颅咽管瘤及其生长激素替代治疗

颅咽管瘤(CP)是一种起源于颅咽峡囊(Rathke囊)的先天性肿瘤,占颅内肿瘤总数的4%～6%,是儿童鞍区常见的先天性肿瘤之一。手术切除肿瘤仍是目前的主要治疗手段,但术后多数患儿下丘脑-垂体功能受到不同程度的影响,发生多项垂体激素分泌缺乏(MPHD)的症状。生长激素(GH)对儿童CP患者长期生存的意义重大,若长期的生长发育得不到充足的GH将影响患儿的正常生长发育,甚至心理成长。目前重组人生长激素(rhGH)治疗因生长激素缺乏(GHD)所致矮小疗效肯定,有效及时的替代治疗能使患儿整体呈现有效的快速生长追赶。总的来说rhGH的替代治疗安全性良好,既不增加新发恶性肿瘤的风险,也不增加中枢神经系统肿瘤的复发率,但仍有进一步研究的必要。     

青春期生长激素缺乏症患者重组人生长激素治疗的剂量及安全性

目的探讨重组人生长激素(rhGH)治疗青春期生长激素缺乏症(GHD)患者的疗效及安全性。方法选择80例临床确诊的已接受rhGH治疗6个月以上的青春期GHD患儿,随机分为低剂量组43例和高剂量组37例,低剂量组rhGH治疗剂量为0.033 mg/(kg.d),高剂量组为0.070 mg/(kg.d),观察治疗1年后两组实际年龄的身高均值标准差、年生长速度以及用药安全性。结果治疗后高剂量组身高均值标准差改变量及年生长速度均高于低剂量组(P<0.05);治疗期间两组未见严重不良反应发生。结论对于青春期才开始治疗的GHD患儿必须采用足够剂量的rhGH才能获得满意的青春期身高增长。     

生长激素缺乏症治疗前后胰岛素样生长因子及其结合蛋白的变化

20 0 1年 6月至 2 0 0 2年 1 0月 ,我们对 46例生长激素缺乏症 ( GHD)儿童进行生长激素类激素 ( r-h GH)替代治疗 ,观察其血清胰岛素样生长因子( IGF- 1 )、胰岛素样生长因子结合蛋白 ( IGFBP- 3)变化 ,从而为 GHD疗效观察提供依据。1　资料与方法1 .1　临床资料　本文 GHD患儿 46例 ,男 30例 ,女1 2例 ,年龄 4～ 1 2岁。患儿均有典型 GHD症状与生长发育特征 ,身高低于同性别同年龄儿童第三百分位数 ,年身高生长速度 <2 .5 cm,骨龄落后于同类正常儿童至少两年 ;两项生长激素 ( GH)药物激发试验(可乐宁、精氨酸 ) GH峰值 <1 0 μg…     

吡啶斯的明与左旋多巴联合激发试验对儿童生长激素缺乏症的诊断价值

目的　评价吡啶斯的明 (PD)加左旋多巴 (L dopa)联合激发试验对儿童生长激素缺乏症(GHD)的诊断价值。方法　 79例生长迟缓儿童 ,根据生长学资料、临床表现及血胰岛素样生长因子Ⅰ(IGF Ⅰ )、胰岛素样生长因子结合蛋白 3 (IGFBP 3 )水平分为临床拟诊GHD组 ( 3 9例 )与非GHD (NGHD)组 ( 4 0例 ) ,全部进行PD L dopa联合激发并随机分别另行精氨酸激发试验 (ARG ,43例 )或胰岛素耐量试验 (ITT ,3 6例 )。比较三种试验的生长激素 (GH)激发峰值及诊断敏感度、特异度、精确度 ,绘制受试者工作特性曲线 (ROC)及精确度曲线。结果　PD L dopa联合激发试验GH峰值在NGHD组高于ARG(P <0 .0 1)或ITT(P <0 .0 5 ) ,在GHD组差异无显著性。PD L dopa联合激发试验的准确度、特异度明显高于ARG或ITT ,敏感度与ARG或ITT相近。GH峰值取 7μg/L为正常截断值时 ,PD L dopa联合激发试验的敏感度、特异度与准确度均最高 ,超过 80 %。结论　PD L dopa联合激发试验对儿童GHD诊断价值优于ARG或ITT ,是一种适合儿童的有效、简便、安全的检测手段     

生长激素治疗特发性矮小症的研究进展

特发性矮小症(ISS)是一种病因未明的矮小症,目前较常用的治疗药物是生长激素(GH),本文就GH治疗ISS的适应证、有效性、安全性及目前的争议进行综述.     

