生长激素在儿科临床的应用棗现状与循证

1956年 Raben从人垂体中分离和提纯生长激素( human growth hormone,hGH),并随之应用于治疗生长激素缺乏症( growth hormone deficiency,GHD).垂体源性 hGH来源少,其临床应用范围有限,但在美国至少有 8000名儿童接受了这种 hGH治疗,临床发现其具有很好的促线性生长作用.至 1985年相继报道了约 60名垂体源性 GH应用者并发致命的退行性神经疾病即 Creutzfeldt-Jakob病,同年被 FDA禁用. 1985年体外成功合成重组人生长激素( recombined human growth hormone,rhGH)并可以无限量生产,从而使 hGH的大量临床应用成为可能. GH应用于临床迄今已有约五十年的历史,逾二十万患者接受治疗.美国 FDA继 1985年批准 hGH用于儿童 GHD之后,先后批准其应用于慢性肾功能不全肾移植前( 1993年)、 HIV感染相关性衰竭综合征( 1996年)、 Turner综合征( 1996年)、成人 GHD( 1997年)、 Prader-Willi综合征( 2000年)、小于胎龄儿( 2001年)和特发性矮身材( 2003年)等,而新的非生长激素缺乏性疾病应用指征仍在不断探讨. GH在儿科临床的应用日益广泛,有关其应用指征、剂量、疗效和安全性的研究也在逐渐深入.     

人生长激素同型异构体比例变化与特发性矮小症的相关性

人生长激素(human growth hormone,hGH)是出生后促进生长的主要激素,生长激素在调节生长的许多方面都起作用,生长激素缺乏会引起生长激素缺乏性矮小(growth hormone deficiency,GHD),但特发性矮小症患儿(idiopathic short stature,ISS)并不存在生长激素(GH)缺乏[1],其发病机制一直是研究的热点,有研究认为hGH同型异构体(humangrowth hormone isoforms,hGHI)比例的变化可能是ISS的发病机制之一[2,3],hGH有多种同型异构体,在垂体、胎盘和外周血中均存在,各种hGHI单体型的22kDa!hGHI含量最丰富,20kDa!hGHI含量次之,它们在结构上有…     

重组人生长激素治疗特发性矮小儿童12例

目的　观察重组人生长激素 (rhGH)治疗特发性矮小儿童促生长作用。方法　对 12例特发性矮小儿童使用rhGH治疗 0 .5 7± 0 .18年 ,比较治疗前后年生长速率和预测成年身高结果。结果　经治疗后特发性矮小儿童的年生长速率和预测成年身高有显著提高 ,身高年龄增长明显快于生活年龄和骨龄的增长。结论　rhGH对特发性矮小儿童具有促生长作用     

矮小儿童下丘脑-垂体及其胰岛素样生长因子轴功能检查的意义

目的检测矮小儿童下丘脑-垂体及其胰岛素样生长因子(IGF-1)生长轴(GHRH-GH-IGF-1)功能,了解矮小儿童的发病因素及确定下丘脑-垂体及其IGF轴功能缺陷病因分类。方法矮小儿童30例。用统一印制的矮小儿童表格记录其临床特征。对矮小儿童进行甲状腺功能测定;用胰岛素 左旋多巴行生长激素(GH)刺激试验;放射免疫法测定血清IGF-1和血清胰岛素样生长因子结合蛋白-3(IGFBP-3)水平;同时行患儿骨龄、垂体增强MRI扫描、染色体核型分析、性激素测定。根据矮小症诊断标准和2004年Rosenfeld RG和GHRH-GH-IGF-1轴缺陷不同,将矮小儿童进行病因定位和分类。结果矮小儿童30例中,下丘脑-垂体及其IGF轴功能缺陷12例,占40%,其中肯定生长激素缺乏(GHD)4例,怀疑生长激素不敏感综合征2例,可疑GHD 6例。Turner′s综合征2例,占6.67%;体质性青春期延迟2例,占6.67%;特发性矮小14例,占46.6%。磁共振发现垂体微腺瘤2例;垂体发育不良12例。结论1.矮小儿童所占比例最大的为特发性矮小,其次为下丘脑-垂体及其IGF轴功能缺陷。2.IGF-1水平和IGFBP-3水平与生长激素刺激试验测定生长激素水平不一致,考虑存在生长激素抵抗和受体缺陷。3.矮小儿童可能存在先天性垂体发育异常,致使垂体分泌生长激素不足。     

