Long-term response to human growth hormone in 36 children with idiopathic growth hormone deficiency

The results of long term treatment with human growth hormone (Crescormon^®, 12.4 IU/m²/week) in 36 patients with idiopathic growth hormone deficiency are given. Birth trauma—in particular assisted breech delivery (30%)—is the major aetiological cause. Twelve patients had isolated growth hormone deficiency (IGHD), 24 had multiple pituitary hormone deficiencies (MPHD) of which 19 were treated with additional thyroid hormones. The results were judged by the criteria of height velocity, total height gain and change of height prediction (TW₂, age based).It is concluded that the growth hormone dose chosen in many cases is insufficient to maintain high growth rates after the first year of treatment, when catch-up no longer takes place. The tendency of patients supplemented with thyroid hormone to grow better—without additional bone-age advancement—calls for careful search for hypothyroidism and suggests the use of thyroxin in cases of doubt.     

Foot length before and during insulin-like growth factor-I treatment of children with laron syndrome compared to human growth hormone treatment of children with isolated growth hormone deficiency

OBJECTIVE: To compare foot length deficits between patients with Laron syndrome (LS) (primary growth hormone [GH] insensitivity) and congenital isolated GH deficiency (IGHD) and their response to replacement therapy with insulin-like growth factor-I (IGF-I) and hGH, respectively. DESIGN: Data for the study were collected from the records of nine children with LS (3 M, 6 F) 7.8 +/- 4.8 years old (mean +/- SD), and nine children with IGHD (3 M, 6 F), 3.8 +/- 3.3 years old. Fifteen non-treated adult patients with LS were also included in the study. METHODS: Measurements of foot length were recorded without treatment and monitored during 9 years of treatment in the children and in the untreated adult patients. For statistical analysis the non-parametric Mann-Whitney U test was used. RESULTS: With almost similar basal values in growth deficit and pre-treatment growth velocities, the achievements towards norms after 9 years of treatment were greater in the patients with IGHD than in the patients with LS: foot length reached -1.4 +/- 0.8 vs. -3.3 +/- 1.0 SDS (mean +/- SD), and body height -2.2 +/- 1.0 vs. -3.9 +/- 0.5 SDS. The difference between the two groups could be due to the initiation of replacement therapy in the patients with IGHD at a younger age. Adult foot size of untreated patients with LS is small but less retarded than the height deficit. CONCLUSIONS: Both IGF-I and hGH are potent growth stimulating hormones of linear growth and acrae as exemplified by foot growth.     

生长激素缺乏症患儿重组人生长激素治疗前、后肾上腺皮质功能的变化

目的观察生长激素缺乏症(GHD)患儿重组人生长激素(rh GH)治疗前、后肾上腺皮质功能的变化。方法选取72例确诊GHD并接受rh GH治疗6个月以上的患儿,其中32例伴促肾上腺皮质激素(ACTH)缺乏,回顾性分析其在接受rh GH治疗前及治疗后3、6个月时清晨空腹血皮质醇(COR)、ACTH水平的变化。结果 32例伴ACTH缺乏患儿通过外源性补充氢化可的松(HC)使COR达正常水平后,再开始rh GH治疗,治疗前COR水平和使COR达正常下限时的HC剂量呈显著负相关(r=-0.899,P0.01)。单纯HC治疗1个月后COR水平较治疗前明显增高,ACTH水平明显下降,差异均有统计学意义(P0.001);经rh GH和HC替代治疗后3、6个月后COR及ACTH水平与单纯HC治疗1个月差异无统计学意义(P0.05)。40例无ACTH缺乏患儿在rh GH治疗后COR水平显著降低,与治疗前比较差异有统计学意义(P0.01),其中10例MRI显示下丘脑-垂体异常患儿表现为COR水平低下。结论 GHD患儿在rh GH治疗过程中可出现肾上腺皮质功能减低,特别是MRI显示垂体异常的患儿,应注意监测肾上腺皮质功能,及早干预。     

Prediction of growth response in prepubertal children treated with growth hormone for idiopathic growth hormone deficiency