生长激素缺乏症生化检测综合分析

目的以临床诊断作为矮小症患儿(可疑GHD)诊断标准,评估生长激素激发试验、胰岛素样生长因子Ⅰ(IGFⅠ)及IGF结合蛋白3(IGFBP3)对GHD的诊断价值。方法放免方法检测84例可疑GHD患者及63例非GHD患者GH峰值、IGFⅠ及IGFBP3,运用ROC曲线方法选定各生化检测的最佳截定值,并计算各最佳截定值的敏感性(sensitivity,S)、特异性(specificity,Sp)及诊断有效率(diagnosticefficiency,DEf)。结果ROC曲线显示GH激发试验GH峰值7.65μg/L为最佳截定值,DEf达84.4%,S为75.9%,Sp达94.9%;IGFⅠSDS最佳截定值为-1.85,S为70.2%、Sp为83.1%、DEf为70.2%;IGFBP3SDS最佳截定值为-1.55,比传统-2SD高,DEf为64.3%,Sp较高(89.8%),但S仅为45.8%。联合使用上述3种测定有较佳的DEf(91.2%),S(89.3%)和Sp(93.7%)。结论GH激发试验如选取一个好的截定值(本研究为GH峰值7.65μg/L),则该试验对GHD具有较高诊断价值;单个IGFⅠ检测则逊于GH激发试验;IGFBP3单独诊断GHD价值不大。三者联合使用诊断率及准确率皆很高,最具诊断价值。     

重组人生长激素治疗单纯性生长激素缺乏症和特发性矮小症患儿血清C型利钠肽氨基末端浓度与生长速率的变化

目的 探讨单纯性生长激素缺乏症(isolated growth hormone deficiency,IGHD)以及特发性矮小症(idiopathic short stature,ISS)患儿经重组人生长激素(recombinant human growth hormone,rhGH)治疗后,血清C型利钠肽氨基末端(NTproCNP)浓度的变化及其与生长速率(growth velocity,GV)的关系.方法 共有48例青春期前的患儿纳入研究(IGHD 25例,ISS 23例),并给予rhGH治疗1年.治疗前及治疗后6个月分别测血清胰岛素样生长因子-Ⅰ (IGF-Ⅰ)和NTproCNP的浓度.治疗1年后,计算所有患儿的GV、身高Z积分(HTSDS)以及身高Z积分的变化值(△HTSDS).结果 IGHD组中,治疗前后IGF-I Z积分的变化值(△IGF-ISDS)、NTproCNP浓度的变化值(△NTproCNP)与治疗1年中GV呈正相关(r=0.407,P=0.044;r=0.490,P=0.013);治疗前生长激素(CH)峰值也与治疗前IGF-ISDS、NTproCNP浓度(r=0.558,P=0.004;r=0.630,P=0.001)以及治疗后△IGF-ISDS与△NTproCNP呈正相关(r=0.466,P=0.019).而在ISS患儿中,治疗1年中GV只与治疗后△NTproCNP相关(r=0.845,P＜0.01).结论 在IGHD和ISS患儿应用rhGH的促生长治疗中,NTproCNP水平随着生长速率的增加而增加.因此除了IGF-I,NTproCNP作为一种新的生化标记物,也可用于评估和预测这两类患儿在rhGH治疗后的GV变化.     

血清生长介素水平对内分泌性矮小儿的诊断价值

本文报告102例矮小病人血清生长介素(SM-C)水平及其对生长激素缺乏症(GHD)的诊断价值。51例单纯GHD患者血清SM-C水平为0.14±0.18kU/L,GHD合并甲低和GHD继发于脑肿瘤的11例病人血清SM-C水平分泌为0.09±0.06和0.09±0.08kU/L,与单纯GHD者无差别,均明显低于正常同龄儿童。34例GH正常矮小儿童血清SM-C水平0.89±0.98kU/L,高于GHD患儿水平而低于正常同龄儿童。本文提出1～8岁儿童血清SM-C水平<0.15kU/L、9～17岁者<0.45kU/L应高度怀疑GHD。     

