Treatment of patients with Ullrich-Turner syndrome with conventional doses of growth hormone and the combination with testosterone or oxandrolone: Effect on growth,IGF-I and IGFBP-3 concentrations

Thirty-nine girls with Ullrich-Turner syndrome (UTS) (median age 9.5 years) were treated with growth hormone (GH) with either 12 or 18 IU/m² per week for 12 months followed by combination therapy with either oxandrolone (Ox) (0.0625 mg/kg/day po) or low-dose testosterone (T) (5 mg im every 2 weeks). Growth velocity improved significantly after 12 IU/m² per week (6.4±1.7 cm/year vs 4.0±1.3 cm/year, x±SD,P<0.001) and 18 IU/m² per week of GH (6.5±1.3 cm/year vs 4.5±1.4 cm/year,P<0.001). Ox, but not T was effective in maintaining growth velocity during the 2nd year of therapy (6.9±1.3 vs 5.3±1.5 cm/year). Basal insulin-like growth factor-I (IGF-I) concentrations were in the lower normal range and increased significantly in patients treated with 18 IU/m² per week (357±180 ng/ml vs 160±84 ng/ml) and 12 IU/m² per week (273±121 ng/ml vs 140±77 ng/ml). IGF-I concentrations increased further after addition of Ox (533±124 ng/ml,P<0.001) or T (458±158,P<0.05). IGFBP-3 concentrations were in the upper normal range before therapy and increased only moderately in both GH dosage groups. However, IGF binding protein-3 (IGFBP-3) concentrations were not affected by additional Ox or T treatment.Conclusions 1. Conventional GH doses are effective in increasing growth velocity in UTS, especially, when combined with Ox. This additive effect is not evident when GH is combined with low dose T. 2. Changes in growth velocity are accompanied by an increase of the IGF-I/IGFBP-3 ratio. 3. Ox obviously acts by increasing IGF-I levels independent of the GH status.     

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     

Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls

A survey to identify children and adolescents with primary growth hormone insensitivity syndrome (GHIS) yielded 38 patients who were positively identified using a scoring system that included five criteria: height, basal growth hormone (GH), GH binding protein, basal insulin-like growth factor 1 (1GF-I) and the increase of IGF-I after 4 days of GH administration (IGF generation test). Because of an overlap of the accepted and excluded groups with respect to points scored, an attempt was made to improve the scoring system. The new criteria were: height below –3 SDS, basal GH 4 mU/I or above, GH binding below 10%, basal IGF-I and basal IGF binding protein-3 (IGFBP-3) below the 0.1 centile for age, an increase of IGF-I in the IGF generation test less than 15 μg/1, and the increase of IGFBP-3 less than 0.4 mg/1. With this scoring system, a clear separation between the accepted and the excluded groups was obtained. IGFBP-3 was included to give the GH-dependent parameters of the IGF system more weight and because the accuracy of IGFBP-3 in the IGF generation tests was greater than the accuracy of IGF-I, when the group of patients with GHIS was compared with a group of patients with GH deficiency. Unexpectedly, the IGF generation test was unable to segregate both cohorts completely. In the GHIS-positive group, a significant correlation was found between basal IGF-I or IGFBP-3 levels corrected for age (SDS) and height SDS ( r = 0.49, p < 0.002 and r = 0.61, p < 0.0001, respectively). There was also a significant correlation between the changes of IGF-I or IGFBP-3 in the IGF generation test and height SDS. That is, the patients with a slight response to GH were those with the least growth retardation, suggesting the existence of partial GH insensitivity.     

