生长激素缺乏症临床分析

生长激素缺乏症（growth hormone defeiciency，GHD）是导致儿童身材矮小的常见原因之一，2006至2008年我科矮小门诊在以身材矮小为主诉就诊的儿童中查出GHD患者27例，报告如下。     

重组人生长激素鼻腔给药系统研究进展

重组人生长激素（Recombinant human growth hormone，rhGH）具有与人体内源生长激素同等的作用，临床广泛用于内源性生长激素缺乏症、慢性肾功能衰竭、特纳氏综合征所致儿童生长缓慢以及重度烧伤的治疗。鼻粘膜给药避开了胃肠道消化酶的破坏及肝脏首关效应的影响，既提高了生物利用度，又避免了因药物引起的胃肠道反应，降低肝脏对药物代谢的负荷及药物对肝脏的不良反应。重组人生长激素的鼻腔给药主要是利用各种促进剂来增强鼻腔对生长激素的吸收。     

GHRP-6对培养的垂体生长激素腺瘤和正常胚胎垂体细胞促GH分泌特征

目的　研究人工合成的生长激素释放剂GHRP 6对体外培养的人垂体生长激素腺瘤细胞GH分泌影响 ,并分析其可能的临床意义。方法　用原代细胞培养技术 ,观察了 6例垂体GH腺瘤细胞和 4例正常胚胎垂体细胞对GHRP 6、生长释放激素 (GH releasinghormone,GHRH)和生长抑素 (somatostatin ,SS)的体外分泌效应。 结果　GHRP 6对所有 6例GH腺瘤细胞GH分泌表现出明显的刺激效应 (P <0 0 1) ,但远不如正常垂体细胞敏感 ,但GH腺瘤细胞对持续的GHRP 6刺激反应时间延长。GHRH和SS仅对部分GH腺瘤细胞有作用 ,且SS不能完全阻断GHRP 6对于GH分泌的刺激效应。结论　GH腺瘤细胞对于体外GHRP 6持续刺激的异常反应 ,表明垂体GH腺瘤中可能存在GH释放剂受体 (GHS R)所固有的负反馈机制———“脱敏”机制的减弱 ,且与肿瘤发病机制有关     

成人生长激素缺乏症与骨质疏松

成人生长激素缺乏症（adult growth hormone deficiency,AGHD）是一组临床表现变化多样的综合征,以体质量减少、骨密度（bone mineral density,BMD）下降、内脏脂肪增多[1]、胰岛素抵抗、血脂异常、肌肉强度及活动耐量减弱、生活质量下降[2]等为特点。骨质疏松特征为BMD降低所致的骨脆性增加,因而轻微创伤即可导致骨折,其发病机制包括成年期低峰值BMD的获得导致骨质疏松风险增高和绝经后骨质快速丢失。     

非肽类生长抑素类似物研究进展

天然的生长抑素（Somatostatin,SST）是一种小的调节肽,作为生长激素释放抑制因子于1973年从羊的下丘脑腺体分离出来,广泛分布于人体各个系统,包括下丘脑一垂体、内分泌、胃肠道消化、脉管、免疫、中枢和外周神经、造血系统等。天然SST分布广泛、作用多样,但半衰期短（小于3min）,故人们对其肽骨架进行了各种结构修饰,     

聚乙二醇对生长激素释放肽的化学修饰

目的为得到生长激素释放肽-2(growth hormone releasing peptide-2,GHRP-2)的聚乙二醇(mPEG)修饰产物并考察其稳定性。方法采用mPEG-NHS活性酯,在不同的溶剂条件下,用不同的投料比对GHRP-2进行修饰;HPLC检测反应结果;Sephadex 75凝胶层析法进行分离纯化。结果确定以无水二甲基甲酰胺为溶剂,m(PEG-NHS)∶m(GHRP-2)=1∶1为最佳条件,原料基本消失,主要得到单修饰的GHRP-2。所得产物在pH7.4、pH8.4、pH9.4缓冲液中50 d时的释药率分别为2.1%、7.2%、20.5%。结论无水条件更有利于mPEG-NHS活性酯对GHRP-2的修饰,产物在体外弱碱性条件下较稳定。     