矮身材儿童尿中hGH的排泄与垂体分泌的关系

该作者用高敏感的酶联免疫和放射免疫技术测定尿中人生长激素(hGH)含量,其目的:(1)对矮身材儿童进行药理和物理检验期间,尿中hGH是否与血浆hGH水平相关;(2)尿中hGH测定能否说明儿童hGH分泌的缺乏。     

儿童特发性矮小临床治疗新进展

特发性矮小是一种在儿童中较常见的身材矮小,其病因及发病机制尚不明了,迄今尚无确切的治疗方案.目前对儿童特发性矮小的临床治疗丰要集中在重组人生长激素(rhGH)、促性腺激素释放激素类似物(GnRHa)和芳香化酶抑制剂(AI).文章就其新研究新进展进行综述.     

用rhGH治疗GHD儿童GH-AB的5年随访

白蛋氨酸重组人生长激素(met -rhGH)广泛用于临床,许多受治者出现生长激素抗体(GH-AB)。该文探讨了met-rhGH治疗的生长激素缺乏(GHD)儿童血循环GH-AB水平。病人与方法46名GHD儿童,二种药物刺激试验GH<20mU/L(或10μg/L),均无基因缺陷。Ⅰ组20名,试验前从未用过hGH治疗,Ⅱ组26名,试验前曾     

垂体侏儒诊断和治疗的新进展

垂体侏儒诊断方面,提出刺激试验生长激素(GH)峰值<5ng/ml为GH完全性缺乏,5～10ng/ml为部分性缺乏。刺激试验GH正常的矮小儿童中,有些可能为GH神经分泌功能失调。生长激素释放激素(GHRH)刺激试验可鉴别GH缺乏病变在下丘脑或垂体。用人生长激素(hGH)治疗垂体侏儒30年来积累了丰富的经验。因发现hGH的可能带有亚急性痴呆样疾病(CJD)的病原而停用了。近年来生物工程合成GH。已试用于临床,疗效好,无副作用。GHRH也能被合成并试用于治疗,对下丘脑性垂体侏儒有效。     

矮小症的生长激素测定方法及护理

矮小症是指身材低于本民族、本地区健康的和同龄同性别儿童的平均身高2个标准差。严重者称为侏儒症，病因可分为内分泌紊乱，慢性系统疾病、体质性生长及发育延迟、遣传及染色体畸变、骨病、社会心理障碍等。随着近代分子生物研究发展，重组人GH(生长激素)、IGF-1(胰岛素样生长因子)以及合成的GHRH(促生长激素释放激素)、GHRP(生长激素抑制激素)皆已问世，为矮小症尤其GH-IGF     

改善矮小儿童成年身高的药物研究进展

儿童的身高问题越来越被社会、家长及广大儿科医生关注,该文重点介绍改善矮小儿童成年身高的药物研究进展。生长和最终身高与遗传、宫内发育、出生后的营养、环境和内分泌激素等均有关。重组人生长激素、长效人重组生长激素对已批准的适应证改善儿童成年终身高的疗效是确定的,目前主要进行长效人重组生长激素品种的研发上市以及扩大适应证的临床试验。重组人类胰岛素生长因子-1（IGF-1）是治疗IGF-1缺乏的主要药物,使用中要注意低血糖和肿瘤的风险。促性腺激素释放激素类似物（GnRHa）、第三代非甾体类芳香化酶抑制剂等可有效延缓骨骺融合,联合长效人重组生长激素（rhGH）治疗对改善终身高有一定益处,但其疗效与病因、年龄、遗传身高、治疗疗程等因素有关,临床应综合考虑药物远期安全性、疗效以及经济等因素,谨慎评估、选择。修饰后的重组C型利钠肽已完成Ⅲ期临床试验,对改善软骨发育不全儿童的身高有一定获益。期望能继续开发出安全、有效、优质、稳定的新药用于改善儿童矮身材,促进矮小儿童的身心健康。     

Growth hormone replacement therapy in children with leukemia in remission

We describe a patient with leukemia in remission for 7 years who developed growth hormone (GH) deficiency and was treated with recombinant human growth hormone (rhGH). We compare her growth with that of patients from the National Cooperative Growth Study (NCGS) database, 145 with leukemia in remission and 725 with idiopathic growth hormone deficiency (IGHD) on treatment with rhGH. We also review the literature on the risk of relapse of leukemia in similar patients. The patients with leukemia in remission from the NCGS database had a significantly lower change of mean height standard deviation score than that of IGHD patients in the first, second, and third year of rhGH treatment. The relapse rate of leukemia in patients treated with rhGH is between 0.8% and 2%. Starting rhGH therapy in patients with leukemia in remission and with GH deficiency at an adequate dosage and without undue delay would improve their growth response. Such therapy does not appear to increase the risk of leukemia.     

