Aging Systems in Geriatrics: the Male Gonadal Axis

描述（由申请人提供）：健康男性在75岁时体内睾酮（Te）的可用性比25岁时下降35-50%。疾病、创伤、手术、营养不良、疼痛、压力、药物治疗和住院治疗进一步降低了老年受试者体内睾酮（Te）的可用性。然而，与年龄相关的进行性雄激素消耗的主要原因尚不清楚。这个问题很重要，因为合成代谢不良加重了身体虚弱，加剧了合并症，降低了生活质量，增加了医疗成本。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)下丘脑促性腺激素释放激素（GnRH）的释放减少，后者驱动垂体黄体生成素（LH）的分泌；（ii） leydigi -cell对LH脉冲的反应性受损；减少了Te对GnRH和LH分泌的反馈。最后一个问题是理解衰老如何破坏男性GnRH-LH-Te轴的核心，因为该轴是一个平衡的前馈和反馈系统。因此，该提案的第一个主要目标是使用R21 AG23777-02下刚刚开发的新型临床范例和分析方法确定反馈失败的基础。假设1 .年龄破坏了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，这是在选择性下丘脑垂体反馈钳下量化的。除了与年龄相关的可得性下降外，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。应激同时改变合成代谢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，衰老是如何影响Te、GH和皮质醇这三种激素的应激适应的？这个基本问题将在第二个主要目标下加以解决，这是一个假设。假设2。实验控制的代谢、炎症和生活方式（睡眠剥夺）压力源将在更大程度上抑制GnRH-LH-Te的分泌，并揭示GH-IGF-I和acth -皮质醇轴的压力适应的年龄相关失败。揭示老年男性雄激素耗竭的基础应该激发新的预防策略，以避免合成代谢驱动的失败，从而保持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. PUBLIC HEALTH RELEVANCE: Aging results in thinner bones, weaker muscles, more abdominal fat, higher blood glucose, greater risk of a heart attack, reduced sexual energy, forgetfulness and increased medical disability. Certain outcomes are related to lower male sex hormones, which fall by about 50% between the ages of 25 and 75 years. Why or how the decline occurs is not known. This grant studies mechanisms in the brain, pituitary (master) gland and testis (male gonad), which begin to fail in aging men under stress.