Several multiple regression models have been developed to predict the first-year growth response to human growth hormone (hGH) in children with growth hormone deficiency (GHD). It was the aim of this study to analyse the significance of various growth parameters for a height prediction model. Data from 148 prepubertal children with idiopathic GHD were evaluated. The prediction model was developed by means of univariate and stepwise linear regression analysis and an “all possible” regression approach using Mallow's C(p) statistics. Six out of eight selected variables had a significant influence on the first-year growth rate. The most important parameter was the difference between target height SDS and height SDS at the start of therapy (THSDS - HSDSC0), accounting for 23.95% and 25.74% of the variability. No other single variable or combination of variables was more informative than the variable THSDS - HSDSC0 alone. From these data, growth velocity for the first year of hGH treatment was estimated as 1.106 (THSDS - HSDSC0) + 6.8 cm/y ± 2.2 cm (SE), allowing a prediction for different intervals between THSDS and HSDSC0. This equation was validated in a small group of 18 GHD patients demonstrating a predicted vs. observed first-year growth rate of 9.4 ± 1.1 vs. 9.5 ± 2.6 cm/y. We conclude that the difference between THSDS and height SDS at the start of therapy is an important predictor of the first-year growth response in children treated with hGH for idiopathic GHD. Unlike in previous studies, additional parameters did not increase predictability.     

Single dose and pulsatile treatment with human growth hormone in growth hormone deficiency.

The growth and growth hormone profiles in four children receiving three different regimens of treatment with human growth hormone (hGH) were compared. There was no significant difference in the rate of growth between the regimens; the rate of growth fell dramatically after treatment. Pulsatile administration of hGH was no better than conventional treatment.     

Growth hormone testing in short children and their response to growth hormone therapy

Because current concepts of growth hormone (GH) testing and GH treatment have become controversial, we investigated the GH secretory patterns in children with normal and short stature. Twenty-four-hour serum GH levels were evaluated in three groups of children. Group 1 was composed of children with normal height (mean height = 0.02 SD, n = 33); group 2 was composed of short children (less than 5th percentile, n = 63) with normal results on provocative GH testing; and group 3 was composed of short children (less than 5th percentile, n = 7) with subnormal results on provocative GH testing. Mean +/- SD (range) GH levels during 24-hour studies of GH secretion were 1.6 +/- 1.1 (0.5 to 5.6), 1.8 +/- 1.2 (0.6 to 6.3), and 0.9 +/- 0.4 (0.5 to 1.7) ng/ml in groups 1, 2, and 3, respectively. No statistical difference existed in mean GH levels between groups 1 and 2 or between groups 1 and 3. The mean GH concentration from 24-hour studies in group 2 children did not correlate with chronologic age, height standard deviation, growth rates, or insulin-like growth factor 1 levels. The linear growth rate of 26 of 28 children in group 2 who received GH therapy for 6 months improved by 2 cm/yr or more; the mean +/- SD growth rate was 4.0 +/- 1.3 and 8.8 +/- 2.0 cm/yr during control and treatment periods, respectively, for these 28 children. Mean GH levels from testing did not predict response to GH during 6 months of therapy. Children with slower growth rates responded better to GH therapy (p less than 0.05). We conclude that (1) in 24-hour studies, GH levels in normal children overlapped with those of short children, including those with classic GH deficiency, (2) in 24-hour studies, GH levels did not predict responses of linear growth to short-term GH treatment, nor did they correlate with children's heights or growth velocities, and (3) the majority of short children in group 2 treated with GH for 6 months had an increase in linear growth velocity, the mean +/- SD change being 4.8 +/- 2.0 cm/yr.     

Growth hormone deficiency in a child with Williams-Beuren syndrome. The response to growth hormone therapy

Pre- and postnatal growth retardation of unknown pathogenesis is a common clinical feature in patients with Williams-Beuren syndrome (WBS). However, growth hormone deficiency (GHD) has not been considered a major cause of growth retardation. There is only one patient in the literature with confirmed GHD who responded well to human growth hormone (hGH) therapy. We report a female infant with confirmed WBS who, through provocative testing, was found to have GHD and who responded satisfactorily to hGH therapy. Height SDS was -4.2 at the age of 12 months when hGH was initiated and increased to -0.8 at the age of 4.25 years. The pathogenesis of GHD in our patient is unclear. Nevertheless, the elevated levels of prolactin and the response of hGH to growth hormone releasing hormone (GHRH) administration are indicative of a hypothalamic rather than pituitary defect. In conclusion, GH deficiency might contribute to the growth failure in a number of patients with WBS and in such cases hGH therapy will most likely improve final height.     

