Growth hormone treatment of Turner syndrome patients with insufficient growth hormone response to pharmacological stimulation tests

Growth before and during treatment with biosynthetic human growth hormone (hGH) was studied in 13 patients with Turner syndrome (TS) and a growth hormone (GH) response of less than 10 g/l to two standard provocative tests. During 1 year of treatment with hGH (0.15 IU/kg per day) height velocity (mean±SD) increased significantly (P<0.001) from 3.7±1.8 cm/year to 7.6±1.5 cm/year. The auxological data in these girls before and during treatment with hGH were similar to those observed in TS patients with a normal response of GH to pharmacological stimuli. It is concluded that in girls with Turner syndrome GH testing should only be performed when height velocity is below the Turner norm. In TS patients with residual growth potential a clinically significant growth acceleration can be obtained with a higher-than-replacement dose of hGH, i.e. 0.15 IU/kg per day, regardless of GH testing.     

Low insulin, IGF-I and IGFBP-3 levels in children with Prader-Labhart-Willi syndrome

It is well established that insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and insulin are low in growth hormone deficiency, but due to their dependence on nutrition, they are elevated in healthy obese children. As the presence of growth hormone deficiency in Prader-Labhart-Willi syndrome (PWS) is still controversial, we studied insulin, IGF-I and IGFBP-3 levels in 19 children with PWS (age range 0.5–14.6 years). Serum concentrations of insulin (SDS: −0.7±0.9, P=0.01) and IGF-I (SDS: −0.7±0.8,P=0.002) were low, but IGFBP-3 (SDS: −0.3±1.2, P=0.2) was normal compared to normal weight age-matched children. Since children with PWS are typically obese, insulin, IGF-I and IGFBP-3 levels should be compared to normal obese children who present increased levels of these hormones. In comparison to data of healthy obese children reported in the literature, not only IGF-I, but also IGFBP-3 levels are low and fasting insulin levels even very low, suggesting a growth hormone deficiency. Received: 19 November 1997 / Accepted in revised form: 2 March 1998     

Combined therapy with growth hormone and oxandrolone in adolescent girls with Turner syndrome

Five adolescent girls with Turner syndrome (mean age 13.9 years, mean bone age 12.0 years) were treated with both recombinant human growth hormone (rhGH) and oxandrolone for 2 years with an average increment in height of 13.4 cm. The mean bone age advanced by only 1.2 years, providing an increase in the mean estimated mature height of 9.2 cm. We conclude that rhGH and oxandrolone benefit older teenagers with Turner syndrome because of an increased growth rate with slow progression of skeletal maturation.     

The influence of growth hormone monotherapy and growth hormone in combination with oxandrolone or testosterone on thyroxid hormone parameters and thyrxine binding globulin in patients with Ullrich- Turner syndrome

 Administration of human growth hormone (GH) has yielded conflicting results concerning its role on thyroid function in patients with Ullrich-Turner syndrome. Therefore, we investigated the course of thyroid hormone parameters and thyroxin binding globulin in relation to GH therapy, IGF-I and additional oxandrolone-(Ox) or testosterone (T) treatment in 20 patients with Ullrich-Turner syndrome. During the 1st year the patients received only GH. There was no change in T4, fT4, and TSH levels, T3 increased significantly (P <  0.01) after 6 and 12 months, resulting in a higher T3/T4 ratio. TBG (P < 0.05) and IGF-I (P < 0.01) increased after 6 months and remained elevated at 12 months. A significant positive correlation was found between the change of T4 and TBG after 6 months (r = 0.47, P < 0.05) and after 12 months (r = 0.69, P < 0.005). Thirteen patients were further investigated after addition of an anabolic compound; 7 received Ox (0.0625 mg/kg/day po) and 6 low dose T (5 mg i.m. every 14 days). Chronological age was comparable in these groups (10.7 ±  2.7 vs 10.7  ± 3.6 years). After 6 months of combination therapy with Ox, T4, T3 and TSH decreased. As T4 and T3 showed a parallel decrease the T3/T4 ratio remained elevated. TBG declined after 6 and 12 months (P < 0.05), while IGF-I showed a further increment (P < 0.05). There was no correlation between the changes in T4 and IGF-I, TSH and TBG, respectively. In the T-treated group only IGF-I increased (P < 0.05) to the same extent as in the Ox-treated patients, whereas the thyroid parameters did not change. Conclusion The observed changes in thyroid hormone and TBG levels in the Ox group were not mediated by GH or IGF-I. The Ox-induced TBG decrease might be linked to altered pancreatic functions regulating carbo-hydrate metabolism. Received: 22 April 1996 / Accepted: 1 August 1996     

Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably

We have compared the growth and the body composition in children with Prader-Willi syndrome (PWS) with and without growth hormone treatment (recombinant GH 0.1 IU/kg/day) after a 1-y period. Twenty-nine prepubertal children with PWS, with mean body mass index (BMI) SDS of 2.2, and 10 (control) healthy obese children with mean BMI SDS of 5.6, underwent 24-h frequent blood sampling. Both PWS and control obese children had low and similar GH levels (0.7 /ng/l ± 0.4 SD). Serum IGF-I levels, however, were significantly lower in children with PWS (-1.5 SDS ± 0.8 SD vs -0.2 SDS ±0.8 SD). The 29 PWS children were randomized into 2 groups of 15 and 14 subjects for GH treatment and no treatment, respectively. Height velocity increased from -1.9 SDS to + 6.0 SDS in the treated group ( p < 0:001) and decreased from -0.1 SDS to -1.4 SDS in the control PWS group during the study year. BMI decreased significantly for the treated group (+3.0 SDS to + 2.0 SDS). Relative fat mass decreased significantly, while fat-free mass increased ( p < 0:001) for the treated group. No significant changes were noticed in body composition in the control PWS group. In conclusion, the low spontaneous 24-h GH secretion, regardless of body weight, and the exceptional response to growth hormone treatment together with the finding of low IGF-I levels suggest that growth hormone deficiency is a common feature of PWS, as a result of hypothalamic dysfunction. Treatment with growth hormone is beneficial for the majority of PWS children.     

Influence of maternal smoking on neonatal aortic intima-media thickness,serum IGF-I and IGFBP-3 levels

Epidemiological studies have reported associations between a range of cardiovascular risk factors such as smoking and intima-media thickness (IMT). Some reports indicate that the maternal tobacco smoking causes disturbances of the endocrine status of the foetus. There are several potential mechanisms by which insulin-like growth factor I (IGF-I) could modify atherosclerotic processes either locally or in a systemic manner. The aim of this study was to investigate the influence of maternal smoking on neonatal aortic IMT (aIMT), serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels. Aortic intima-media thickness was measured in 28 neonates whose mothers smoked during the pregnancy and 28 control neonates. Mean and weight-adjusted aIMT were significantly greater in the neonates whose mothers smoked (0.455 ± 0.009 mm and 0.151 ± 0.005 mm/kg, respectively) than in controls (0.403 ± 0.029 mm and 0.118 ± 0.014 mm/kg, respectively). Birth-weight of newborns whose mothers smoked was less than that of the controls. The decreases in serum IGF-I and IGFBP-3 observed in the infants whose mothers smoked were non-significant. Mean aIMT was negatively associated with birth-weight and IGF-I level. In conclusion, neonates whose mothers smoked have significantly increased aIMT. It might play a role in the pathogenesis of atherosclerosis in adult life.     

Predicting the response to recombinant human growth hormone in Turner syndrome: KIGS models

A mathematical model for predicting the growth response in patients with Turner syndrome who received growth hormone (GH) therapy was developed by analysing data from KIGS, the Pharmacia & Upjohn International Growth Database. A Model for year 1 of GH therapy explained 46% of the variability of the growth response, with GH dose being the most important of the predictors of height velocity. In years 2-4 of therapy, height velocity during the previous year was the most important predictor, suggesting that an individual's initial response to GH may determine the height outcome of treatment. Additional treatment with oxandrolone. The predictions in all 4 years were highly accurate, as indicated by the low error SDs. However, relatively low predictive power ( R ) during years 2-4 of treatment suggests the models are missing other parameters that would explain more of the variability of the growth response. These growth prediction models could help clinicians to design individualized treatment regimens, provide realistic expectations of therapy outcomes, and adjust treatment on the basis of detected differences between observed and predicted height velocities.     