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     

Changes in growth, growth hormone, and insulin-like growth factor-I (IGF-I) after orthotopic liver transplantation

Growth failure is an important consequence of chronic liver disease in childhood. Insulin-like growth factor-I (IGF-I), which is synthesized and released by the liver, plays an important role as a growth regulator in humans. We examined the growth hormone (GH)/IGF-I axis before and after orthotopic liver transplantation (LT) in 14 children aged between 2 and 11 years (mean 5.6 ± 1.1 years). Pre-transplantation serum GH levels (7.5 ± 1.2 ng/ml) were significantly higher (P < 0.001) compared with controls (5 ± 0.5 ng/ml). However, post-transplantation levels (1.8 ± 0.8 ng/ml) did not differ from those in the control group. Serum IGF-I levels showed a statistically significant increase after LT (20.1 ± 9.4 vs 190 ± 66.2 ng/ml; P < 0.001) and became indistinguishable from the levels in the control group (180 ± 96 ng/ml). In comparison with pre-transplantation data (z− 2.70), there was an increase in height 4 years postoperatively (z− 1.68). Catch-up growth was highly significant, in particular during the 1st year after LT (z−1.58 ± 1.63 vs 2.59 ± 5.29; P < 0.01). We conclude that a GH resistance state found in patients with severe chronic liver disease reverted following LT. Given that IGF-1 depends upon liver function, this could be one of the main factors in the significant catch-up growth in pediatric LT recipients.     

Serum levels of insulin-like growth factor-I,-II and insulin-like growth factor binding proteins-2 and-3 in children with acute lymphoblastic leukaemia

Abstract The insulin-like growth factor (IGF) signaling pathway may be of importance for the proliferation of different tumours (e.g. breast cancer and Wilms tumour). The bioavailability of both IGF-I and IGF-II is regulated by specific IGF-binding proteins (IGFBPs). IGFBP-2 is the predominant binding protein during fetal life, where it is expressed in most tissues. In contrast, postnatally it is mainly released by specific cell types (hepatocytes, astroglia, kidney cells, prostate cells) and a range of tumour cell lines. Furthermore, phytohaemagglutinin stimulated normal lymphoblasts and malignant lymphoblasts express IGFBP-2. In order to investigate the IGF regulatory pathway in leukaemia serum levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were determined in 28 leukaemic children. Whereas serum levels of IGF-I (mean/range: –2.7/–0.1 to –6.7 SDS), IGF-II (–3.6 SDS/–1.3 to –8.7) and IGFBP-3 (–2.0/+2.2 to –7.1 SDS) were significantly decreased comparable to levels in growth hormone deficiency, IGFBP-2 levels (+4.0/–0.45 to +7.4 SDS) were found to be markedly elevated and inversely correlated to IGF-I (r=–0.51,P=0.013). After haematological remission upon chemotherapy all four parameters had normalized in the 16 re-investigated children. Similar findings have been observed in one boy with a relapse including CNS leukaemia.Conclusion This study demonstrates that the proliferation of malignant lymphoblasts (at diagnosis vs treatment) occurs in the presence of decreased serum levels of IGF-I, IGF-II and IGFBP-3 and that diminished production of these peptides may contribute to impaired growth. It further indicates that serum levels of IGFBP-2 may be directly related to the proliferation of lymphoblasts.     

Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion

In order to validate an association between pituitary size and severity of growth hormone deficiency (GHD) we evaluated the magnetic resonance images (MRI) of 107 children with different causes of short stature. Ninety-one MRIs were evaluable (64 male, 27 female; age: 9.1 ± 3.9 years). The levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3), and tests of GH stimulation and spontaneous secretion, led to the following sub-groups: severe isolated GHD (SIGHD) (GH < 7 ng/ml) (n = 21); partial, isolated GHD (GH 7–10 ng/ml) (n = 22); multiple pituitary hormone deficiency (MPHD) (n = 13); neurosecretory dysfunction (n = 10); non-classifiable diagnosis (NC) (n = 13); idiopathic short stature (n = 9); and intra-uterine growth retardation (n = 3). Pituitary height (PHT) was measured and hypoplasia was assumed when PHT was <−2 SDS. An ectopic posterior pituitary with missing stalk and a hypoplastic anterior pituitary was present in 12 (57%) SIGHD cases, 12 (92%) MPHD cases and 1 patient from the NC group. An isolated hypoplastic anterior pituitary was observed in 15%−33% of the other groups. PHT (mm; mean, SD) in MPHD (1.7 ± 0.5) was lower than in SIGHD (2.7 ± 1.0, P < 0.05), with PHT of both groups being lower than in all the other groups (3.8 ± 0.9, P < 0.0001). PHT SDS correlates with IGF-I SDS (r = 0.48, P < 0.0001), IGFBP-3 SDS (r = 0.46, P < 0.0001) and the highest peaks in tests of GH stimulation and GH spontaneous secretion (r = 0.36, P < 0.0001). In contrast to all the other groups, no correlation with age was observed in MPHD and SIGHD. Breech delivery was recorded in up to 26% of patients in all seven groups. Surprisingly, only 1 out of 23 patients with an ectopic posterior pituitary was born by breech delivery, suggesting that ectopia of the posterior lobe is not necessarily related to breech delivery. Conclusion PHT is significantly correlated with GH secretion in several types of short stature. Patients with␣ectopic posterior pituitary, missing stalk and hypoplastic␣anterior pituitary either suffer from SIGHD or MPHD, and this anatomical defect is not necessarily related to breech delivery. Received: 1 December 1996 and in revised form: 8 February 1997 / Accepted: 18 February 1997     

Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children

Schwarze CP, Wollmann HA, Binder G, Ranke MB. Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children. Acta Paediatr 1999; Suppl 428:200-8. Stockholm. ISSN 0803-5326
The present study included a cohort of 42 children aged between 1.7 and 15.4 years, who presented with short stature and growth failure. Basal and generated serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3), measured in an IGF generation test following four or seven daily injections of growth hormone (GH), 0.1 IU/kg (0.033 mg/kg), were analysed in these patients. The growth response to 1 year of GH treatment, 0.6 IU/kg/week (0.2 mg/kg/week), was also investigated. Median height velocity of these patients increased from-1.6 SDS (range, -4.6 to -0.3 SDS) to 3.3 SDS (range, -0.2 to 7.1 SDS) after 1 year of GH treatment, and median height SDS increased by 0.7 SDS (range, 0.1 to 2.2 SDS). Strong correlations were observed between basal and generated IGF-I and IGFBP-3 levels. The increase in IGEBP-3 levels in response to GH in the generation test was a strong predictor of the growth response to GH therapy. All the patients in the present study could be differentiated from patients with GH insensitivity syndrome (GHIS) using the criteria of a diagnostic scoring system for GHIS. The most valuable parameters were the increases in IGF-I and IGFBP-3 levels in the generation test, which excluded 95.2% of the patients from a diagnosis of GHIS. □ Growth hormone treatment, insulin-like growth factor I, insulin-like growth factor binding protein-3, insulin-like growth factor generation test     

