DIAGNOSTIC AND THERAPEUTIC APPLICATIONS OF GROWTH HORMONE-RELEASING HORMONE

生长激素(GH)，一种刺激体态生长的脑下垂体激素 和新陈代谢，由两个下丘脑肽调节：GH释放 激素(GHRH)和生长抑素(SRIF)。大多数生长激素缺乏症患者 (GHD)有GHRH分泌不足。该项目旨在 描述GHRH和SRIF调节的生理学并将其应用于 生长激素缺乏和过度的诊断和治疗。 多巴胺能(DA)和去甲肾上腺素(NE)都能刺激生长激素 分泌，而β-肾上腺素能药物(E)刺激SRIF；但 对这一制度的详细监管尚不清楚。赠送猴子 二乙基二硫代氨基甲酸酯(DDTC)抑制DA向NE的转化，显示 显著降低对GHRH和自发GH分泌的反应，这是 不能被β-肾上腺素能阻滞剂逆转。这表明DA需要 局部转化为去甲肾上腺素刺激GHRH分泌，去甲肾上腺素可能抑制 分泌SRIF。接受慢性DDTC治疗的大鼠表现出生长减慢。 这为可逆性GHD提供了一种新的模型。 由于GHD在很大程度上是由于GHRH缺乏所致，GHRH治疗可以治疗 生长激素缺乏症。我们已经进行了一项为期一年的GHRH治疗的合作试验 一大群GHD儿童。促性腺激素释放激素完全有效地恢复正常 大多数患者的生长速度较快。 由于GHRH的可变干扰，GH对GHRH的反应是高度可变的 SRIF。我们已经测试了联合管理SRIF封锁的效用 GHRH联合治疗生长激素缺乏症。初步结果表明，E 阻滞剂可增强生长对GHRH的反应。 GHRH是一个大分子，但我们已经发现GH释放的程度很高 口服有效的人工合成六肽(GHRP)的活性。温室气体排放计划 似乎能刺激GHRH的释放。 垂体瘤高分泌生长激素(肢端肥大症)对 GHRH，尽管全身性反调节反应(SRIF)增加。 我们已经开发出一种候选配体导向的细胞毒剂用于治疗。 通过将GHRH偶联到一种有机硼化合物来治疗肢端肥大症 阿尔法暴露在中子中时会衰变。因此，GHRH可能构成小说的基础 生长激素缺乏症和生长激素过多的治疗方法。

Growth hormone (GH), the pituitary hormone which stimulates statural growth and metabolism, is regulated by two hypothalamic peptides: GH-releasing hormone (GHRH) and somatostatin (SRIF). Most patients with GH deficiency (GHD) have a deficiency of GHRH secretion. This project aims to characterize the physiology of GHRH and SRIF regulation and to apply these findings in the diagnosis and therapy of GH deficiency and excess. Both dopaminergic (DA) and noradrenergic (NE) agents stimulate GH secretion, while beta-adrenergic agents (E) stimulate SRIF; but the detailed regulation of this system is not understood. Monkeys given diethyldithiocarbamate (DDTC), which inhibits conversion of DA to NE, show markedly reduced responses to GHRH and spontaneous GH secretion, which is not reversed with beta-adrenergic blockade. This indicates that DA requires local conversion to NE to stimulate GHRH secretion, and that NE may inhibit secretion of SRIF. Rats given chronic DDTC treatment show reduced growth. This provides a new model of reversible GHD. Since GHD largely results from deficiency of GHRH, GHRH therapy can treat GHD. We have conducted a cooperative trial of 1 year GHRH therapy in a large group of GHD children. GHRH is fully effective in restoring normal growth velocity in the majority of patients. GH responses to GHRH are highly variable, due to variable interference by SRIF. We have tested the utility of coadministration of SRIF blockade in combination with GHRH therapy of GHD. Preliminary results suggest that E blockade enhances the growth response to GHRH. GHRH is a large molecule, but we have found a high degree of GH-releasing activity in a synthetic hexapeptide (GHRP) which is effective orally. GHRP appears to stimulate release of GHRH. Pituitary tumors hypersecreting GH (acromegaly) retain responsivity to GHRH, although systemic counterregulatory responses (SRIF) are increased. We have developed a candidate ligand-directed cytotoxic agent for therapy of acromegaly by coupling GHRH to an organoboron compound which undergoes alpha decay when exposed to neutrons. Thus GHRH may form the basis of novel approaches to the therapy of GHD and GH excess.