Age-Dependent Estrogen-Independent Mechanism of Hyposomatotropism in Women

描述（由申请人提供）：R01 AG029362在绝经后妇女中的竞争性更新与正在进行的R37 AG019695（睾酮对衰老男性GH轴的作用）的重点相似。在绝经后妇女中，哨兵问题是残留的内源性卵巢和肾上腺源性雌激素在生长激素调节中的作用，以及雌二醇（E2）调节生长激素产生的下丘脑-垂体机制。内源性E2在生长激素调节中的作用将通过独特的性类固醇钳范式进行研究，该范式旨在抑制雄激素前体合成E2，并阻断E2通过ER的组织作用。E2的作用机制将使用新的肽选择钳范式来研究，以揭示相互作用的肽介导的途径，这些途径共同（整体）调节脉动性GH分泌。脉动性生长激素分泌占每日生长激素总量的85%。E2作用的显著物种差异使得临床研究对机制理解至关重要。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)创新的性类固醇夹；(2)信息多肽特异性gh通路钳；(3)令人信服的新分析方法，以剖析迫使绝经后个体搏动GH分泌下降的整体水平（多途径）机制。在老年女性和男性中，生长激素分泌不足的意义在于腹部肥胖、胰岛素抵抗、血脂异常、心血管死亡率、肌肉减少症、骨质减少和与低生长激素状态相关的身体虚弱的风险增加：预防或补救这些风险是维持美国老年公民健康的核心。因此，目标是促进新的非甾体和非肽基手段的发展，以防止生长激素和igf - 1驱动合成代谢的年龄相关的下降。

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.