Growth hormone and 17β-oestradiol treatment of Turner girls — 2-year results

Girls with Turner syndrome are mainly characterized by growth retardation and gonadal insufficiency. In order to evaluate the effect of growth hormone (GH) and/or low dose 17-oestradiol (E2) on growth and pubertal development, 39 Turner girls with a chronological age (CA) of 7.6–18.1 years were divided into three groups depending on pretreatment bone age (BA). They were treated with either GH 0.1 IE/kg per day (n=13, BA 7.1–10.2), peroral E2 0.01 mg/kg per day (n=8, BA 8.5–12.7) or both (n=18, BA 10.5–15.3). In the 2nd year the E2 group also received GH, while the E2 dose was reduced 30%. In the 1st year height velocity (HV) expressed as standard deviation scores (SDS) increased in all groups (mean): from –0.4 to 3.3 (P<0.01) in the GH group, –0.5 to 2.7 (P<0.01) in the E2 group, and –0.8 to 4.6 (P<0.001) in the GH +E2 group. A possible synergistic effect from combination therapy was seen, as HV increase was higher in group 3 than groups 1 and 2 (P<0.05). In the 2nd year HV was unchanged in groups 1 and 2, while a clear decrease was seen in the GH+E2 group (P<0.001). In the 1st year BA progression in the E2 group was rapid (1.9 BA/CA year) and higher than in the other groups (P<0.05). In the 2nd year progression slowed down-particularly in the E2 group (0.7 BA/CA year,P=0.07). Predicted final height (PFH) increased gradually over the 2 years in the GH group up to 4.1 cm (P<0.01), while in the GH+E2 group PFH increased 2.6 cm (P=0.001) after 1 year, but progressed no further during the 2nd year. In the E2 group PFH decreased –3.1 cm (P=0.055) during the 1st year, while in the 2nd year PFH returned to pretreatment levels. Insulin-like growth factor (IGF-I) increased during the 1st year in the GH and the GH+E2 groups (P<0.01 andP<0.05), while it was unchanged in the E2 group (P>0.4). Except for some of the youngest and oldest girls, breast development was appropriate. No major side-effects were noted. In one girl growth of naevi was noted, but they disappeared spontaneously within 3 months. We conclude that GH and peroral E2 both stimulate HV and appear to have a synergistic effect. The effect of peroral E2 is not mediated by increasing IGF-I. When BA is below 11 years, E2 leads to an accelerated BA maturation, which potentially decreases final height. An initial dose lower than 10 g E2/kg per day and a minimum BA of 11 years are recommended to initiate treatment. Participating in the study: I. L. Pedersen, Paediatric Department, Herning Centralsygehus; M. Rix, Paediatric Department, Aalborg Sygehus Nord; U. Friedrich, Cytogen. Laboratory, Psych. Hospital; K. Lillquist, Paediatric Department, Hjorring Centralsygehus; B. Djernes, C. Pedersen, Paediatric Department, Esbjerg Centralsygehus; N. Clausen, Paediatric Department, Aarhus Kommunehospital; B. Kragh-Olsen, Paediatric Department, Aarhus Kommunehospital; K. Brostrom, Paediatric Department, Hillerod Centralsygehus, I. Pelck, Haderslev; C. Gaardsted, Frederikshavn; I. Ahnfeldt-Mollerup, Bryrup; A. V. Torsson, Paediatric Department, St. Josephs Hospital, Reykjavik, Iceland; L. Kirk, Paediatric Department 5004, Rigshospitalet, Copenhagen; N. C. Christensen, Paediatric Department, Sonderborg, Sygehus; B. B. Jacobsen, Paediatric Department, Odense Sygehus, S. Krabbe, Paediatric Department, Hvidovre Hospital     

Evaluation of growth hormone in thalassaemic boys with failed puberty: Spontaneous versus provocative test

Growth hormone (GH) secretion was determined by evaluating ultradian GH profiles for 12 h and GH responses to insulin stimulated hypoglycaemia (ITT) in 28 stunted boys with -thalassaemia major aged 15.2–17.4 years, who presented with pubertal failure (FP). Healthy non thalassaemia prepubertal boys (n=10) aged 7.5–8.8 years, were studied as controls. All patients had normal responses to ITT with peak GH levels 15 mU/l. Basal GH concentrations (mean±sem) (1.65±0.03 mU/l vs 2.58±0.27 mU/l;P<0.05) and the stimulated GH responses (peak GH=15.4±0.20 mU/l vs 21.08±0.78 mU/l;P<0.001) were significantly lower in the patients with failed puberty than in the controls, indicating that the FP patients had diminished GH reserve and secretory capacity. Moreover, all the GH peak parameters including the maximum spontaneous concentrations (MX-GH) and the area under the GH curve (AUC) were significantly lower in the thalassaemic patients than in the controls (MX-GH=5.2±0.21 mU/l vs 20.42±0.14 mU/l;P<0.001; AUCb=421.22±4.31 mU/l vs 712.20±3.42 mU/l;P<0.001). These observations suggest that the thalassaemic patients had endogenous neurosecretory GH deficiency (GHND). Priming with sex steroid did not cause any improvement in the spontaneous or stimulated GH secretory patterns in thalassaemic patients. It was noteworthy that in neither the patients nor the control subjects, was there a significant correlation between the maximum stimulated and the MX-GH concentrations. These data suggest that the provocative ITT underestimates spontaneous GH secretion and that measurement of spontaneous GH secretion was a more reliable method for identifying patients with GH insufficiency than the ITT.     

