Age-Dependent Estrogen-Independent Mechanism of Hyposomatotropism in Women

女性年龄依赖性、雌激素非依赖性的促生长功能减退机制

• 批准号: 7921961
• 负责人: JOHANNES D VELDHUIS
• 金额: $ 36.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921961
• 关键词: Abbreviations; Abdomen; Abdominal Mass; Address; Age; Aging; Attenuated; Body Composition; Cardiovascular system; Clinical Endocrinology; Clinical Research; Data; Estradiol; Estrogens; Failure; Fatty acid glycerol esters; Feedback; Fostering; Gene Silencing; Gonadal Steroid Hormones; Hormones; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Investigation; Laboratories; Mediating; Menopause; Methodology; Modeling; Morbidity - disease rate; Mutation; Obesity; Osteopenia; Output; Patients; Peptides; Physiological; Postmenopause; Premenopause; Production; Proteins; Quality of life; Regulation; Regulatory Pathway; Relative (related person); Risk; Role; Signal Transduction; Somatostatin; Somatotropin-Releasing Hormone; Testing; Time; Visceral; Woman; abdominal fat; age effect; age related; analytical method; analytical tool; base; bone; deprivation; expectation; ghrelin; growth hormone-releasing peptide; innovation; insight; mortality; muscle form; novel; novel strategies; research study; sarcopenia

DESCRIPTION (provided by applicant): A major unresolved question in clinical endocrinology is how aging impairs the production of anabolic hormones, such as GH and IGF-I. A scientific impasse arises because existing studies are confounded by the strong interdependence between age and gonadal sex steroids, which also maintain GH production. Distinguishing the roles of these two factors is central to framing rational nonsteroidal vis-a-vis steroidal interventions to obviate age-associated loss of trophic-hormone drive. The theme is important, given that diminished GH output is associated with osteopenia, sarcopenia, impaired well being, visceral adiposity, insulin resistance, and increased cardiovascular morbidity and mortality. As a novel approach to this fundamental problem, we recently validated an investigative model of a short-term systemic estradiol (E2) clamp in healthy premenopausal and postmenopausal women that vividly separates the impact of age stratum and estrogen availability on GH secretion and attendant IGF-I production, and discriminates a 23% contribution of abdominal visceral fat mass (AVF). This framework will allow us to parse for the first time the fundamental mechanisms that mediate separate and combined effects of post- and premenopausal age and estrogenic status on GH availability. The thesis advanced is that aging and estrogen deprivation reduce GH secretion by modifying a finite ensemble of interlinked peptides: (i) GH-releasing hormone (GHRH); (ii) GH-releasing . peptide (GHRP/ghrelin); and (iii) somatostatin. The fact that all 3 signals are physiologically interlinked means that no single peptide acts alone or may be validly interpreted in isolation. Ensemble connectivity will be dissected experimentally by delivering peptidyl signals in pairs and then assessing how age and E2 availability (at comparable AVF) determine actions of the third (endogenous) effector peptide. This new stratagem will permit noninvasive quantification of distinct effects of age and E2 under the following hypotheses: Hypothesis I: Age reduces whereas E2 enhances feedforward drive of GH secretion by endogenous GHRH and endogenous ghrelin; and conversely age elevates and E2 attenuates inhibition of GH secretion by endogenous SS. Hypothesis II: Age attenuates and E2 potentiates the putative capabilities of ghrelin to: (i) amplify GH secretion driven by pulsatile GHRH stimulation; and (ii) augment rebound-like GH secretion evoked by intermittent SS inhibition. Hypothesis III: Age and E2 availability jointly modulate concentration-dependent negative feedback by free (protein-unbound) IGF-I, thus controlling mean daily GH secretion. Methodologies will include a low and physiological E2 clamp in both post- and premenopausal women; adjustments for confounding by AVF; and application of a versatile analytical formalism to reconstruct ensemble control of GH secretion. The expectation thereby is to establish the mechanistic contributions of age stratum vis-a-vis estrogen deprivation to hyposomatotropism in the postmenopausal setting. Understanding the fundamental mechanisms by which postmenopausal age, independently of E2 depletion, impairs central regulation of GH production should foster innovative approaches to forestall the decline in GH/IGF-I availability in aging women without necessarily requiring estrogen repletion. Public Precis Estrogen administration in postmenopausal women carries a finite risk and is contraindicated in some patient groups. Therefore, this proposal seeks to unravel fundamental mechanisms that control the production of the major trophic hormones GH and IGF-I, which maintain bone and muscle mass, reduce abdominal fat and enhance quality of life.