基因重组人生长激素治疗儿童生长激素缺乏症26例

目的　探讨基因重组人生长激素 (rhGH)对生长激素缺乏症 (GHD)患儿的疗效。方法　对 2 6例GHD给rhGH治疗 ,0 .1IU/ (kg·d) ,每晚皮下注射 ,疗程 0 .5年。结果　 2 6例身高平均增加 8.2± 0 .8cm/ 6个月 ,生长速率由治疗前 1.5± 0 .4cm/ 6个月增加至 6.5± 1.7cm/ 6个月 ,身高标准差由治疗前 4.5± 1.2减少至3 .2± 1.1,骨龄无明显增加 ,体重也略有增加。治疗期间第 1～ 3个月 75 %左右患儿出现甲状腺功能低下症状 ,但未影响体格线性增长。结论　rhGH是治疗GHD的一种有效、安全的促生长药物     

Anthropometric measurements in patients with growth hormone deficiency before treatment with human growth hormone

In 74 children (52 , 22 ) with growth hormone (GH) deficiency (30 cases with isolated GH-deficiency, two of them familial; 4 familial and one isolated case with tendency for formation of antibodies against hGH; 29 with other pituitary hormone defects; 10 craniopharyngiomas), various anthropometric measurements were analyzed before treatment with hGH. In all groups, standing height, sitting height, and subischial leg height were equally retarded, and bihumeral width was more retarded than biilac width; the head was relatively large; fat tissue was increased with subscapular skinfolds being greater than triceps skinfolds, indicating relative obesity of the trunk; muscle and/or bone mass was reduced. In isolated GH-deficiency, head shape was slightly scaphoid; in combined defects, it was round, and in craniopharyngioma cases, it was brachycephalic. It is concluded that anthropometric measurements may help in differentiating the type of GH-deficiency.Dedicated to Prof. Dr. H.-R. Wiedemann on the occasion of his 65th birthday     

rhGH替代治疗对生长激素缺乏儿童糖代谢的影响

目的探讨重组人生长激素(rhGH)替代治疗对生长激素缺乏症(GHD)儿童糖和胰岛素代谢的影响以及 GH 与糖代谢平衡之间的关系。方法对44例(男28例,女16例)4.5～16.5(10.4±2.6)岁 GHD 患儿在接受 rhGH 治疗前及治疗后每3个月检测体重指数、胰岛素样生长因子-1(IGF-1)、行口服葡萄糖耐量试验,计算稳态模型胰岛素抵抗指数。结果 (1)空腹血糖和 IGF-1在治疗3个月时即显著提高,一直持续较高水平,每个随访时间点与治疗前比较,差异均有统计学意义(F=6.81,7.31,P 均<0.01);稳态模型胰岛素抵抗指数和空腹胰岛素分别在治疗3和9个月时提高(P<0.01和 P<0.05),1年后下降,治疗1年半时与治疗前比较,差异已无统计学意义(均 P>0.05)。(2)相关分析发现,稳态模型胰岛素抵抗指数与体重指数、IGF-1和治疗持续时间显著相关(r=0.251,0.437,0.281,P 均<0.001)。二次方程曲线回归分析发现,稳态模型胰岛素抵抗指数与治疗持续时间呈近似抛物线量变关系。(3)发现2例暂时性高血糖,分别在停用 rhGH 治疗后1个月和5d 血糖恢复正常,再注射 rh GH 后,行口服葡萄糖耐量试验正常。结论 GHD 儿童接受 rhGH 治疗(尤第1年内)可增加胰岛素抵抗,极少数引起短暂糖代谢紊乱。循环 IGF-1可能参与控制胰岛素的敏感性,在 GH 与胰岛素平衡间起重要作用。有必要对所有接受 rhGH 治疗者定期监测糖代谢指标和 IGF-1水平。     

The catecholamine response to hypoglycemia in children with isolated growth hormone deficiency syndromes and multiple pituitary hormone defects