Developmental pattern of fetal growth hormone,insulin-like growth factor I,growth hormone binding protein and insulin-like growth factor binding protein-3

AIMS—To evaluate the developmental pattern of fetal growth hormone (GH), insulin-like growth factor I (IGF-I), GH binding protein (GHBP) and IGF binding protein-3 (IGF-3); to determine the implications for fetal growth.
METHODS—Serum GH, IGF-I, GHBP and IGFBP-3 were measured in 53 fetuses, 41 aged 20-26 weeks (group A) and 12 aged 31-38 weeks (group B). Fetal blood samples were obtained by direct puncture of the umbilical vein in utero. Fetal blood samples were taken to rule out β thalassaemia, chromosome alterations, mother to fetus transmissible infections, and for maternal rhesus factor. GHBP was determined by gel filtration chromatography of serum incubated overnight with ¹²⁵I-GH. GH, IGF-I and IGFBP-3 were determined by radioimmunoassay.
RESULTS—Fetal serum GH concentrations in group A (median 29 µg/l, range 11-92) were significantly higher (P<0.01) than those of group B (median 16.7 µg/l, range 4.5-29). IGF-I in group A (median 20 µg/l, range 4.1-53.3) was significantly lower (P<0.01) than in group B (median 75.2 µg/l, range 27.8-122.3). Similarly, IGFBP-3 concentrations in group A (median 950 µg/l, range 580-1260) were significantly lower than those of group B (median 1920 µg/l, range 1070-1770). There was no significant difference between GHBP values in group A (median 8.6%, range 6.6-12.6) and group B (median 8.3%, range 6-14.3). Gestational age correlated positively with IGF-I concentrations (P<0.0001) and IGFBP-3 (P<0.0001) and negatively with GH (P<0.0001). GHBP values did not correlate with gestational age. Multiple regression analysis showed a negative correlation between GH:IGF-I ratio and fetal growth indices
CONCLUSIONS—The simultaneous evaluation of fetal GH, IGF-I, IGFBP-3 and GHBP suggests that the GH-IGF-I axis might already be functional in utero. The progressive improvement in the efficiency of this axis in the last part of gestation does not seem to be due to an increase in GH receptors.

     

Growth hormone therapy in Silver Russell Syndrome: 5 years experience of the Australian and New Zealand Growth database (OZGROW)

Data were analysed on 33 children (22 males) with Silver Russell syndrome treated with growth hormone for periods up to 5 years. Baseline data (medians) at commencement of growth hormone (GH) therapy were age 6.7 years, bone age delay 1.7 years, height standard deviation score (SDS)-3.2, weight SDS –3.1, and growth velocity 5.7 cm/ year. All were prepubertal. Median birth weight SDS for gestational age was –3.2. GH was commenced at 14 IU/m² per week and subsequently adjusted according to response. Growth velocity and growth velocity SDS for chronological age (CA) improved over baseline and gains in height SDS for CA were 1.0, 1.5 and 1.8 SD over 3, 4 and 5 years respectively (P < 0.001). No significant increase in height SDS for bone age was observed. Increased GH doses were required after the 1st year to maintain growth rates. Mean bone age advancement was 3.1 years after 3 years of treatment, and 6.0 years after 5 years treatment. Younger age was a predictor of the growth response over the 1st year. Predictors of response after 3 years were catch-up growth, low weight SDS at birth and low height SDS for CA. Age at onset of puberty was normal, but height at onset of puberty was lower than normal means. Conclusion We have demonstrated significant improvement in growth in Silver Russell syndrome after 3 years of GH therapy, however data on estimated mature height and final height are insufficient to conclude final outcomes. Further follow up is required to assess the long-term benefit. Received: 19 July 1995 Accepted: 4 March 1996     

