GROWTH HORMONE RELEASING HORMONE ANTAGONIST INFUSION IN ACROMEGALICS

肢端肥大症是一种由生长激素(GH)分泌过多引起的疾病。大多数病例是由于脑下垂体肿瘤。关于这些肿瘤的形成原因有两种理论：(1)细胞染色体的突变导致肿瘤转化和随后的肿瘤形成。(2)生长激素释放激素(GHRH)(一种由下丘脑产生的刺激GH分泌细胞生长和功能的因子)的过度释放会刺激GH分泌细胞增殖并产生大量GH。这两种理论的结合也可能起作用。此外，垂体瘤细胞也可产生GHRH。我们的假设是，GHRH在导致肢端肥大症的垂体肿瘤的形成和维持肢端肥大症的GH过度分泌方面起着重要作用。我们将试图通过给肢端肥大症患者应用GHRH拮抗剂(GHRH-Ant)来回答这个问题，GHRH-Ant是一种合成分子，可以阻断GHRH对GH产生细胞的作用。将对两组患者进行研究：(A)15名患者(A组)将在两个不同的场合进行24小时的血浆GH频繁采血，目的是表明在没有任何干预的情况下，肢端肥大症患者的GH分泌模式不会每天发生变化，因此我们在使用GHRH-Ant期间观察到的任何变化都将是有意义的。(B)10名新近确诊的肢端肥大症患者，计划接受垂体手术(B组)，将接受静脉注射。GHRH-Ant静脉滴注7d。每隔10分钟测定一次血浆GH，持续24小时，检测GH对导致肢端肥大症患者GH异常反应的因素的反应(静脉注射)。促甲状腺激素释放激素(TRH)和口服葡萄糖)和静脉注射。GHRH将在输注GHRH-Ant之前和结束时进行评估。GHRH-Ant对垂体肿瘤大小的影响将通过注射GHRH-Ant前后的垂体MRI扫描来衡量。手术时取垂体瘤标本，在实验室研究GHRH-Ant对肿瘤细胞产生GH的影响。如果GHRH-Ant抑制GH的分泌，缩小垂体肿瘤的大小，我们将得出结论，GHRH在导致肢端肥大症的垂体肿瘤的形成和维持这种疾病的GH异常分泌方面发挥了作用。

Acromegaly is a disease caused by excessive growth hormone (GH) production. The majority of cases are due to pituitary gland tumors. There are two theories about the cause of these tumors formation: (1) A mutation in a chromosome of a cell leads to neoplastic transformation and subsequent formation of a tumor. (2) Excessive release of GH-releasing hormone (GHRH) (a factor produced by the hypothalamus that stimulates the growth and function of GH-secreting cells) stimulates GH-producing cells to multiply and produce large amounts of GH. Combinations of these two theories could be also functional. Moreover, GHRH can be produced by the pituitary tumor cells. Our hypothesis is that GHRH plays an important role in the formation of the pituitary tumors that cause acromegaly, and in maintaining the excessive GH secretion in acromegaly. We will attempt to answer this question by administering GHRH-antagonist (GHRH-Ant), a synthetic molecule that blocks the action of GHRH on the GH-producing cells, to patients with acromegaly. Two groups of patients will be studied: (a) Fifteen patients (group A) will have frequent blood sampling for plasma GH for 24 hours on 2 different occasions with the goal to show that without any intervention the GH secretion pattern in acromegaly does not change from day to day so that any changes that we could observe during administration of GHRH-Ant would be meaningful. (b) Ten patients recently diagnosed with acromegaly, who are scheduled to have pituitary surgery (group B) will receive intravenous (i.v.) infusion of GHRH-Ant for 7 days. Plasma GH will be measured every 10 min for 24 h, and the GH responses to factors that cause abnormal GH responses in acromegaly (i.v. thyrotropin-releasing hormone (TRH) and oral glucose) and to i.v. GHRH will be assessed before and at the end of the GHRH-Ant infusion. The effect of GHRH-Ant on the pituitary tumor size will be measured by pituitary MRI scans before and after the GHRH-Ant infusion. At the time of pituitary surgery, a pituitary tumor sample will be obtained to study the effects of GHRH-Ant on the GH production by the tumor cells in the laboratory. If the GHRH-Ant suppresses the secretion of GH and decreases the size of the pituitary tumors, we will conclude that GHRH plays a role in the formation of the pituitary tumors that cause acromegaly and in maintaining abnormal GH secretion in this disease.