Empty sella, growth hormone deficiency and pseudotumour cerebri: effect of initiation, withdrawal and resumption of growth hormone therapy

An 11- year-old boy with normal visus and eye fundus, but with empty sella, growth hormone (GH) deficiency and central diabetes insipidus was found to have intracranial hypertension with papilloedema after 6 months of catch-up growth under recombinant human GH (rhGH) replacement therapy. Withdrawal of rhGH therapy was associated with normalisation of intra‐cranial?pressure within 1 week. Three months later, resumption of rhGH therapy at a lower dose was again followed by pronounced growth acceleration, but now without papilloedema. Conclusion?Children with empty sella and GH deficiency may be prone to rhGH-induced pseudotumour cerebri which appears to be rapidly reversible and dose-dependent.     

Growth hormone therapy improves growth in children with cystic fibrosis related liver disease

Growth impairment in cystic fibrosis (CF) is worsened by liver disease. Children with CF have serum levels of insulin-like growth factor-I (IGF-I) that are lower than expected for their normal growth hormone (GH) production. In children with CF-related liver disease (CFLD), response to endogenous GH is further reduced. We present our experience with two young children with CFLD given recombinant human GH (rhGH). The first patient was a 5 year-old female with CFLD and poor growth who responded well for 1 1/2 years to rhGH therapy during her initial course and without a significant increase in serum IGF-I, but with a substantial increase in IGF-I concentration when the GH dose was increased. The second patient was a 5 month-old male with advanced liver disease who had transient improved growth and liver function following rhGH. These patients suggest that rhGH is safe and may be effective in children with CFLD.     

Growth Hormone Treatment and Development of Malignancy: Recombinant Human Growth Hormone Does not Induce Leukemia in AKR/O-Mice

In 1988 several reports described leukemia in former/present growth hormone (GH)-treated children, and a doubled incidence of leukemia in GH-treated children was concluded in a workshop in Bethesda. A mouse strain (AKR/O) with a high incidence of leukemia was used as a model. AKR/O-mice in the preleukemic adult age and younger mice during rapid growth were treated with recombinant human GH (rhGH) in human therapeutic doses to see whether this treatment would affect the time and presentation of malignant disease. The malignant development did not appear earlier or in a different way in the animals receiving rhGH from day 6 to 50 than in their appropriate controls. A borderline protective effect to the development of leukemia was seen in the adult group receiving rhGH; in this group antibodies to hGH also developed. We conclude that in this experimental model human therapeutic doses of rhGH do not influence the development of malignancy in the AKR/O mice.     

Effect of Recombinant Human Growth Hormone Therapy on Bone and Clinical Parameters in Girls with Turner's Syndrome

Ferrández, A., Mayayo, E., Arnal, J.M., Garcia, C., Buduel, C., Lasarte, J.J., Anton, R., hyuelo P., and The Spanish Collaborative Group (Endocrine Unit, Children's Hospital, Miguel Servet, Zaragoza, Spain). Effect of recombinant human growth hormone therapy on bone and clinical parameters in girls with Turner's syndrome. Acta Paediatr Scand [Suppl] 356: 87, 1989.
Forty-eight girls with Turner's syndrome were assigned to one of three treatments; recombinant human growth hormone (rhGH) alone, rhGH plus oxandrolone, and rhGH plus ethinyloestradiol. Treatment with rhGH alone or in combination with oxandrolone induced catch-up growth. Older girls treated with rhGH plus ethinyloestradiol showed less marked improvement. The gain in height was associated with a gain in bone diameter and cortical thickness (reflecting increased bone mass). There was a rapid loss of subcutaneous fat. These effects of growth hormone are similar to those observed in patients with growth hormone deficiency.     