重组人生长激素注射液治疗儿童生长激素缺乏症的临床评价

目的 生长激素缺乏症(GHD)有赖于生长激素替代治疗.生长激素注射液可简化注射过程,提高依从性.进一步评价中国重组人生长激素注射液治疗儿童GHD的疗效和安全性.方法 采用多中心、前瞻性、随机开放的研究方法 ,对31例[男20例,女11例,年龄(10.5±4.1)岁]确诊为完全件GHD的患儿,给予重组人生长激素注射液,0.25 mg/(kg·周)[0.107 U/(kg·d)],每晚睡前皮下注射1次,治疗3、6、9、12个月后进行随访,疗程12个月.比较治疗前后的身高增长量(△HT)、年生长速率(growth velocity,GV)、身高均值标准差积分(HT SDS)、血胰岛素样生长因子Ⅰ(IGF-1)、胰岛素样生长因子结合蛋白质3(IGFBP-3)、抗生长激素抗体和骨成熟情况的变化,并评估药物治疗的安全性.结果 (1)治疗3、6、9、12个月后△HT(cm)分别为4.0±1.3、7.0±2.0、10.3±2.6和12.9±3.3(P<0.01),显示治疗后呈良好线性生长;GV(cm/年)治疗前为2.7±0.9,治疗后分别升至16.0±5.1、14.1±4.0、13.7±3.5和12.9±3.3,显示治疗后追赶生长明显,治疗前后比较,差异有统计学意义(P<0.01);HT SDS治疗前为-4.62±1.46,治疗后分别为-3.80±1.53、-3.28±1.60、-2.86±1.75和-2.47±1.86,显示治疗后身高与同年龄同性别正常儿童差距逐步缩小,与治疗前相比差异有统计学意义(P<0.01);(2)血IGF-1(ug/L)治疗前为41±64,治疗后分别为179±155、202±141、156±155和159±167;IGFBP-3(mg/L)治疗前为1540±1325,治疗后分别为3891±1815、4051±1308、3408±1435和3533±1413,显示随着身高增长,IGF-1、IGFBP-3被药物激活到较高水平,治疗前后差异均有统计学意义(P<0.01);(3)在治疗6个月、12个月后进行骨龄评估,骨成熟程度(△BA/△CA)分别为1.01±0.57、1.07±0.75,显示骨龄无加速发展;(4)治疗期间未发生严重不良事件,与药物有关的伴随反应主要表现为甲状腺功能减低.结论重组人生长激素注射液足一种安全有效治疗儿童GHD的药物.     

Growth hormone secretion in children and adolescents with familial tall stature

Sixty-five patients (22 boys and 43 girls) presenting with familial tall stature were investigated with regard to growth hormone (GH) secretion, both physiological and after stimulation with thyrotropin releasing hormone (TRH) and growth hormone relasing hormone (GHRH). Plasma insulin-like growth factor-I (IGF-I) was also measured. Two groups of patients were distinguished according to their physiological secretion of GH: a high secretory group (n=49) with a mean 24 h integrated concentration of GH (IC-GH) of 5.4±2.3 g/l per minute and a large number of peaks (5.1±1.6 in 24 h), and a low secretory group (n=16) with a mean 24 h IC-GH of 2.1±0.5 g/l per minute and few peaks (3.3±1.3 in 24h). Plasma IGF-I levels and GH peak values after the TRH test were significantly higher in the high secretory group. These results indicate that familial tall stature is the consequence either of hypersecretion of GH or of hypersensivity to this hormone (IGF-I levels being normal in spite of low GH levels).     

