Age-Dependent Estrogen-Independent Mechanism of Hyposomatotropism in Women

描述(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激素的产生，如生长激素和胰岛素样生长因子-I。科学僵局的出现是因为现有的研究被年龄和性腺类固醇之间强烈的相互依赖所混淆，性激素也维持GH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以避免与年龄相关的营养激素驱动丧失至关重要。这一主题很重要，因为生长激素输出减少与骨量减少、骨量减少、幸福感受损、内脏肥胖症、胰岛素抵抗以及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，我们最近在健康的绝经前和绝经后妇女中验证了一个短期全身雌二醇(E2)钳夹的研究模型，该模型生动地区分了年龄层和雌激素供应对GH分泌和伴随的IGF-I产生的影响，并区分了腹部内脏脂肪质量(AVF)的23%的贡献。这一框架将使我们能够首次分析绝经后和绝经前年龄和雌激素状态对生长激素可获得性的单独和联合影响的基本机制。本论文提出，衰老和雌激素缺乏可通过改变GH释放激素(GHRH)和GH释放，从而减少GH的分泌。多肽(GHRP/Ghrelin)；和(Iii)生长抑素。所有这三种信号在生理上都是相互关联的，这意味着没有一种单一的多肽是单独作用的，或者可以单独有效地解释。通过成对传递肽信号，然后评估年龄和雌二醇可得性(在可比的AVF)如何决定第三(内源性)效应肽的作用，将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AGE和E_2的不同作用进行无创性量化：假设I：AGE减少，而E_2增强内源性GHRH和内源性GRELIN对GH分泌的前馈驱动；反之，AGE提高内源性SS对GH分泌的抑制，而E_2减弱内源性SS对GH分泌的抑制。假设II：AGE减弱和E2增强Ghrelin的假定能力：(I)放大由脉动性GHRH刺激驱动的GH分泌；(Ii)增加由间歇性SS抑制引起的反弹样GH分泌。假设III：AGE和E2的可获得性通过游离(蛋白质未结合的)IGF-I共同调节浓度依赖的负反馈，从而控制每日平均GH分泌。方法将包括在绝经后和绝经前的妇女中使用低的生理的E2钳；调整AVF的混杂；以及应用通用的分析形式主义来重建GH分泌的整体控制。因此，我们的期望是建立年龄层相对于雌激素缺乏对绝经后环境中的向性欲减退的机制贡献。了解绝经后年龄与雌二醇耗竭无关地损害生长激素产生的中枢调节的基本机制，应该促进创新的方法，以预防老年妇女GH/IGF-I可获得性的下降，而不一定需要雌激素补充。绝经后妇女在绝经前公开服用雌激素具有有限的风险，在某些患者组是禁忌的。因此，这项提议试图揭示控制主要营养荷尔蒙GH和IGF-I产生的基本机制，这两种荷尔蒙维持骨骼和肌肉质量，减少腹部脂肪，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.