within the gland. Within the prostate, the enzyme 51-reductase (51R) is highly expressed resulting in a high intraprostatic concentration of DHT, which has been implicated in the development of prostate disease. In Aim 2 we will determine the hormonal and molecular effects of low and high doses of T in the presence of a 51R inhibitor within the prostate to better characterize this "prostate sparing" androgen replacement strategy. In Aim 3 we will investigate whether the healthy human prostate has the capacity to synthesize DHT and T in situ from adrenal precursors, a mechanism which might contribute to stabilizing intraprostatic androgen concentrations when serum levels fluctuate. We will perform our interventions in humans where we have experience with prostate tissue analyses including quantification of hormones and cell-specific gene expression analysis as a marker of androgen action. These studies will provide an understanding of the hormone-related changes in the prostate microenvironment and will help inform future studies of androgen replacement therapies in older men. PUBLIC HEALTH RELEVANCE: Testosterone use among men has increased substantially over the past decade, fuelled in part by the promise of increases in strength and sexual function. However, there is considerable concern that men taking testosterone will be at increased risk for prostate disease, including prostate cancer, already the most common cancer among men. In the proposed studies we will determine the effects of increasing doses of testosterone on prostate tissue in healthy men. An improved understanding of the impact of testosterone on the prostate will help inform the risk:benefit ratio of testosterone therapies in older men.