Growth and endocrine disorders in optic glioma

Hypothalamo-pituitary function in children with optic glioma may be impaired by the tumour itself and by the high cranial radiation doses used in treatment. This study evaluates the effect of optic glioma and its treatment on patient growth and pubertal development. Twenty-one patients (13 boys, 8 girls), treated for optic glioma by cranial irradiation (45–55 Grays) at a mean age of 5.4 years, were evaluated before (n=10) and/or after (n=21) irradiation. Growth hormone (GH) deficiency was present in only 1 patient tested before irradiation and in all patients after irradiation. Precocious puberty occurred in 7/21 cases, before irradiation in 5 patients and after irradiation in 2 patients. The cumulative height loss during the 2 years after irradiation was 0.2±0.2 SD (m±SEM) in 7 patients with precocious puberty and 1.1±0.2 SD in 14 prepubertal patients (P<0.01). The corresponding bone age advance over chronological age, evaluated 1–3 years after irradiation, was 1.1±0.5 and –0.7±0.3 year in the two groups (P<0.01). The mean height loss between time of irradiation and the final height was 2.3±0.6 SD (n=6). Primary amenorrhoea, associated with low oestradiol levels, occurred in two of the three girls of pubertal age. These data indicate that the high dose of cranial radiation used to treat optic glioma invariably results in GH deficiency within 2 years and that hGH therapy is required when GH deficiency is documented. Precocious puberty, resulting in apparently normal growth velocity in spite of GH deficiency, should be treated with luteinizing hormone-releasing hormone analogues because of the risk of accelerated bone maturation and reduced final height.     

Insulin-Like Growth Factor II Effects Mediated through Insulin-Like Growth Factor II Receptors

ABSTRACT. Insulin-like growth factor II (IGF-II) resembles the homologous peptide insulin-like growth factor I (IGF-I) in that it stimulates cellular growth in vitro. This effect is generally believed to be mediated through IGF type 1 receptors; the role of the IGF type 2 receptor remains, as yet, unknown. IGF-II has been shown to stimulate clonal expansion in cells from the human erythroleukaemia cell line K562, which displays binding of IGF-II and insulin but not IGF-I. This IGF-II effect was dose-dependent and correlated to the amount of specific binding; IGF-I did not stimulate growth. A similar effect on clonal growth was observed in the human T-cell line Jurkat. Furthermore, IGF-II was found to stimulate the cytotoxic activity of natural killer cells (as does interleukin 2). This effect was not inhibited by addition of IGF binding protein 1. Thus, it can be concluded that IGF-II, besides demonstrating standard IGF properties, exhibits unique biological effects in certain cells.     

Growth and growth hormone secretion after treatment for childhood non-Hodgkin's lymphoma

The aim of this study was to evaluate the growth and growth hormone (GH) secretion, as assessed by the rate and pattern of secretion, in patients in remission from non-Hodgkin's lymphoma (NHL) who had been treated with corticosteroids and intense chemotherapy. None of the patients had received cranial irradiation. Twelve children were investigated yearly by taking 24-hour GH profiles starting 1 year from the time of diagnosis. The mean age at onset of the disease was 7.5 years. Another 12 young adults were studied in a cross-sectional manner 4.1–21.3 years (mean, 9.0 years) after diagnosis of NHL. The mean age at onset of the disease was 10.7 years. The median height velocity was significantly decreased during the 1st year following diagnosis (standard deviation scores [SDS] −0.15, P < .001), especially during the first 3 months (SDS −0.75, P < .001) when the most intense treatment was given. During the 2nd year height velocity was still somewhat reduced (SDS −0.13, P < .001). However, there was no reduction in final attained height. Spontaneous GH secretion, in terms of both secretory rate and pulsatile pattern, was evaluated by measuring integrated GH concentrations in 20-minute blood samples collected over a 24-hour period. The plasma GH concentrations were transformed into GH secretion rates by means of a deconvolution technique. Fourier time series analysis was applied to determine possible disturbances of rhythmicity of the GH secretion. The GH secretion rate and the pulsatile pattern of secretion in the NHL patients were similar to those of the reference population of pubertal matched healthy controls. There was no influence of the age at diagnosis or of the time from diagnosis of NHL on the GH secretion rate. Growth impairment in children with a malignant disease treated only with steroids and chemotherapy is therefore probably not caused by disturbed GH secretion, but rather by direct interference with bone growth of the cytotoxic drugs used. There was no significant influence on weight gain during the treatment period so an indirect effect of chemotherapy on bone growth through interference with adequate nutrition seems unlikely. However, GH secretion was not evaluated during the period of growth retardation, and therefore a transient deficiency was not excluded. © 1997 Wiley-Liss, Inc.     

