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逐渐减少。根据目前对游离睾酮和生物可利用睾酮浓度的估计，按年轻人标准，大约30%的60岁健康男性和50%的80岁健康男性睾酮缺乏。流行病学数据表明，低雄激素血症与肌肉减少症、骨质减少症、内脏脂肪增加、生活质量下降和制度化密切相关。然而，老年男性睾丸激素分泌减少的确切机制基础尚不清楚。目前的建议是基于这一论点，即男性性腺轴通过GnRH、LH和睾酮这三种激素之间的调节和相互作用来运作。从这一优势解释，已发表的文献，实验室实验，背景数据和集合反馈/前馈模拟预测，老年男性氢雄激素血症可能不完全通过以下方式发生：(i)下丘脑GnRH流出量减少；（ii）间质细胞甾体生成受损；（三）改变了由睾丸激素引起的负面反馈。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1：下丘脑GnRH驱动降低是老年男性低幅度LH脉冲的基础。这一假设将通过比较内源性gnrh驱动的黄体生成素分泌爆发团对选择性gnrh受体拮抗剂（ganirelix）在老年人和年轻人中增加剂量的抑制敏感性来验证。假设二：受损的间质细胞类固醇生成加剧了衰老过程中的低雄激素血症。为了评估这一问题，我们将比较按年龄划分的（24小时）睾酮分泌反应与在gnrh受体阻断5天的情况下，脉冲静脉输注rh LH所获得的实验性正常化色光刺激。假设二：老年男性低雄激素反馈环境导致黄体生成素释放频率高、幅度小、模式不规则。这一概念将通过定量测定年轻男性和老年男性对血浆生物可利用睾酮浓度的新剂量分层钳的LH分泌适应来检验。对衰老相关性腺功能减退的机制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有能力的独立活动。预期的必然结果是加强青春期和成年期男性性腺轴更微妙的病理生理的诊断、评估和管理。

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.