生长抑素类似物治疗垂体生长激素瘤短期治疗观察

人类天然生长抑素为十四肽，有抑制垂体前叶分泌生长激素（GH）的功能，但其半衰期非常短（3～5分钟），不适于临床应用。国外于八十年代中期开发出半衰期长（约2小时）、结构类似的环状八肽生长抑素Sandostatin，并用于垂体GH瘤的试验性临床治疗。我们于1992年用此药完成3例病     

诊断成人生长激素缺乏症新药-macimorelin acetate研究进展

成人生长激素缺乏症(Adult growth hormone deficiency,AGHD)是一种通常由于肿瘤、手术、放疗或区域的创伤引起脑垂体或下丘脑受损导致生长激素缺乏或继发于儿童期生长激素缺乏的病症。目前,一般临床确诊AGHD均采用生长激素(Growth hormone,GH)兴奋试验,但由于其给药方式为静脉注射,加之存在禁忌证及不良反应,使其临床使用受限。macimorelin acetate作为一种新型口服活性生长激素释放肽受体激动剂,在AGHD诊断中使用方便、分辨率高、重复性好,且不良反应少,已被美国FDA批准用于成人生长激素缺乏症的诊断。本文对该药的作用机制、药动学、药效学、不良反应等方面进行综述。     

妊娠对肢端肥大症的影响

肢端肥大症是一种起病隐匿的慢性进展性内分泌疾病,其主要特征是体内产生过量生长激素(growth hormone,GH),而大多数的肢端肥大症患者是由于GH分泌性垂体细胞腺瘤所致。近日法国学者Caron等进行了一项多中心回顾性研究。该研究选择46例患有垂体生长激素细胞腺瘤的女性作为研究对象,其中7例为垂体微腺瘤,39例为垂体大腺瘤,平均年     

饥饿激素可能影响酒精依赖

胃制造的一种帮助引起饥饿的激素——生长激素释放肽（Ghrelin）可能也在酒精依赖的发展中起作用。Elisabet Jerlhag及其同事发现，给小鼠服用生长激素释放肽导致了酒精摄入的增加，而阻断生长激素释放肽的作用能减少酒精摄入。     

The Growth Hormone‐Releasing Hormone Receptor: Desensitisation Following Short‐Term Agonist Exposure*

Abstract: We have investigated the effect of short‐term preexposure of growth hormone‐releasing hormone (GHRH) on the subsequent response to GHRH in a baby hamster kidney (BHK) cell line expressing the human GHRH receptor and in primary rat pituitary cells. In the BHK cells the receptor was rapidly desensitised in a homologous fashion. Preexposure with agents directly stimulating the cAMP pathway like forskolin and db‐cAMP had no effect. In rat pituitary cells we also observed a rapid desensitisation of the GHRH response in an apparently homologous fashion. In both systems the desensitisation was dose‐dependent with no change in the potency of the hormone in a subsequent stimulation, only the efficacy was decreased. In the rat pituitary cell, the response measured as growth hormone release was more sensitive to the agonist‐induced desensitisation than the cAMP response. No indication of depletion of growth hormone (GH) stores was seen. In rat pituitary cells, contrary to observations in BHK cells, preexposure with both forskolin and db‐cAMP desensitised a subsequent growth hormone‐releasing hormone stimulation, indicating a heterologous desensitisation. Phorbol‐12‐myristate 13‐acetate (PMA), on the other hand, had no effect. In the baby hamster kidney cells it was demonstrated that the GHRH receptor surface expression decreased following preexposure with GHRH. This phenomenon was observed only in whole cells suggesting a rapid internalisation process. Together, these data indicate that after short‐term GHRH preexposure, both in a human and rat system, the following GHRH response is desensitised. In BHK cells this desensitisation is strictly homologous. In rat pituitary cells, on the other hand, the desensitisation is a mixed homologous/heterologous type.     

