New Approaches to Evaluation and Treatment of Acromegaly

该项目的总体目标是建立和验证治疗肢端肥大症的最佳生化终点。在肢端肥大症中，慢性GH和IGF-I过量导致多系统表现，明显残疾和寿命缩短。有了现代的生化评估方法和新的药物治疗，特别是长效生长抑素类似物和生长激素拮抗剂，我们可能能够改善肢端肥大症的预后。然而，我们需要完善我们目前对肢端肥大症治疗的最佳靶点的理解，以便我们能够测量“GH充分性”，同时也识别轻微的GH过剩和预防由于治疗而导致的GH缺乏症。这个项目的目的就是满足这一需求。第一个特定的目标是确定那些将使肢端肥大症的长期结果正常化的血清IGF-I和GH水平。我们将建立口服葡萄糖后生长激素抑制的标准，用高灵敏度的生长激素测定来预测术后疾病的复发，并验证IGF-I作为疾病活动性的标志。 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，特别是胰岛素抵抗，以及身体成分(肢端肥大症中生长激素作用的临床标志)与有效的生长激素拮抗剂聚乙二醇胺治疗期间特定的胰岛素样生长因子-I水平的关系，来检测血清IGF-I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，通过它我们可以衡量治疗的最佳IGF-I目标。第三个目的是在一项针对活动期肢端肥大症患者的随机研究中，比较生长抑素类似物和聚乙二醇胺治疗，以确定哪种疗法在使IGF-I水平和胰岛素敏感性正常化方面是最佳的。第四个目的是研究肢端肥大症患者Ghrelin的分泌，Ghrelin是一种新发现的激素，与营养状态和GH轴密切相关。肢端肥大症患者的胃促生长素分泌异常和治疗后胃促生长素的进一步变化可能与代谢和生化异常有关，并可能影响身体成分。到目前为止，我们的工作已经稳固地建立了一个独特的巨大的肢端肥大症患者队列，并为这个项目奠定了基础。PI在开发和评估这一队列方面的经验，以及她在这些新医疗疗法方面的临床经验，以及合作研究团队在身体成分分析、胰岛素作用、生物统计学和脑下手术等领域的专业知识，使该团队有能力实现这项提案的目标。

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.