不同治疗方案对先天性卵巢发育不全症患儿身高增长的疗效比较

目的比较不同治疗方案对先天性卵巢发育不全症（Ｔｕｒｎｅｒ综合征,ＴＳ）患儿身高增长的疗效。方法回顾性分析两组ＴＳ患儿的疗效：一组（６例）接受小剂量康力龙治疗５～１６个月,另一组（１２例）接受同样剂量的康力龙与生长激素（ＧＨ）联合治疗６～１４个月。结果单用康力龙组生长速度（ＧＶ）达到（５５４±１４６）ｃｍ／ａ,身高Ｚ评分（ＨｔＳＤＳ）由－３９１±１３４提高到－３５３±１４３。联合治疗组生长速度为（８５３±２５７）ｃｍ／ａ,ＨｔＳＤＳ由－３３６±１１６提高到－２６１±１０４。联合治疗组疗效较单用康力龙组为优（Ｐ＜００５）,其治疗期间ＧＶ与患儿年龄呈负相关（ｒ＝－０８０,Ｐ＜００１）。结论联合应用ＧＨ与小剂量康力龙治疗ＴＳ疗效确切,适宜临床应用。     

Turner syndrome: Spontaneous growth in 150 cases and review of the literature

The spontaneous growth of 150 patients with Turner syndrome from three German centers-90 with 45,X0 constitution, 60 with other chromosomal abnormalities-has been analyzed. The mean adult height was found to be (n=14) 146.8 cm. It was observed that growth in these patients can be divided into four phases: (1) Intrauterine growth, which is retarded; (2) Height development, which is normal up to abone-age of about 2 years; (3) Between a bone-age of 2 and 11 years when stunting of growth is most marked; (4) After a bone-age of 11 years—the time at which puberty should normally start—the growth phase is prolonged, but total height gain is only little below normal levels. No difference in height could be observed between cases with X0 karyotype and other chromosomal variants. The data are compared with those in the literature.     

Morning versus evening administration of estradiol to girls with Turner syndrome receiving growth hormone: impact on growth hormone and metabolism. A randomized placebo-controlled crossover study

Timing of 17beta-estradiol (E2) administration in relation to that of GH could influence the "first pass effect" of E2 on hepatic IGF-I secretion. In order to test this hypothesis, a randomized double-blind placebo-controlled crossover study was conducted. Nine Turner girls (12.8-20.0y) were treated for 2 mo periods with GH 0.1 IU/kg/d sc at bedtime, and oral E2 6-11 microg/kg/d in the morning and placebo in the evening in one 2-mo period and vice versa in the other period. After each period, 24-h blood sampling was performed. IGF-I and mean 24-h integrated GH were comparable. However, the IGF-I/IGFBP-3 ratio was higher (p = 0.05) and insulin levels were lower after evening administration of E2 (24 h: p = 0.03). During an oral glucose tolerance test in the morning, glucagon and insulin were lower following evening E2 administration (ANOVA: glucagon, p = 0.03; insulin, p = 0.04), as well as insulin resistance tended to be lower (p = 0.09). CONCLUSION: The timing of oral E2 supplementation modulates the IGF-I/IGFBP-3 ratio, insulin and glucagon levels in Turner syndrome during GH treatment, Evening administration of oral estrogen together with evening injections of GH may be preferable.     