Empty sella, growth hormone deficiency and pseudotumour cerebri: effect of initiation, withdrawal and resumption of growth hormone therapy

An 11- year-old boy with normal visus and eye fundus, but with empty sella, growth hormone (GH) deficiency and central diabetes insipidus was found to have intracranial hypertension with papilloedema after 6 months of catch-up growth under recombinant human GH (rhGH) replacement therapy. Withdrawal of rhGH therapy was associated with normalisation of intra‐cranial␣pressure within 1 week. Three months later, resumption of rhGH therapy at a lower dose was again followed by pronounced growth acceleration, but now without papilloedema. Conclusion Children with empty sella and GH deficiency may be prone to rhGH-induced pseudotumour cerebri which appears to be rapidly reversible and dose-dependent. Received: 4 August 1995 / 26 October 1995     

Effect of recombinant human growth hormone (rhGH) on hemoglobin concentration in children with idiopathic growth hormone deficiency-related anemia

Normocytic-normochromic anemia (NC/NC) has been attributed to impaired bone marrow erythropoiesis in growth hormone (GH)-deficient patients. Moreover, the GH/insulin-like growth factor-1 (IGF-1) axis has been implicated in erythropoiesis regulation. In this retrospective multicenter study, we evaluated the incidence of NC/NC anemia in 279 children (196 boys), median age 10.52 years, with isolated idiopathic GH deficiency, and the effect of recombinant human growth hormone (rhGH) therapy on hemoglobin levels. At 6-month intervals, we recorded the Hb standard deviation score (Hb-SDS), the IGF-1-SDS, weight, height, and pubertal stage. Forty-one boys and 7 girls had NC/NC anemia before starting substitutive therapy (-2.59 SD). The Hb-SDS was significantly increased (P<0.05) after 12 months of rhGH therapy. The effect of rhGH continued up to 48 months (-0.39 SD), at which point all children had normal hemoglobin values. In conclusion, rhGH therapy resulted in normal hemoglobin values in all children enrolled in the study. These data support the concept that the GH/IGF-1 axis promotes erythropoiesis in vivo.     

Recombinant human growth hormone treatment in children with thalassemia major

BACKGROUND: To evaluate the growth hormone reserve and the growth hormone response to recombinant human growth hormone (GH) in prepubertal thalassemic children with growth retardation. METHODS: Twenty thalassemic patients with short stature and delayed bone age were studied. Patients were randomized into GH-treated (n = 10) and non-GH treated (control; n = 10) groups. The GH-treated group received recombinant human (rh)-GH (Genotropin) at the dose of 0.7 IU/kg per week for 12 months. RESULTS: There was a significant discordance between GH response to pharmacologic stimuli and physiological secretion of GH/GHRH testing. Following the administration of rhGH, growth velocity increased from 2.47 +/- 0.48 cm/year to 6.27 +/- 0.76 cm/year (P = 0.005), whereas there was not a similar change in the non-GH-treated group. The height velocities of the two groups during the 1 year follow-up period were significantly different (6.27 +/- 0.76 vs 3.99 +/- 0.34 cm/year; P = 0.025). There were significant differences between the height velocity improvements and height velocity standard deviation scores of the two groups as well. CONCLUSION: The present study has demonstrated that rhGH is a safe and efficacious mode of treatment in thalassemic children.     

Comparison of growth hormone releasing hormone therapy and growth hormone therapy in growth hormone deficiency

Seven children with growth hormone deficiency of hypothalamic origin responded to an i.v. bolus of growth hormone releasing hormone (GHRH) (1–29)-NH2 with a mean serum increase of 10.7 ng/ml growth hormone (GH) (range 2.5–29.3 ng/ml). Continuous s.c. administration of GHRH of 4–6 g/kg twice daily for at least 6 months did not improve the growth rate in five of the patients. One patient increased his growth rate from 1.9 to 3.8 cm/year and another from 3.5 to 8.2 cm/year; however, the growth rate of the latter patient then decreased to 5.4 cm/year. When treatment was changed to recombinant human growth hormone (rhGH) in a dose of 2 U/m² daily, given s.c. at bedtime, the growth rate improved in all patients to a mean of 8.5 cm/year (range: 6.2 to 14.6). Presently GHRH cannot be recommended for the routine therapy of children with growth hormone deficiency since a single daily dose of rhGH produced catch-up growth which GHRH therapy did not.Abbreviations GH growth hormone - GHD growth hormone deficiency - GHRH growth hormone releasing hormone - hGH human growth hormone - rhGH recombinant human growth hormone - SM C/IGF I somatomedin C/insulin-like growth factor I On the occasion of the 85th birthday of Prof. Dr.Dr.h.c. mult. Adolf Butenandt     

Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.