描述（由申请人提供）：临床内分泌学中一个未解决的主要问题是衰老如何损害合成代谢激素（例如 GH 和 IGF-I）的产生。科学僵局之所以出现，是因为现有的研究因年龄和性腺性类固醇之间的强烈相互依赖性而混淆，而性类固醇也维持生长激素的产生。区分这两个因素的作用对于制定合理的非类固醇与类固醇干预措施至关重要，以避免与年龄相关的营养激素驱动力丧失。鉴于 GH 输出减少与骨质减少、肌肉减少症、健康受损、内脏肥胖、胰岛素抵抗以及心血管发病率和死亡率增加相关，这一主题很重要。作为解决这一基本问题的新方法，我们最近在健康的绝经前和绝经后女性中验证了短期全身雌二醇（E2）钳夹的研究模型，该模型生动地区分了年龄层和雌激素可用性对 GH 分泌和随之而来的 IGF 的影响。 I 产生，并区分腹部内脏脂肪量 (AVF) 的 23% 贡献。这个框架将使我们首次解析介导绝经后和绝经前年龄以及雌激素状态对 GH 可用性的单独和综合影响的基本机制。该论文提出，衰老和雌激素剥夺通过改变有限的相互连接的肽集合来减少 GH 分泌：（i） GH 释放激素（GHRH）； (ii) GH 释放。肽（GHRP/生长素释放肽）； (iii) 生长抑素。所有 3 个信号在生理学上都是相互关联的，这意味着没有任何单个肽可以单独发挥作用或可以单独有效地解释。通过成对传递肽基信号，然后评估年龄和 E2 可用性（在可比较的 AVF 下）如何决定第三个（内源性）效应肽的作用，通过实验剖析整体连接性。这一新策略将允许在以下假设下对年龄和 E2 的不同影响进行无创量化： 假设 I：年龄降低，而 E2 增强内源 GHRH 和内源 ghrelin 对 GH 分泌的前馈驱动；相反，随着年龄的增长，E2 会减弱内源性 SS 对 GH 分泌的抑制。假设 II：年龄会减弱，E2 会增强 ghrelin 的推定能力：(i) 增强脉动 GHRH 刺激驱动的 GH 分泌； (ii) 增强间歇性 SS 抑制引起的反弹样 GH 分泌。假设 III：年龄和 E2 可用性通过游离（蛋白质未结合）IGF-I 共同调节浓度依赖性负反馈，从而控制平均每日 GH 分泌。方法包括对绝经后和绝经前女性进行低生理 E2 钳夹； AVF 混杂调整；以及应用多功能分析形式来重建 GH 分泌的整体控制。因此，期望确定年龄层相对于雌激素剥夺对绝经后体质低下的机制贡献。了解绝经后年龄（与 E2 消耗无关）损害 GH 产生的中央调节的基本机制，应促进创新方法，以防止老年女性 GH/IGF-I 可用性下降，而无需补充雌激素。绝经后妇女使用公共 Precis 雌激素的风险有限，并且在某些患者群体中是禁忌的。因此，该提案旨在揭示控制主要营养激素 GH 和 IGF-I 产生的基本机制，这些激素维持骨骼和肌肉质量，减少腹部脂肪并提高生活质量。