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: 8111746
• 负责人: JOHANNES D VELDHUIS
• 金额: $ 35.19万
• 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/8111746
• 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 mass; 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）：临床内分泌学中的一个主要未解决的问题是衰老如何损害GH和IGF-I等合成代谢激素的产生。出现科学僵局是因为现有研究与年龄和性腺性类固醇之间的强烈相互依存相混淆，后者也维持GH的产生。区分这两个因素的作用是构架有理的非甾体类固醇干预措施以消除与营养激素驱动的年龄相关的损失。鉴于GH输出减少与骨质减少，肌肉减少症，健康状况受损，内脏肥胖，胰岛素抵抗以及心血管发病率和死亡率增加有关，因此这一主题很重要。作为解决这个基本问题的一种新型方法，我们最近验证了一种在健康前体和绝经后妇女中的短期全身性雌二醇（E2）夹的研究模型，该模型生动地分开了年龄层的影响和雌激素对GH分泌的影响对GH分泌的影响对分泌物的分泌对IGF-I的生产，并侵害了23％的AB量（AVFF）的贡献（AVFF）的贡献（AVFF）占了23％的贡献。该框架将使我们能够首次解析基本机制，这些机制介导了绝经后年龄和雌激素对GH的可用性的分离和综合作用。论文的提前是，衰老和雌激素剥夺通过修饰有限的相互链接肽的合奏来减少GH分泌：（i）GH-释放激素（GHRH）； （ii）释放GH。肽（GHRP/GHRELIN）; （iii）生长抑素。所有3个信号在生理上相互联系的事实意味着没有单一的肽单独起作用或可以隔离地有效解释。将通过成对传递肽基信号，然后评估年龄和E2的可用性（在可比AVF上）确定第三（内源性）效应子肽的作用，从而通过实验进行集合连通性。在以下假设下，这种新的策略将允许对年龄和E2的不同效应进行非侵入性量化：假设I：年龄降低，而E2则增强了内源性GHRH和内源性生长素素的GH分泌驱动。相反，年龄升高，E2会减轻内源SS对GH分泌的抑制。假设II：年龄减弱和E2增强了生长素素的推定能力为：（i）放大由脉冲GHRH刺激驱动的GH分泌； （ii）增强间歇性SS抑制引起的类似反弹的GH分泌。假设III：年龄和E2的可用性共同调节浓度依赖性的负面反馈（蛋白质 - 无抗能）IGF-I，从而控制平均每日GH分泌。方法论将包括后期和绝经前妇女的低和生理E2夹；对AVF混淆的调整；并应用多功能分析形式主义来重建对GH分泌的集合控制。因此，期望是建立年龄层相对于雌激素剥夺对绝经后环境中低体性的机械贡献。了解绝经后年龄独立于E2耗竭的基本机制，损害了GH产量的中心调节，应促进创新的方法来阻止衰老妇女的GH/IGF-I可用性下降，而不必需要雌激素。绝经后妇女的公共雌激素给药具有有限的风险，并且在某些患者组中被禁忌。因此，该提案试图阐明控制主要营养激素GH和IGF-I的产生的基本机制，以维持骨骼和肌肉质量，减少腹部脂肪并提高生活质量。