DIAGNOSTIC AND THERAPEUTIC APPLICATIONS OF GROWTH HORMONE-RELEASING HORMONE

生长激素（GH），垂体激素，刺激身高增长 和代谢，由两种下丘脑肽调节：GH释放 激素（GHRH）和生长抑素（SRIF）。大多数GH缺乏症患者 (GHD)缺乏GHRH分泌。该项目旨在 描述GHRH和SRIF调节的生理学特征，并将其应用于 GH缺乏和过量的诊断和治疗中的发现。 多巴胺能（DA）和去甲肾上腺素能（NE）药物均刺激GH 分泌，而β-肾上腺素能药物（E）刺激SRIF;但 对这一制度的详细规定尚不了解。给予的猴子 二乙基二硫代氨基甲酸酯（DDTC），抑制DA转化为NE，显示 显著降低对GHRH和自发GH分泌的反应， β-肾上腺素能阻滞剂不能逆转。这表明DA需要 局部转化为NE刺激GHRH分泌，NE可抑制 SRIF的分泌。长期给予DDTC治疗的大鼠表现出生长减缓。 这提供了一种新的可逆性GHD模型。 由于GHD主要是由于GHRH缺乏，GHRH治疗可以治疗 GHD。我们进行了一项为期1年的GHRH治疗合作试验， 一群GHD儿童。GHRH完全有效地恢复正常 大多数患者的生长速度。 GH对GHRH的反应是高度可变的，这是由于 SRIF。我们已经测试了SRIF封锁联合给药的效用， 联合GHRH治疗GHD。初步结果表明，E 阻断增强了对GHRH的生长反应。 GHRH是一种大分子，但我们发现， 活性的合成六肽（GHRP），这是有效的口服。GHRP 刺激GHRH的释放。 高分泌GH的垂体瘤（肢端肥大症）对 GHRH，尽管系统性反调节反应（SRIF）增加。 我们已经开发了一种候选的配体导向的细胞毒性药物用于治疗 通过将GHRH与有机硼化合物偶联， 当暴露在中子中时发生α衰变。因此，GHRH可能构成小说的基础， GHD和GH过量的治疗方法。

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.