We examined the catecholamine response to insulin-induced hypoglycemia in 46 short children evaluated for growth hormone (GH) deficiency by both pharmacologic stimulation and integrated concentration of GH. Twelve patients had quantitatively normal GH secretion by both pharmacologic stimulation and integrated concentration of GH (GHNORM). Twenty-two patients had normal GH to pharmacologic stimulation but subnormal integrated concentration of GH (GHND). Twelve patients had GH deficiency by both tests (GHD): six had isolated GH deficiency (GHD type 1) and six had multiple hormone deficiencies (GHD type 2). There was no significant difference between the peak epinephrine, norepinephrine, and cortisol responses of GH-NORM, GHND, and GHD type 1 patients. The mean peak epinephrine response of GHD type 2 patients was significantly lower (564 +/- 561 pg/ml, p less than 0.03) compared to the other patient groups. There was no significant difference between the peak norepinephrine levels between GHD type 2 patients and the remaining groups. There was no correlation between decrease in blood glucose and either increase in growth hormone, catecholamine, or cortisol concentrations. There was a significant correlation between log peak epinephrine and peak cortisol response (r = 0.53, p less than 0.0002) of the 46 subjects. Neither the basal nor stimulated catecholamine levels correlated with the integrated concentration of cortisol. We conclude that isolated GH deficiency is not associated with impairment of the catecholamine response to hypoglycemia; impairment of the epinephrine response to hypoglycemia is only associated with multiple pituitary hormone deficiencies; in children, the degree of glucose lowering is not correlated with the magnitude of peak GH, catecholamine, or cortisol responses.     

Psychological response to growth hormone treatment in short normal children

Indian childhood cirrhosis (ICC) is an almost uniformly fatal disease whose outcome may be modified with penicillamine if given at a sufficiently early stage. Twenty nine children with ICC seen in Pune, India, in 1980-7, who had survived at least five years from onset of penicillamine treatment, were reviewed aged 6.3 to 13 years. They were assessed clinically, biochemically, histologically, and by duplex Doppler ultrasound examination. None had symptoms suggestive of liver disease. There were no toxic effects of penicillamine other than asymptomatic proteinuria. Hepatosplenomegaly reduced significantly and liver function tests returned to normal in all. In four children, significant hepatosplenomegaly was associated with an abnormal duplex Doppler hepatic vein flow pattern and micronodular cirrhosis on biopsy. Clinical findings, growth and development, and ultrasound examination were normal in the remainder. Review of serial liver biopsy specimens showed a sequence of recovery from ICC through inactive micronodular cirrhosis to virtually normal histological appearances. The four children who still have micronodular cirrhosis beyond four years from onset remain on penicillamine treatment. In the others penicillamine was stopped after 1-7 (mean 3.5) years without relapse, strong evidence that ICC is not due to an inborn error of copper metabolism.     

Growth hormone treatment in short children with intrauterine growth retardation

The aim of this prospective controlled study was to assess the effect of rhGH in short prepubertal children with intrauterine growth retardation and normal growth hormone status. Twenty-six children were randomized into treatment (12F, 4M) and control (6F, 4M) groups. Mean ages were 5.3 (1.3) yr and 4.3 (1.7) yr, respectively. rhGH (Genotropin) was used at a dose of 0.2 IU/kg/day as daily s.c. injections for two years. In the treated group, mean height SDS increased from -3.0 (0.5) to -1.9 (0.7) and height velocity SDS showed a significant increase from -1.3 (2.0) to 3.7 (1.8) in the first year (p < 0.001) and 1.6 (1.8) (p < 0.01) in the second year of treatment. In the controls, height SDS, initially -2.7 (1.4), and height velocity SDS, initially -0.9 (1.1), remained essentially the same during two years of follow-up. Height SDS for bone age changed by 0.6 in the treated group and 0.4 in the control group. Target height SDS--initial height SDS in the treated group improved by 1.1 SD but declined in the control group. IGF-I levels increased from 9.5 (4.2) nmol/l (72 [31.8] ng/ml) to 32.5 (27.0) nmol/l (244.4 [202.8] ng/ml) (p = 0.004) in the treated group while no change was observed in the controls. No adverse effects were encountered during rhGH therapy. It was concluded that rhGH treatment induces a significant increase in growth velocity in the short term. This outcome, as opposed to the unchanged indices in the control group over the same period, may be indicative of an improved height prognosis in short children born with intrauterine growth retardation treated with rhGH.