Dose-response relationships between circulating and intraprostatic androgens in m

描述(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，是正常的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，但前列腺癌的发病率随着年龄的增长而显著增加。雄激素替代疗法对患有年龄相关性“雄激素缺乏症”的老年男性会对肌肉和骨骼产生有益的合成代谢作用，并可以改善性功能和力量，但人们对可能加重前列腺癌的可能性存在重大担忧。因此，治疗性雄激素治疗的目标是最大化合成代谢作用，同时将对前列腺的影响降至最低。以前的研究已经证明，T的合成代谢益处表现出线性的剂量反应效应，但提示前列腺对血清雄激素的增加没有类似的剂量反应。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，因为面对血清雄激素的变化，前列腺维持着独特的雄激素环境。在拟议研究的目标1中，我们将确定血清T浓度的增加是否会改变前列腺内的雄激素环境，并在腺体内产生下游细胞后果。在前列腺内，酶51-还原酶(51R)高度表达，导致前列腺内DHT浓度较高，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51R抑制剂的情况下，低剂量和高剂量T对激素和分子的影响，以更好地描述这种“保留前列腺”的雄激素替代策略。在目标3中，我们将研究健康的人前列腺是否具有从肾上腺前体原位合成DHT和T的能力，这一机制可能有助于在血清水平波动时稳定前列腺内雄激素浓度。我们将在我们有前列腺组织分析经验的人类身上进行干预，包括激素的量化和作为雄激素作用标志的细胞特异性基因表达分析。这些研究将提供对前列腺微环境中与激素相关的变化的了解，并有助于为未来老年男性雄激素替代疗法的研究提供信息。 与公共健康相关：在过去十年中，男性的睾丸素使用量大幅增加，部分原因是力量和性功能的承诺增加。然而，人们相当担心，服用睾丸素的男性患前列腺癌的风险会增加，包括前列腺癌，前列腺癌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丸素对健康男性前列腺组织的影响。对睾酮对前列腺影响的更好的理解将有助于了解睾酮治疗在老年男性中的风险：益处比率。

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.