Dose-response relationships between circulating and intraprostatic androgens in m

男性循环雄激素和前列腺内雄激素之间的剂量-反应关系

• 批准号: 7944196
• 负责人: STEPHANIE T PAGE
• 金额: $ 31.98万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944196
• 关键词: Address; Adrenal Glands; Age; Aging; Androgen Therapy; Androgens; Apoptosis; Area; Biological Preservation; Castration; Cell physiology; Cells; Clinical; Data; Development; Dose; Endocrine Physiology; Environment; Enzymes; Epithelial Cells; Exhibits; Face; Future; Gene Expression; Gland; Goals; Guidelines; Hand; Health; Homeostasis; Hormonal; Hormones; Human; Human Characteristics; Hypogonadism; In Situ; Incidence; Inflammation; Intervention; Knowledge; Libido; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metabolism; Molecular; Muscle; Nobel Prize; Normal Range; Organ; Oxidoreductase; Pathway interactions; Peripheral; Phenotype; Play; Prostate; Prostatic; Prostatic Diseases; Recording of previous events; Replacement Therapy; Research; Risk; Role; Serum; Sex Functioning; Stanolone; Steroid biosynthesis; Steroids; Testing; Testosterone; Tissues; United States; Withdrawal; bone; dehydroepiandrosterone; design; disorder risk; experience; healthy volunteer; high risk; improved; inhibitor/antagonist; lower urinary tract symptoms; men; middle age; mortality; muscle strength; older men; placebo controlled study; prevent; primary outcome; public health relevance; randomized placebo controlled trial; response; risk benefit ratio

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.

说明书（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，前列腺疾病的发病率随着年龄的增长而显著增加。对于年龄相关性“雄激素缺乏”的老年男性，雄激素替代疗法可对肌肉和骨骼产生有益的合成代谢作用，并可改善性功能和力量，但存在可能加剧前列腺疾病的重大担忧。因此，治疗性雄激素疗法的目标是使合成代谢作用最大化，同时使对前列腺的影响最小化。先前的研究表明，T的合成代谢益处表现出线性的剂量-反应效应，但前列腺对血清雄激素的增加并没有表现出类似的剂量-反应。我们假设前列腺内外源性雄激素的剂量-反应效应不是线性的，因为前列腺在面对血清雄激素变化时保持着独特的雄激素环境。在拟进行的研究的目的1中，我们将确定血清T浓度升高是否会改变前列腺内雄激素环境并对腺体内的下游细胞产生影响。在前列腺内，51-还原酶（51R）的高表达导致前列腺内DHT的高浓度，这与前列腺疾病的发展有关。在Aim 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的激素和分子效应，以更好地表征这种“前列腺保留”雄激素替代策略。在Aim 3中，我们将研究健康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。我们将在人类中进行干预，我们有前列腺组织分析的经验，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记。这些研究将提供对前列腺微环境中激素相关变化的理解，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。