生长激素与儿童骨发育

生长激素 (GH)通过双重作用机制增加成骨、破骨细胞的增殖 :GH促进前体细胞的分化 ,而胰岛素样生长因子 (IGF) 1促进已分化细胞的增殖。并且IGF 1、2和胰岛素样生长因子结合蛋白 (IGFBP)分别通过抑制和增加生长激素受体 (GHR)的活性来调节GH的作用。GH缺乏 (GHD)儿童的骨形成指标降低 ,但却不影响骨吸收指标。GH治疗促进儿童骨形成和骨吸收指标的上升 ,增加骨密度 ,减少GHD儿童成年后骨折的发生率。对GHD儿童用GH治疗的指标不仅要看其身高而且要看峰骨量是否形成。     

警惕生长激素治疗特发性矮小症出现误区

特发性矮小症(ISS)的病因具有异质性及复杂性,不仅涉及生长激素(GH)—胰岛素样生长因子(IGF)轴,又涉及诸多与生长板调控软骨细胞增殖、凋亡有关的激素及局部因子。近年来,ISS已被批准为GH治疗的适应证,由于其病因难以明确,疗效又难预测,因此为追求促生长效应,大剂量、长疗程的治疗原则已被认可。但应引起关注的是潜在的某些副作用或风险势必增大。目前,对少数偏矮实属非矮小的正常儿童有扩大应用GH治疗的趋势,故临床医师应严格掌握GH治疗的指征,警惕滥用导入误区。     

Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues

BACKGROUND AND OBJECTIVE Growth hormone treatment In children with Idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with Idiopathic short stature. DESIGN We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m² body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n= 21) were compared to those of an untreated control group with ISS (ISS controls, n= 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n= 7). RESULTS In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from ?3.8±0.7 to ?2.3±0.9 (mean±standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from ?3.9±0.6 to ?1.8±0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated In the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was ?2.6±1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome. CONCLUSION rhGH treatment In this group of children with Idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.     

Principles of growth hormone and insulin-like growth factor-I treatment in children with idiopathic short stature

Until recently, growth hormone (GH) was the only treatment available to improve growth rate in short, prepubertal children. Insulin-like growth factor I (IGF-I) is now approved in the United States and the European Union for treatment of short stature in children with severe primary IGF-I deficiency, a condition characterized by unresponsiveness to GH in IGF-I-producing tissues. This has increased the focus on the growth response to GH therapy in short children treated according to current recommendations. In particular, children with idiopathic short stature (ISS) may have some degree of GH insensitivity that decreases their response to GH treatment. This minireview discusses data on the response to GH treatment in patients with ISS and recent studies on the use of IGF-I in subgroups of patients with ISS. The rationale for future combination treatment with GH plus IGF-I is also discussed.     

Growth outcomes in individuals with idiopathic short stature treated with growth hormone therapy

The few studies that have evaluated the long-term height outcomes following growth hormone (GH) treatment in children with idiopathic short stature (ISS) have shown a growth response to GH treatment similar to that in GH-deficient children. A literature search of all randomized and nonrandomized studies of GH treatment in children with ISS from prepubertal years to adult height or near-adult height published over the last 10 years identified six publications (none was a classic meta-analysis). Several studies showed a dose-dependent response in height outcome. Overall, the younger the patient and the greater the difference in current height vs. parental height at start of treatment, the more substantial the gain in height. Height improvement ranged from 0.5 to 1.3 standard deviation score (SDS). The magnitude of height gain was substantial, even after adjustment for growth changes in control subjects (0.5 to 1 SDS), and it was comparable to that seen in other non-GH-deficient syndromes. Only two studies reported data from matched control subjects. Interestingly, there was no difference in height gain between familial short stature and non-familial short stature after adjusting for spontaneous height gain to adult age in non-GH-treated control subjects. To summarize, patients with ISS can benefit from GH treatment with respect to growth outcome, with results maintained into adulthood.     

Increased melatonin concentrations in children with growth hormone deficiency

A relationship between melatonin and growth hormone (GH) is poorly understood. We compare circadian melatonin rhythms in short children with normal and decreased GH secretion. The analysis included 22 children (20 boys and 2 girls) aged 11.1-16.9 yr (mean +/- S.E.M. = 14.1 +/- 0.3 yr) with short stature (height SDS below -2.0). Based on the GH peak in stimulation tests patients were divided into two groups: idiopathic short stature (ISS, n = 11; GH peak > or = 10 ng/mL) and GH deficiency (GHD, n = 11; GH peak < 10 ng/mL). In all patients the circadian melatonin rhythm was assessed on the basis of nine blood samples, collected in 4-hr intervals during the daytime and 2-hr intervals at night, with dark period lasting from 22:00 to 06:00 hr. Magnetic resonance imaging examination excluded organic abnormalities in central nervous system in all patients. Melatonin concentration at 24:00, 02:00 and 04:00 hr as well as the area under curve of melatonin concentrations (AUC) were significantly higher in the patients with GHD than in individuals with ISS. Significant correlations between GH secretion and melatonin concentrations at 24:00, 02:00 and 04:00 hr, and AUC were also observed. On the basis of these data it seems that the assessment of nocturnal melatonin secretion might be a valuable diagnostic tool used for the improvement of the difficult diagnosis of short stature in children.     

