New Approaches to Evaluation and Treatment of Acromegaly

肢端肥大症评估和治疗的新方法

• 批准号: 7190523
• 负责人: PAMELA U FREDA
• 金额: $ 33.84万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7190523
• 关键词: Acromegaly; Address; Age; Area; Biochemical; Biochemical Markers; Biological Assay; Biometry; Body Composition; C-reactive protein; Characteristics; Chronic; Clinical; Clinical Markers; Cohort Studies; Cross-Over Studies; Data; Desire for food; Disease; Disease Marker; Disease remission; End Point; Ensure; Evaluation; Glucose; Goals; Homocysteine; Homocystine; Hormones; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Interleukin-6; Lead; Link; Lipids; Lipoprotein (a); Lipoprotein (a-); Longevity; Medical; Metabolic; Metabolic Marker; Methods; Modality; Modems; Morbidity - disease rate; Nutritional; Operative Surgical Procedures; Oral; Other Therapy; Outcome; Patients; Pituitary Gland; Postoperative Period; Radiation therapy; Randomized; Range; Recurrence; Research; Risk Marker; Sandostatin Lar Depot; Series; Serum; Somatostatin Analog Therapy; System; Therapeutic; Time; Weight Gain; Work; base; cardiovascular risk factor; cohort; comparative; disability; disorder control; experience; falls; ghrelin; human GHR protein; improved; indexing; insulin sensitivity; mortality; novel strategies; pegvisomant; prevent; prospective; somatostatin analog

The overall goal of this project is to establish and validate the optimal biochemical endpoints for the therapy of acromegaly. In acromegaly, chronic GH and IGF-I excess lead to multi-system manifestations, marked disability and a shortened life span. With modern methods for biochemical evaluation and new medical therapies, in particular long acting somatostatin analogs and the GH antagonist, pegvisomant, we may be able to improve outcome in acromegaly. However, we need to refine our current understanding of the optimal targets for therapy of acromegaly so that we can gauge "GH sufficiency", but also identify mild GH excess and prevent GH deficiency due to treatment. The aims of this project address this need. The first specific aim is to establish those levels of serum IGF-I and GH that will normalize long term outcome in acromegaly. We will establish criteria for GH suppression after oral glucose with a highly sensitive GH assay that may predict postoperative disease recurrence and validate IGF-I as a marker of disease activity based on comparison to morbidity and mortality outcomes. The second aim is to examine serum IGF-I level as a marker of disease control by assessing metabolic abnormalities, in particular insulin resistance, and body composition, a clinical marker of GH action in acromegaly, in relation to specific IGF-I levels during treatment with the potent GH antagonist, pegvisomant. It is our hypothesis that these combined assessments will give us a sensitive index by which we can gauge optimal IGF-I goals for therapy. The third aim is to compare somatostatin analog vs. pegvisomant therapy in a randomized study of patients with active acromegaly in order to determine which therapy is optimal in terms of normalizing IGF-I levels and insulin sensitivity. The fourth aim is to study the secretion of ghrelin, the newly identified hormone strongly linked to nutritional state and the GH axis, in acromegaly. Dysregulated ghrelin secretion and further ghrelin changes with therapy may be related to metabolic and biochemical abnormalities and could impact on body composition in acromegaly. Our work to date has firmly established a uniquely large cohort of patients with acromegaly and set the groundwork for this project. The experience of the PI in developing and evaluating this cohort and her clinical experience with these new medical therapies as well as the expertise of the collaborative research team covering areas of body composition analysis, insulin action, biostatistics and pituitary surgery make the team well equipped to accomplish the aims of this proposal.

该项目的总体目标是建立和验证肢端肥大症治疗的最佳生化终点。在肢端肥大中，慢性GH和IGF-I过剩会导致多系统表现，明显的残疾和寿命缩短。借助生化评估和新的医学疗法的现代方法，特别是长期表现的生长抑素类似物和GH拮抗剂Pegvisomant，我们可能能够改善杂技的结果。但是，我们需要完善我们目前对肢端肥大治疗的最佳目标的理解，以便我们可以衡量“ GH充足性”，但也可以确定温和的GH过量并防止因治疗而导致的GH缺乏症。该项目的目的解决了这一需求。第一个具体目的是建立将在肢端肥大中长期结局正常化的血清IGF-I和GH水平。我们将在口服葡萄糖和高度敏感的GH测定后建立抑制GH的标准，该测定可能预测术后疾病复发并验证IGF-I作为疾病活动的标志 基于与发病率和死亡率结果的比较。第二个目的是通过评估代谢异常，尤其是胰岛素抵抗和身体成分，这是肢端肿瘤中GH作用的临床标志，与特定的IGF-I水平相关，通过评估代谢异常，特别是胰岛素抵抗和身体成分，将血清IGF-1水平作为疾病控制的标志。我们的假设是，这些联合评估将为我们提供一个敏感的指数，我们可以通过该指数来衡量最佳的IGF-I治疗目标。第三个目的是在一项对活跃肢端肥大症患者的随机研究中比较生长抑素模拟与PEGVISOMANT疗法，以确定哪种治疗在标准化IGF-I水平和胰岛素敏感性方面是最佳的。第四个目的是研究新近鉴定的激素与营养状态和GH轴的分泌。血清素分泌失调和治疗的进一步变化可能与代谢和生化异常有关，并可能影响肢端肥大症的人体组成。迄今为止，我们的工作已经牢固地建立了一大批具有肢端肥大的患者，并为该项目奠定了基础。 PI在开发和评估这些队列的经验以及她在这些新的医疗疗法方面的临床经验以及涵盖人体组成分析，胰岛素动作，生物统计学和垂体手术领域的协作研究团队的专业知识，使团队能够很好地完成该提案的目标。