Mean 24-hour growth hormone and testosterone concentrations in relation to pubertal growth spurt in boys with normal or delayed puberty

The mean growth hormone concentration during a 24-hour period in 7 boys of short familial stature and a growth rate of 3.2–5.4 cm/year was between 1.0 and 4.6 ng/ml serum. In 7 boys with pubertal growth spurt and familial tallness (growth rate 7.2–11.0 cm/year) it varied from 0.97 to 4.4 ng/ml and in 6 boys with constitutional delay of puberty (a growth rate of 4.2–5.2 cm/year prior to puberty) from 1.3 to 4.3 ng/ml.No correlation was found between the 24-hour mean growth hormone concentration and the mean 24-hour testosterone concentration in serum or the growth rate, but a correlation was found between testosterone and the growth rate.It is concluded that the growth spurt in puberty is not due to a change in growth hormone concentration but rather to the increase of androgen production in puberty.Supported by Deutsche Forschungsgemeinschaft, SFB 51.     

Linear growth in patients with Turner syndrome: Influence of spontaneous puberty and parental height

Growth data on 100 patients with Turner syndrome are reported. Seventeen had spontaneous puberty. Between the ages 11 and 13 years, height and height velocity were higher in these girls than in those with induced puberty. Final adult height, however, was not different. Patients disomic for Xp chromosome were taller than the monosomic ones, and the majority of them had spontaneous puberty. Significant positive correlations were found between height of Turner syndrome patients and corrected mid parental height, mother's height and father's height from the age of 6 years. It is concluded that in patients with Turner syndrome spontaneous puberty and parental height should be accounted for in the evaluation of linear growth.     

Effect of growth hormone therapy on feeding problems and food intake in children with growth disorders

To assess the effect of therapeutic doses of growth hormone (GH) on the feeding problems, food intake, body fat and mealtime interactions of children with growth disorders, an age-matched group of 46 children with Turner syndrome (TS) or Silver Russell syndrome (SRS) was examined using questionnaire measures and direct observation. The children's body fat was measured using bio-electrical impedance analysis and skinfold thickness measurements. Children receiving GH consumed significantly more energy, protein, fat and carbohydrate than did the children who were not receiving GH, independent of the extent of the child's feeding problems. Children receiving GH had less body fat than did children who were not receiving GH. Children who were not receiving GH distracted their parents from the mealtime significantly more often and received more negative prompting and coaxing from their parents to eat than did children who were receiving GH. This study provides evidence to support the theory that appetite and intake is determined in part by growth and growth potential. Feeding problems seen in children with growth disorders are partly due to parental attempts to impose control over their child's intake, when their child consumes less than the parent believes to be adequate. Conclusion: GH has a significant impact on both the food intake and parent-child interaction at mealtimes of children with SRS and TS.     

IGF-1和IGFBP-3在生长激素治疗中的安全性和有效性的研究

基因重组人生长激素(recombinant human growth hormone,rhGH)已广泛应用于儿科临床治疗生长激素缺乏症,并已取得较满意的疗效.生长激素(growth hormone,GH)通过刺激肝脏细胞产生胰岛素样生长因子(insulin-like growth actor,IGF-1)来介导GH的促生长作用.血浆中大部分IGF-1与胰岛素样生长因子结合蛋白3结合,IGF-1具有促进细胞有丝分裂抑制细胞凋亡的作用,近年来发现IGF-1与肿瘤的发生发展有一定相关性,因而引发了对rhGH治疗的安全性和有效性的关注.     

Effect of growth hormone on bacterial translocation in experimental short-bowel syndrome