生长激素缺乏症的诊断和治疗

生长激素缺乏症(GHD)在儿童主要以身材矮小、生长障碍为主要表现,成人患者表现多无特异性,可有身体组分改变、血脂紊乱、骨密度降低、运动耐力下降、胰岛素抵抗、心血管风险增加、生活质量下降等.临床一般需要结合病史、发育状况、症状、体征、影像学资料、生长激素(GH)-胰岛素样生长因子(IGF)轴相关生化指标及GH激发试验来作...     

Constitutional growth delay pattern of growth in velo-cardio-facial syndrome: longitudinal follow up and final height of two cases

We report two patients with velo-cardio-facial syndrome (VCFS) who were admitted to our pediatric endocrinology clinic because of short stature and followed longitudinally until attainment of final height. Both patients followed a growth pattern consistent with constitutional delay of puberty with normal and near normal final height. Case 2 also had partial growth hormone (GH) deficiency and severe short stature (height SDS -3.4 SDS), but showed spontaneous catch-up and ended up with a final height of -2 SDS. These cases suggest that short stature in children with VCFS is due to a pattern of growth similar to that observed in constitutional delay of growth and puberty.     

Exon 3-deleted genotype of growth hormone receptor (GHRd3) positively influences IGF-1 increase at generation test in children with idiopathic short stature

CONTEXT: A GHR-exon 3 polymorphism has been reported to influence the growth response to hGH therapy in short stature children. None of these studies provided data on IGF-1 generation test. OBJECTIVE: To evaluate the influence of the GHR-exon 3 polymorphism on the generation test in children with idiopathic short stature (ISS). DESIGN AND PATIENTS: A total of 45 prepubertal ISS children were submitted to IGF-1 and IGFBP-3 generation test (4 days of hGH 33 microg/kg/day). Children were genotyped for GHR-exon 3: full-length (fl) and exon 3-deleted (d3) alleles. MEASUREMENTS: IGF-1 and IGFBP-3 increment as absolute values and standard deviation scores (SDS). RESULTS: Basal clinical and laboratory data were similar among patients with different genotypes (fl/fl vs. fl/d3 or d3/d3). All patients presented IGF-1 increase >or= 15 microg/l at generation test. Children with GHRd3 allele, as a group, presented a statistically significant higher IGF-1 SDS increase at generation test than children homozygous for GHRfl allele (1.0 ranging from 0.1 to 3.7 for fl/fl vs. 1.2 ranging from 0.3 to 4.4 for fl/d3 and d3/d3; P = 0.037). Multiple linear regression found a positive association between increase in IGF-1 SDS with chronological age (P = 0.007) and GHR genotype (P = 0.027), which together explain 24% of the variability of IGF-1 SDS increment at generation test. There was no difference in IGFBP-3 generation test between the two genotype groups. Conclusion: This study demonstrates that ISS children carrying the GHRd3 allele, as a group, present a slightly higher GH sensitivity regarding short-term IGF-1 generation during hGH stimulus than children homozygous for GHRfl allele.     

ORIGINAL ARTICLE: Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency

Context Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses. Design Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2‐year randomized trial of either individualized GH treatment with six different GH doses (range, 17–100 μg/kg/day) or a standard dose (43 μg/kg/day). Objective To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD. Hypothesis Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD. Results We observed a narrower variation for fasting insulin (?34·2%) and for homoeostasis model assessment (HOMA) (?38·9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Δ) height SDS correlated with Δinsulin‐like growth factor I (IGF‐I), Δleptin and Δbody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Δlean body mass (LBM) SDS and ΔIGF‐I SDS] clustered together and correlated strongly with Δheight SDS and GH dose, whereas lipolytic variables [Δfat mass (FM) SDS and Δleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for ΔLBM SDS and Δheight SDS, but not for changes in FM. Conclusions Individualized GH dosing during catch‐up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.