Effect of human chorionic gonadotropin on growth velocity and biological growth parameters in adolescents with thalassaemia major

The effect of long-term human chorionic gonadotropin (HCG) therapy on the linear growth and biological growth parameters was studied in six thalassaemic boys aged 14.5–15.5 years old with hypogonadotropic hypogonadism. A significant (P<0.001) increase in growth velocity (from 3.3±0.3 to 7.6±0.6 cm/year) was found after 6–12 months of therapy, without acceleration of bone age. A striking improvement in pubertal development was observed. The treatment significantly increased growth hormone (GH) response to l-dopa administration (P<0.025) as well as sleep GH secretion (P<0.025). Serum growth factors, evaluated as thymidine activity during deep sleep, increased (P<0.001), but somatomedin C (Sm-C) levels did not. Prior to treatment, baseline and peak values of plasma growth hormone releasing hormone (GH-RH) following l-dopa were low. After HCG therapy, GH-RH response to l-dopa increased significantly (from 9.2±5.6 to 20.2±6.2 pg/ml; P<0.05), but remained (P<0.001) lower than in normal prepubertal children. This study suggests that in thalassaemia major an impaired GH-RH release can be observed, in addition to the described alteration in Sm-C generation.Abbreviations LH luteinising hormone - FSH follicle stimulating hormone - HCG human chorionic gonadotropin - GH growth hormone - GH-RH growth hormone releasing hormone - GnRH gonadotropin releasing hormone - TA thymidine activity - Sm-C somatomedin C     

Circulating somatomedin-C levels and the effect of growth hormone-releasing factor on plasma levels of growth hormone and somatostatin-like immunoreactivity in obese children

The effect of growth hormone-releasing factor (GRF) 1-44 on growth hormone and somatostatin release in plasma has been studied in 20 obese children. Twenty age and sex-matched children with normal weight served as controls. Mean peak growth hormone response in obese children after 1 g/kg body wt. GRF 1-44 was significantly lower than in controls (23.7±3.6 ng/ml vs. 41.1±3.0 ng/ml;P<0.01), as were mean integrated growth hormone response areas (1544±272 ng×ml^-1×2 h vs. 2476±283 ng×ml^-1×2 h;P<0.01). Mean plasma levels of somatostatin-like immunoreactivity did not change after GRF in both goups. Mean somatomedin-C levels in obese children were significantly higher compared to controls (1.6±0.4 U/ml vs. 0.86±0.4 U/ml;P<0.01). Somatomedin-C levels were not related to the integrated growth hormone responses. In conclusion there is no relation between somatomedin-C levels and the reduced growth hormone-releasing effect of GRF in obese children. GRF does not alter peripheral somatostatin-like immunoreactivity levels either in normal or obese children.Abbreviations Sm-C somatomedin C - GRF growth hormone-releasing factor - GH growth hormone - SLI somatostatin-like immunoreactivity     

肠道炎症阻滞儿童体格生长的免疫和内分泌机制

肠道炎症常伴发儿童的生长落后。生长激素(GH)和胰岛素生长因子-1(IGF-1)是调控出生后骨骼纵向生长的重要物质,抑制GH/IGF轴可阻滞儿童体格生长。肠道发生炎症时,异常升高的促炎症因子IL-1β、IL-6和TNF-α通过干扰GH/IGF轴,系统性以及在生长板局部水平影响骨骼生长,进而导致儿童生长阻滞。