DIAGNOSTIC AND THERAPEUTIC APPLICATIONS OF GROWTH HORMONE-RELEASING HORMONE

生长激素释放激素与生长抑素 (SRIF)是两种共同控制下丘脑的多肽 生长激素(GH)合成和释放。该项目的目标是：a) 研究神经内分泌对生长激素分泌的调节；b) 明确不同生理状态下生长激素释放激素反应的变化 并确定其原因；以及c)探索 生长激素释放激素及其类似物治疗生长激素缺乏症的疗效观察 和过度。1)我们研究了 联合应用促生长激素释放激素间接刺激生长激素 胰岛素诱导低血糖(ITT)。ITT有能力增强 即使是对最大刺激量的GHRH的反应， 表明ITT必须激活除释放之外的其他机制 内源性GHRH。最有可能的是ITT 抑制生长抑素的分泌。2)GH分泌残留物 两组正常人GHRH持续混乱时的搏动性 和肢端肥大症患者，表明生长抑素的分泌是 也是间歇性的，并且可变地阻断对GHRH的反应。这个 大鼠GHRH输注过程中GH脉冲频率增加 正常，但在肢端肥大症中没有变化。这表明 SRIF脉冲性分泌可随血容量升高而改变 GH或GHRH--我们在下丘脑证实了这一发现 体外灌流--以及间歇性分泌物的频率 注射GHRH的正常人与肢端肥大症相似。3) 一项正在进行的长期剂量反应研究表明， 每日10mcg/kg GHRH可恢复正常生长速度 许多GH缺乏症患者。我们没有看到显著的 根据管理模式的不同，反应也不同，因此 只要每天的总量足够。生长激素的增强 改变SRIF的药物对急性剂量GHRH的反应 分泌物使我们研究SRIF的变化是否可能 也增强了对慢性GHRH治疗的生长反应。

Growth hormone-releasing hormone (GHRH) and somatostatin (SRIF) are the two hypothalamic peptides which together control growth hormone (GH) synthesis and release. This project aims: a) to study the neuroendocrine regulation of GH secretion; b) to define alterations in GHRH responses in different physiologic states, and to determine their cause; and c) to explore the efficacy of GHRH and analogues for treatment of GH deficiency and excess. 1) We have studied the mechanism underlying the indirect stimulation of GH by co-administering GHRH with insulin-induced hypoglycemia (ITT). ITT is capable of enhancing the response to even a maximally stimulating dose of GHRH, indicating that ITT must activate mechanisms other than release of endogenous GHRH. The likeliest possibility is that ITT suppresses somatostatin secretion. 2) GH secretion remains pulsatile during the continuous confusion of GHRH in both normal and acromegalic subjects, suggesting the somatostatin secretion is also intermittent, and variably blocks the response to GHRH. The frequency of GH pulses increases during GHRH infusions in normals, but is unchanged in acromegalics. This suggests that SRIF pulsatile secretion can change in response to elevations of GH or GHRH -- a finding we have confirmed in hypothalamic perifusions in vitro -- and that the frequency of episodic secretion in GHRH-infused normals resembles that seen in acromegaly. 3) An ongoing long-term dose-response study suggests that a dose of 10mcg/kg GHRH per day can restore normal growth velocity in many patients with GH deficiency. We do not see a significant different in response based on the pattern of administration, so long as the total daily is sufficient. The enhancement of GH responses to acute doses of GHRH by drugs which alter SRIF secretion has led us to study whether alteration of SRIF might also enhance the growth response to chronic GHRH therapy.