Role of Glucocorticoids in Fasting-induced Changes in Hypothalamic and Pituitary Components of the Growth Hormone (GH)-axis

To directly test if elevated glucocorticoids are required for fasting-induced regulation of growth hormone (GH)-releasing hormone (GHRH), GHRH receptors (GHRH-R) and ghrelin receptors (GHS-R) expression, male rats were bilaterally adrenalectomized or sham operated. After 7 days, animals were fed ad libitum or fasted for 48 h. Bilateral adrenalectomy increased hypothalamic GHRH to 146% and decreased neuropeptide Y (NPY) mRNA to 54% of SHAM controls. Pituitary GHRH-R and GHS-R mRNA levels were decreased by adrenalectomy to 30% and 80% of sham-operated controls. In shamoperated rats, fasting suppressed hypothalamic GHRH (49%) and stimulated NPY (166%) mRNA levels, while fasting increased pituitary GHRH-R (391%) and GHS-R (218%) mRNA levels. However, in adrenalectomized rats, fasting failed to alter pituitary GHRH-R mRNA levels, while the fasting-induced suppression of GHRH and elevation of NPY and GHS-R mRNA levels remained intact. In fasted adrenalectomized rats, corticosterone replacement increased GHRH-R mRNA levels and intensified the fasting-induced decrease in GHRH, but did not alter NPY or GHS-R response. These data suggest that elevated glucocorticoids mediate the effects of fasting on hypothalamic GHRH and pituitary GHRH-R expression, while glucocorticoids are likely not the major determinant in fasting-induced increases in hypothalamic NPY and pituitary GHS-R expression.     

胰岛素左旋多巴激发生长激素试验

目的探讨胰岛素、左旋多巴在生长激素激发试验中的应用。方法对74例发育迟缓患儿在空腹状态下，分别在用胰岛素、左旋多巴的0、15、30、45、60、90、120min采静脉血送检。结果在试验的74例患儿中，除1例患儿因胰岛素渗入皮下需择日重做外，无一例出现严重低血糖反应或其他并发症。结论同时应用胰岛素、左旋多巴做生长激素激发试验是安全可靠值得推广的新技术。     

Effect of hydrocortisone on the pituitary response to growth hormone releasing hormone

RATIONALE: In depression, the growth hormone (GH) response to clonidine and L-tryptophan (L-TRP) is reduced, suggesting reduced alpha2-adrenergic and serotonin (5-HT)1A receptor function. Pretreatment with hydrocortisone (100 mg, orally 11 h before) also blunts the GH response to L-TRP. This effect may be mediated at the hypothalamic level via reduced 5-HT1A receptor function or at the pituitary level, either by a direct effect on somatotrope cells or via enhanced insulin-like growth factor-1 (IGF-1) or somatostatin (SS) release. OBJECTIVES: To examine the effects of acute and chronic exposure to hydrocortisone on baseline and stimulated GH release from the pituitary. METHODS: Twelve healthy male volunteers received pretreatment with acute hydrocortisone (100 mg, 11 h before), chronic hydrocortisone (20 mg twice a day for 1 week) and placebo in a double blind, balanced order, crossover design. Serial measurements of plasma GH, IGF-1 and thyroid stimulating hormone (TSH) levels were made at baseline and following intravenous administration of 1 mcg/kg GHRH. RESULTS: The GH response to growth hormone releasing hormone (GHRH) was significantly blunted by pretreatment with both acute and chronic hydrocortisone. Baseline IGF-1 levels were significantly lower at baseline after chronic hydrocortisone compared with placebo. Baseline TSH levels were significantly lower after acute hydrocortisone compared with placebo, suggesting an increase in somatostatin levels. CONCLUSIONS: These data suggest that hydrocortisone acts at the pituitary level to reduce GH release. The TSH and IGF-1 data support the hypothesis that hydrocortisone reduces GH release by enhancing somatostatin and IGF-1 release.     

