Age-Dependent Estrogen-Independent Mechanism of Hyposomatotropism in Women

描述（由申请人提供）：临床内分泌学中一个尚未解决的主要问题是衰老如何损害合成代谢激素（如GH和IGF-I）的产生。一个科学的僵局出现了，因为现有的研究是混淆的年龄和性腺性类固醇，这也维持生长激素的生产之间的强烈的相互依赖性。区分这两个因素的作用是核心，以制定合理的非甾体类维斯甾体类干预措施，以减少与营养激素驱动的损失。这个主题很重要，因为GH输出减少与骨质减少、肌肉减少、健康受损、内脏肥胖、胰岛素抵抗和心血管发病率和死亡率增加有关。作为解决这一基本问题的一种新方法，我们最近验证了健康绝经前和绝经后妇女短期全身雌二醇（E2）钳夹的研究模型，该模型生动地分离了年龄层和雌激素可用性对GH分泌和伴随的IGF-I产生的影响，并区分了腹部内脏脂肪量（AVF）的23%贡献。这一框架将使我们能够解析第一次调解单独的和综合的影响绝经后和绝经前的年龄和雌激素状态的GH可用性的基本机制。本论文提出，衰老和雌激素剥夺通过改变有限的相互连接的肽系综来减少GH分泌：（i）GH释放激素（GHRH）;（ii）GH释放。肽（GHRP/生长激素释放肽）;和（iii）生长激素抑制素。所有3种信号在生理学上相互关联的事实意味着没有单一肽单独起作用或可以单独有效地解释。将通过成对递送肽基信号，然后评估年龄和E2可用性（在相当的AVF下）如何决定第三（内源性）效应肽的作用，来实验性地剖析包封连接性。这种新的策略将允许非侵入性量化的年龄和E2的不同影响下，以下假设：假设一：年龄降低，而E2增强前馈驱动内源性GHRH和内源性生长激素释放肽的GH分泌;相反，年龄升高和E2减弱内源性SS的GH分泌抑制。假设二：年龄减弱和E2增强了生长激素释放肽的推定能力：（i）放大脉冲GHRH刺激驱动的GH分泌;和（ii）增加间歇性SS抑制引起的反弹样GH分泌。假设三：年龄和E2利用率通过游离（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。方法将包括一个低和生理E2钳在绝经后和绝经前妇女;调整混杂AVF;和应用一个多功能的分析形式主义，以重建合奏控制GH分泌。因此，期望建立机制的贡献，年龄层相对维斯雌激素剥夺的低促生长性在绝经后的设置。了解绝经后年龄的基本机制，独立于E2耗竭，损害GH生产的中央调节应促进创新的方法，以防止老年妇女GH/IGF-I的可用性下降，而不一定需要雌激素补充。绝经后妇女公开服用雌激素具有有限的风险，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。

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.