Ensemble Disruption of the GnRH-LH-Testosterone Axis

描述（由申请人提供）：男性衰老导致全身雄激素可用性的进行性降低。根据目前对游离睾酮和生物可利用睾酮浓度的估计，大约30%的60岁健康男性和50%的80岁健康男性按成年人标准睾酮缺乏。流行病学数据表明，低雄激素血症与肌肉减少、骨质减少、内脏脂肪增多、生活质量下降和机构化密切相关。然而，老年男性睾丸激素产生减少的确切机制基础尚不清楚。 目前的建议是基于这样的论点，即男性性腺轴通过GnRH，LH和睾酮三者之间的相互作用来调节和相互作用。从这一Vantage解释，已发表的文献，实验室实验，背景数据和合奏反馈/前馈模拟预测，在老年男性的氢雄激素血症可能会出现非排他性的方式：（i）减少下丘脑GnRH流出;（ii）受损Leydig细胞类固醇生成;和（iii）改变睾酮强制负反馈。 为了研究与衰老相关的睾酮耗竭的主要机制，我们提出了以下三个可检验的临床假设：假设一：老年男性下丘脑GnRH驱动降低是低幅度LH脉冲的基础。将通过比较老年和年轻个体内源性GnRH驱动的LH分泌爆发质量对选择性GnRH受体拮抗剂（加尼瑞克）剂量递增的抑制敏感性来检验这一假设。 假设二：睾丸间质细胞类固醇生成受损加重了衰老时的低雄激素血症。为了评估这个问题，我们将比较（24小时）睾酮分泌反应的年龄，以实验标准化lutropic刺激实现脉动静脉注射rh LH下GnRH受体阻断5天。 假设三：老年男性的低雄激素反馈环境导致LH释放的高频率、低幅度和不规则模式。这一概念将通过定量LH分泌适应年轻和老年男性的血浆生物可利用的睾酮浓度的一种新的剂量分层钳检查。 对衰老相关性性腺功能减退症的机械理解的长期目标是激发对干预策略的新见解，以保持老年人的生活质量，身体和认知功能以及独立活动能力。预期的必然结果是加强诊断，评估和管理更微妙的病理生理学的男性性腺轴在青春期和成年期。

DESCRIPTION (provided by applicant): Aging in men results in progressive impoverishment of systemic androgen availability. Based on current estimates of free and bioavailable testosterone concentrations, approximately 30% of healthy men aged 60 and 50% aged 80 years are testosterone deficient by young-adult standards. Epidemiological data establish a close association between hypoandrogenemia and sarcopenia, osteopenia, increased visceral adiposity, reduced quality of life and institutionalization. However, the precise mechanistic bases of reduced testosterone production in the older male are not known. The present proposal is predicated on the thesis that the male gonadal axis operates via regulated and reciprocal interactions among all three of GnRH, LH and testosterone. Interpreted from this vantage, published literature, laboratory experiments, background data and ensemble feedback/feed forward simulations predict that hydroandrogenemia in aging men could arise nonexclusively by way of: (i) reduced hypothalamic GnRH outflow; (ii) impaired Leydig-cell steroidogenesis; and (iii) altered testosterone-enforced negative feedback. To investigate the primary mechanisms of aging-related testosterone depletion, we pose the following three testable clinical hypotheses: HYPOTHESIS I: Reduced hypothalamic GnRH drive underlies low-amplitude LH pulses in older men. This postulate will be tested by comparing inhibitory susceptibility of endogenously GnRH-driven LH secretory-burst mass to escalating doses of a selective GnRH-receptor antagonist (ganirelix) in aging and young individuals. HYPOTHESIS II: Impaired Leydig-cell steroidogenesis accentuates hypoandrogenemia in aging. To appraise this issue, we will compare the (24-h) testosterone secretory response by age to an experimentally normalized lutropic stimulus achieved by pulsatile i.v. infusion of rh LH under GnRH-receptor blockade for 5 days. HYPOTHESIS Ill: The low androgen-feedback milieu in aging men contributes to high frequency, low amplitude and irregular patterns of LH release. This concept will be examined by quantitating LH secretory adaptations in young and older men to a novel dose-stratified clamp of plasma bioavailable testosterone concentrations. The long-term goal of mechanistic understanding of aging-related hypogonadism is to stimulate novel insights into interventional strategies to preserve quality of life, physical and cognitive function and capable independent activities of older citizens. Expected corollary outcomes are enhanced diagnosis, assessment and management of more subtle pathophysiology of the male gonadal axis in puberty and adulthood.