Growth hormone-releasing activity of hexarelin in humans

Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH₂) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·g·kg^–1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (C_max) were 3.9, 26.9, 52.3, 55.0 ng·ml^–1 after 0, 0.5, 1 and 2 g·kg^–1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC_0–180) were 0.135, 1.412, 2.918 and 3.695 g·min·ml^–1. The theoretical maximum response (E_max) and the dose that produces half of the maximum response (ED₅₀) were estimated using logistic regression. The calculated ED₅₀ values were 0.50 and 0.64 g·kg^–1 for C_max and AUC_0–180, respectively. The corresponding E_maxs were 55.1 ng·ml^–1 and 3936 ng·min·ml^–1, thus indicating that the effect after the 2 g·kg^–1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.     

矮小儿生长激素激发实验中生长激素高峰时间的探讨

目的寻找生长激素激发实验中激素水平高峰时间,以减少临床抽血次数,减少患儿痛苦。方法对2010年1月至2012年4月因矮小(符合中华医学会儿科学会内分泌遗传代谢学组2008年指定的身材矮小诊断标准)来笔者所在医院儿科生长发育及内分泌专业就诊,且完成生长激素刺激试验的416例患儿的生长激素激发试验检查结果进行分析,以了解生长激素刺激试验中的生长激素达峰时间的规律。结果生长激素刺激试验后90min生长激素水平(5.09±4.96pg/mL)高于0min(1.66±2.60 pg/mL)、30min(2.04±3.62pg/mL)、60min(4.46±5.57pg/mL)、120min(3.10±3.62pg/mL),60min生长激素水平高于0min、30min及120min生长激素水平,具有统计学差异(P<0.05)。结论精氨酸与左旋多巴联合激发试验可于试验后60min及90min采取血样测试,以减少患儿采血所带来的痛苦。     

Small molecule mimetics of GHRP-6

In 1981, Bowers reported that xenobiotic peptides, derived from the Leu- and Met- enkephalins, demonstrated novel growth hormone (GH) secretory activity. The most potent peptide reported, GH releasing peptide-6 (GHRP-6), was shown to release GH by a different pathway to the known signalling peptide, growth hormone releasing hormone (GHRH). The discovery of a peptidyl GH secretagogue laid the foundation for the search for smaller, orally active mimetics of GHRP-6, as well as for its mechanism of action. This review focuses on the recent developments in the field of small molecule GH secretagogues from a medicinal chemistry perspective, and discusses various structural classes of mimetics recently reported in the literature.     

Antineoplastic action of growth hormone-releasing hormone (GHRH) antagonists

Some of the antagonists of growth hormone-releasing hormone (GHRH) are able to inhibit the growth of various experimental human cancers. The antitumor effects of first antagonists seemed to be dependent mainly on the disruption of pituitary secretion of growth hormone (GH), followed by the reduction in the levels of circulating insulin-like growth factor (IGF)-1, an important growth factor for cancer cells. It seems obvious, that growth hormone deficiency (GHD) induced by GHRH antagonists with all its complications, could limit the beneficial effects of GHRH antagonists therapy, and decrease patients' quality of life. The discovery of local autocrine/paracrine production of GHRH and other related growth factors in many tumoral tissues, in combination with the wide expression of GHRH receptors on cancer cells, directed the research to the synthesis of more potent GHRH antagonists. These compounds exert strong inhibitory effects directly on tumor growth, with scarce endocrine action. The receptor-mediated mechanisms comprise complex and still not completely understood effects on intracellular signaling pathways that are strictly related to human tumorigenesis. This review summarizes recent patents and latest observations on the antineoplastic role of GHRH antagonists in human tumors with emphasis on potential therapeutic applications in clinical oncology.     

生长激素促生长作用的疗效观察

目的 观察国产基因重组生长激素（r-hGH)的促生长作用。方法 对11例矮小症儿童作用r-hGH，对2例真性性早熟患儿联合应用r-hGH和促性腺激素释放激素类似物（GnRHa)，治疗3个月，比较其治疗前后的生长速率（GV）和身高标准差得分（HtSDS)。结果 经治疗，各类矮小症儿童的GV和HtSDS均有显著提高，其中生长激素缺乏症患儿提高最显著；性早熟组儿童联用GnRHa和r-hGH治疗时的GV略高于未用药时自然GV，其中1例联用时GV明显高于单用GnRHa时GV。结论 r-hGH对各类矮小症患儿和性早熟儿童均有促生长作用。