Aging Systems in Geriatrics: the Male Gonadal Axis

描述（由申请人提供）： 与25岁时相比，75岁时健康男性的睾酮（Te）全身利用率下降35-50%。疾病、创伤、手术、营养不良、疼痛、压力、药物和机构化进一步降低了老年受试者的Te可用性。然而，进行性年龄相关雄激素耗竭的主要原因尚不清楚。这个问题很重要，因为贫困人口会加重身体虚弱，加剧并发症，降低生活质量，增加医疗费用。 迄今为止完成的研究表明，多种（而不是单一）机制介导老年男性的Te消耗，即：(i)减少释放下丘脑促性腺激素释放激素（GnRH），这驱动垂体促黄体生成激素（LH）分泌;（ii）受损Leydig细胞对LH脉冲的反应;和减少反馈Te对GnRH和LH分泌。最后一个问题对于理解衰老如何破坏男性GnRH-LH-Te轴至关重要，因为该轴作为平衡的前馈和反馈系统运行。因此，本提案的第一个主要目标是使用根据R21 AG 23777 -02刚刚开发的新型临床范例和分析方法来确定反馈失败的基础。假设一 年龄干扰雄激素和雌激素受体介导的GnRH流出和/或垂体LH分泌的负反馈，如选择性下丘脑维斯垂体反馈钳下所定量。 除了与年龄相关的Te可用性下降外，叠加的急性疾病和慢性疾病进一步抑制了任何年龄的GnRH-LH-Te轴。介导抑制作用的机制尚不清楚。压力伴随着改变合成代谢GH-IGF-I和分解代谢ACTH-皮质醇轴。这些观察结果提出了一个问题，衰老如何影响Te，GH和皮质醇三者之间的压力适应？这一基本问题将在第二个主要目标下讨论，作为一个假设。假设二。 实验控制的代谢，炎症和生活方式（睡眠剥夺）的压力将抑制GnRH-LH-Te分泌在更大程度上在老年男性比年轻男性，并揭示伴随的年龄相关的失败的压力适应的GH-IGF-I和ACTH-皮质醇轴。 揭示老年男性雄激素耗竭的基础应该会引发新的预防策略，以防止合成代谢驱动的失败，从而保护老年人的生活质量和功能。

DESCRIPTION (provided by applicant): The systemic availability of testosterone (Te) in healthy men declines by 35-50% by age 75 compared with age 25 yr. Illness, trauma, surgery, inanition, pain, stress, medications and institutionalization further reduce Te availability in elderly subjects. However, the primary cause of progressive age-related androgen depletion is not known. The issue is significant, because impoverished anabolism accentuates physical frailty, exacerbates comorbidity, reduces quality of life and expands health-care costs. Studies accomplished to date suggest that multiple (rather than single) mechanisms mediate Te depletion in older men, viz.: (i) decreased release of hypothalamic gonadotropin-releasing hormone (GnRH), which drives pituitary luteinizing hormone (LH) secretion; (ii) impaired Leydig-cell responsiveness to LH pulses; and reduced feedback by Te onto GnRH and LH secretion. The last issue is central to understanding how aging disrupts the male GnRH-LH-Te axis, because the axis operates as a counterbalanced feedforward and feedback system. Accordingly, the first major objective of this proposal is to determine the basis of feedback failure using a novel clinical paradigm and analytical methodology just developed under R21 AG23777-02. Hypothesis I. Age disrupts androgen and estrogen receptor-mediated negative feedback on GnRH outflow and/or pituitary LH secretion, as quantified under a selective hypothalamic vis-¿-vis pituitary feedback clamp. In addition to the age-associated decline in Te availability, superimposed acute illness and chronic disease further suppress the GnRH-LH-Te axis at any age. The mechanisms mediating inhibitory effects are unknown. Stress concomitantly alters the anabolic GH-IGF-I and catabolic ACTH-cortisol axes. These observations raise the question, How does aging impact stress adaptations among all 3 of Te, GH and cortisol? This fundamental issue will be addressed under the second major objective, stated as a hypothesis. Hypothesis II. Experimentally controlled metabolic, inflammatory and lifestyle (sleep-deprivation) stressors will inhibit GnRH-LH-Te secretion to a greater extent in older than young men, and unmask concomitant age-related failure of stress adaptations of the GH-IGF-I and ACTH-cortisol axes. Unraveling the bases of androgen depletion in the aging male should spark new preventive strategies to obviate failure of anabolic drive, and thus preserve quality of life and function in older individuals.