Age-Dependent Estrogen-Independent Mechanism of Hyposomatotropism in Women

描述（由申请方提供）：R 01 AG 029362在绝经后女性中的竞争性更新与正在进行的R37 AG 019695（替吉奥对衰老男性GH轴的作用）的重点相似。在绝经后妇女中，前哨问题是残留的内源性卵巢和肾上腺源性雌激素在GH调节中的作用，以及雌二醇（E2）调节GH产生的下丘脑-垂体机制。内源性E2在GH调节中的作用将使用独特的性类固醇钳夹范例进行研究，该范例旨在抑制雄激素前体的E2合成，并通过ER阻断E2的组织作用。E2作用的机制将使用新的肽选择性钳范例进行研究，以揭示相互作用的肽介导的途径，共同（在合奏）调节脉冲GH分泌。脉冲式GH分泌占每日总GH产量的> 85%。 E2作用的显著物种差异使得临床研究对于机制理解至关重要。临床研究难度的增加反过来又要求应用更强大的分析技术。因此，目前的更新结合了所有三个（1）创新的性类固醇钳;（2）信息肽特异性GH通路钳;和（3）引人注目的新分析方法，剖析整体水平（多途径）机制，迫使绝经后个体的脉冲GH分泌下降。老年女性和男性GH分泌不足的重要性是增加了与低GH状态相关的腹内肥胖、胰岛素抵抗、血脂异常、心血管死亡、肌肉减少、骨质减少和身体虚弱的风险：预防或补救这些风险是维持老年美国公民健康的核心。因此，目标是促进新的非甾体和非肽基手段的开发，以阻止GH和IGF-I驱动的年龄相关性减少。 公共卫生相关性：尽管绝经后年龄会降低，雌激素会刺激GH分泌，但年龄和雌激素发挥作用的机制仍不清楚。目前的研究引入了新的临床范例和更新的技术来解决这两个问题。期望是培养新的方法来限制女性与年龄相关的脆弱性，而不使用雌激素本身。

DESCRIPTION (provided by applicant): This competitive renewal of R01 AG029362 in postmenopausal women parallels the focus of ongoing R37 AG019695 (Actions of Testosterone on the Aging Male GH Axis). In postmenopausal women, sentinel questions are the roles of residual endogenous ovarian and adrenal-derived estrogen in GH regulation, and the hypothalamo-pituitary mechanisms by which estradiol (E2) regulates GH production. The roles of endogenous E2 in GH regulation will be investigated using a unique sex-steroid clamp paradigm designed to inhibit E2 synthesis from androgen precursors, and block tissue actions of E2 via ER. The mechanisms of E2 action will be studied using novel peptide-selective clamp paradigms created to unmask interacting peptide-mediated pathways that jointly (in ensemble) regulate pulsatile GH secretion. Pulsatile GH secretion accounts for > 85% of total daily GH production. Prominent species differences in E2 action make clinical investigations essential for mechanistic understanding. The increased difficulty level of clinical studies in turn requires the application of more powerful analytical technology. Accordingly, the present renewal combines all three of (1) innovative sex-steroid clamps; (2) informative peptide-specific GH-pathway clamps; and (3) compelling new analytical methods to dissect ensemble-level (multipathway) mechanisms forcing the decline of pulsatile GH secretion in postmenopausal individuals. The significance of impoverished GH secretion in aging women and men is the increased risk of intra-abdominal obesity, insulin resistance, dyslipidemia, cardiovascular mortality, sarcopenia, osteopenia and physical frailty associated with the low-GH state: Prevention or remediation of these risks is central to maintaining the health of older U.S. citizens. The goal thereby is to promote the development of new non-steroidal and non-peptidyl means to forestall age-related decrements in GH and IGF-I drive to anabolism. PUBLIC HEALTH RELEVANCE: Although postmenopausal age diminishes and estrogen stimulates GH secretion, the mechanisms by which age and estrogen exert their effects remain unknown. The present studies introduce new clinical paradigms and newer technologies to resolve both issues. The expectation is to foster novel ways to limit age-related frailty in women without using estrogen per se.