Despite the adaptive process triggered in the remaining intestine by massive bowel resection, bacterial translocation (BT) is frequent under these conditions. Several trophic factors, including growth hormone (GH), are involved in the process of adaptation in short-bowel syndrome (SBS). However, the effect of GH on BT has not been investigated experimentally. The aim of this study was to test the hypothesis that GH administration prevents BT in rats with SBS receiving only parental nutrition (PN). Nineteen adult Wistar rats underwent central venous cannulation and were randomly assigned to one of two groups receiving for 10 days two treatment regimes: PN group (n = 10): fasting, all-in-one PN solution (300 ml · kg · 24 h, 280 kcal/kg · 24 h), 80% gut section including ileocecal valve; GH group (n = 9): fasting, same PN regime and resection plus GH 1 mg/kg s.c). At the end of the experiment, the rats were killed and mesenteric lymph nodes (MLN) and samples of systemic and portal blood were obtained and cultured. Several samples of full-thickness jejunal wall were taken for determining cell proliferation index (PCNA) and mucosal thickness. Jejunal mucosal thickness increased by 30% and PCNA index by 35% in GH-treated rats in comparison with those treated with PN alone. However, contrary to our expectations, BT expressed by positive culture of intestinal flora in portal blood, MLN, or systemic blood was found in 60% of PN and 87% of GH animals (P = 0.1). Translocation to the general circulation expressed by the presence of organisms in systemic blood was detected in 0% of PN and 44% of GH rats (P < 0.05). Although exogenous GH improves gut mucosal structure in rats with SBS treated with PN, it seems to increase rather than decrease mucosal permeability to intestinal bacteria.     

Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance

Twelve children with documented Prader-Labhart-Willi syndrome were treated with human growth hormone (24 U/m²/week) during 1 year. The children were divided into three groups: group 1: overweight and prepubertal (n = 6, age 3.8–7.0 years); group 2: underweight and prepubertal (n = 3, age 0.6–4.1 years); group 3: pubertal (n = 3, age 9.2–14.6 years). In group 1, height increased from −1.7 SD to −0.6 SD, while weight decreased from 1.1 SD to 0.4 SD, with a dramatic drop in weight for height from 3.8 SD to 1.2 SD. Hand length increased from −1.5 SD to −0.4 SD and foot length from −2.5 SD to −1.4 SD. Body fat, measured by dual X-ray energy absorptiometry, dropped by a third, whereas muscle mass increased by a fourth. Physical capability (Wingate test) improved considerably. The children were reported to be much more active and capable. In group 2, similar changes were seen, but weight for height increased, probably because muscle mass increase exceeded fat mass decrease. Changes in group 3 were similar as in group 1, even though far less distinct. Conclusion Growth hormone treatment in Prader-Labhart-Willi syndrome led to dramatic changes: distinct increase in growth velocity, height and muscle mass, as well as an improvement in physical performance. Fat mass and weight for height decreased in the initially overweight children, and weight for height increased in underweight children. Received: 25 July 1997 / Accepted in revised form: 3 November 1997     

Crouzon综合征合并生长激素缺乏症1例报告及重组人生长激素治疗随诊

目的报告1例Crouzon综合征合并生长激素缺乏症(GHD)患儿及其重组人生长激素(rhGH)治疗结果。方法回顾分析患儿以rhGH治疗2年的临床资料。结果患儿女性,5岁4月龄时身高98.2 cm(P_3),有特殊面容(舟状头、突眼、反颌畸形等)。基因检测示FGFR2基因存在c.1061CG(p.Ser354Cys)杂合变异,源自母亲,为已知的致病变异,诊断为Crouzon综合征。同时相关检查提示患儿合并GHD。给予rhGH治疗2年,身高117 cm,平均生长速率为9.4 cm/a。治疗期间,头颅磁共振监测提示侧脑室及第三脑室略扩张等表现未进展,眼科随诊示左眼视盘水肿程度较前减轻,未发现不良反应。结论矮小可能是Crouzon综合征的表型,rhGH治疗可以改善Crouzon综合征合并GHD患儿的身高,且未引起患儿颅内压增高等不良反应。     

Absence of hypoglycemia in response to varying doses of recombinant human insulin-like growth factor-I (rhIGF-I) in children and adolescents with low serum concentrations of IGF-I

