Aging Systems in Geriatrics: the Male Gonadal Axis

描述(由申请人提供)：与25岁相比，健康男性的睾酮(Te)在75岁时的系统利用率下降了35-50%。疾病、创伤、手术、空虚、疼痛、压力、药物治疗和住院进一步减少了老年受试者的TE可获得性。然而，与年龄相关的雄激素逐渐枯竭的主要原因尚不清楚。这个问题很重要，因为贫困的合成代谢加剧了身体的虚弱，加剧了共病，降低了生活质量，并增加了医疗费用。到目前为止已完成的研究表明，多种(而不是单一的)机制介导了老年男性Te的耗竭，即：(I)下丘脑促性腺激素释放激素(GnRH)的释放减少，它驱动垂体黄体生成素(LH)的分泌；(Ii)间质细胞对Lh脉冲的反应受损；以及Te对GnRH和Lh分泌的反馈减少。最后一个问题是理解衰老如何扰乱男性GnRH-Lh-Te轴的核心问题，因为该轴作为一个平衡的前馈和反馈系统运行。因此，这项建议的第一个主要目标是使用R21AG23777-02刚刚开发的新的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/或垂体促黄体生成素分泌的负反馈，在选择性下丘脑-垂体反馈钳下定量。除了与年龄相关的Te可获得性下降外，急性疾病和慢性病的叠加进一步抑制了任何年龄的GnRH-Lh-Te轴。调节抑制效应的机制尚不清楚。应激同时改变合成代谢的GH-IGF-I和分解代谢的ACTH-皮质醇轴。这些观察提出了一个问题，衰老如何影响Te、GH和皮质醇这三个人的压力适应？这一根本问题将在第二个主要目标下讨论，这是一个假设。假设II：实验控制的代谢、炎症和生活方式(睡眠剥夺)应激源将在比年轻男性更大程度上抑制GnRH-LH-Te的分泌，并揭示与年龄相关的GH-IGF-I和ACTH-皮质醇轴的压力适应失败。解开老年男性雄激素耗竭的基础，应该会引发新的预防策略，以避免合成代谢驱动的失败，从而保护老年人的生活质量和功能。 与公共健康相关：衰老会导致骨骼变薄，肌肉变弱，腹部脂肪增多，血糖升高，心脏病发作的风险增加，性能量降低，健忘和医疗残疾增加。某些结果与男性荷尔蒙降低有关，在25岁到75岁之间，男性荷尔蒙下降了约50%。这种下降的原因或方式尚不清楚。这项拨款研究的是大脑、脑下(主)腺和睾丸(男性性腺)的机制，这些机制在老年男性压力下开始失效。

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.