AIM: To determine whether recombinant human insulin-like growth factor-I (rhIGF-I) administration to children with low IGF-I and relatively low insulin-like growth factor binding protein-3 (IGFBP3) serum concentrations would result in hypoglycemia. METHODS: Eighteen children age 11-19 y with serum levels of IGF-I< -2 SDS and IGFBP3< 0 SDS were randomly assigned to receive rhIGF-I at 80 microg/kg body weight daily (n = 6), 40 microg/kg twice daily (n = 6), or 80 microg/kg twice daily (n = 6). After a 10-d dose escalation and 15 d of treatment at the specified dosage, a 25-h pharmacokinetic/pharmacodynamic profile was obtained, which included 22 blood glucose measurements. Regular meals and snacks were provided. RESULTS: No signs or symptoms of hypoglycemia were noted throughout the study. There were no differences in mean blood glucose concentrations among the three dosage groups. The lowest glucose value recorded, 3.44 mmol/l, was 15 min after a morning injection of 80 microg/kg IGF-I, and promptly rose. Although subjects were selected on the basis of low concentrations of IGF-I to represent proposed candidates for rhIGF-I therapy, the mean and range of SDS for height were not different from those of previously studied normal Ecuadorian controls. CONCLUSION: In normal individuals with low serum concentrations of IGF-I and relatively low concentrations of IGFBP3, the administration of therapeutic doses of rhIGF-I, while maintaining reasonable food intake, does not result in hypoglycemia.     

Pharmacokinetics and pharmacodynamics of recombinant human growth hormone by subcutaneous jet- or needle-injection in patients with growth hormone deficiency

Eighteen growth hormone (GH) deficient children and adolescents (11 6/12–20 9/12 y) participated in a randomized open, two-period (4 weeks) cross-over study to evaluate the pharmacokinetics and pharmacodynamics of recombinant human growth hormone (rhGH) administered daily, either by subcutaneous jet-injection or conventional needle-injection. Plasma growth hormone (GH), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), glucose, insulin, HbAlc and serum-free fatty acids (FFA) levels were analysed repeatedly. GH absorption characteristics, expressed as AUC_0-x, Cmax and Tmax ratio (%) jet-injected over needle-injected were similar in both groups. IGF-I and IGFBP-3 plasma levels were identical in both groups. Serum FFA concentrations were comparable after GH administration with either injection device. Surprisingly nocturnal blood glucose decreased to asymptomatic hypoglycaemic levels in all patients. The results of this study showed equal responses concerning absorption and bioavailability of growth hormone administered daily for 4 weeks by either a jet or a needle-injection device in GH-deficient children and adolescents.     

Arm span, serum IGF-1 and IGFBP-3 levels as screening parameters for the diagnosis of growth hormone deficiency in patients with myelomeningocele – preliminary data

Short stature is a common problem in patients with myelomeningocele (MMC) and hydrocephalus. We evaluated auxological and laboratory parameters to differentiate short stature due to neurological defect from short stature additionally caused by growth hormone deficiency (GHD). In a group of 38 prepubertal patients with MMC and hydrocephalus aged 3.8–11.0 years, auxological parameters, including arm span and bone age, and serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels were measured. Patients with normal supine length (n = 15) had normal arm span. Serum IGF-1 and IGFBP-3 levels were normal (≥ 10th percentile) in 14/15 patients. Twenty-three MMC patients had short stature (height SDS < −2), 11/23 patients had reduced arm span (SDS < −2), and 12/23 had normal arm span. Serum IGF-1 and IGFBP-3 levels were normal in 10/12 of short statured patients with normal arm span, but low (<10th percentile) in those patients with reduced arm span (IGF-1: 8/11 patients, P<0.05; IGFBP-3: 9/11 patients, P<0.005). In 7/11 short statured MMC patients with reduced arm span and low serum IGF-1 and IGFBP-3 levels, growth hormone secretion was investigated. All had a disturbed growth hormone secretion (GHD: n = 4; neurosecretory dysfunction: n = 3). Conclusion Arm span, serum IGF-1 and IGFBP-3 levels are estimated to be appropriate screening parameters for GHD in patients with MMC. Initiating growth hormone therapy should be considered not only according to endocrine findings but also with respect to neurological and orthopaedic anomalies. Received: 27 March 1997 / Accepted: revised form 18 September 1997