Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3 and insulin in obese children.

In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are diminished. However, this diminished GH secretion does not result in decreased somatic growth in obese children. Although the increased insulin level, low insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as being involved, the exact mechanism has not yet been established. We investigated serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39 non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I, free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not significantly different from those in the control group. A positive correlation was found between body mass index (BMI) and IGF-I in the obese children (r = 0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p < 0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p = 0.05) in the obese children. We concluded that normal growth in obese children might be maintained through normal IGF-I and increased IGFBP-3 levels, which are stimulated by increased insulin levels or nutritional factors or by increased responsiveness to GH.     

Effect of zinc supplementation on growth hormone secretion, IGF-I, IGFBP-3, somatomedin generation, alkaline phosphatase, osteocalcin and growth in prepubertal children with idiopathic short stature

Controversy exists about the effect of zinc on growth and the GH-IGF system. Zinc supplementation has been shown to stimulate linear growth in zinc-deficient children. However the mechanism of this effect has not been well characterized. Furthermore, the effect of zinc supplementation on non-zinc-deficient short children is unknown. We investigated the effect of zinc supplementation on endogenous GH secretion, serum IGF-I and IGFBP-3 concentrations, IGF-I and IGFBP-3 generation in response to exogenous GH, bone formation markers, and linear growth of non-zinc-deficient children with idiopathic short stature. We analyzed prospectively serum zinc, IGF-I, IGFBP-3, alkaline phosphatase, osteocalcin, and GH response to clonidine test, and performed a somatomedin generation test before and 6 weeks after zinc supplementation in 22 (16 M, 6 F) prepubertal children with idiopathic short stature. Serum IGF-I increased from 67.4+/-70.6 to 98.2+/-77.3 ng/ml (p <0.001), IGFBP-3 from 2326+/-770 to 2758+/-826 ng/ml (p <0.001), alkaline phosphatase from 525+/-136 to 666+/-197 U/l (p <0.0001), and osteocalcin from 16.8+/-10.6 to 25.8+/-12.8 ng/ml (p <0.05) after zinc supplementation despite there being no difference in GH response to clonidine after zinc supplementation (peak GH 11.6+/-6.9 vs 13.4+/-7.8 ng/ml, GH area under the curve during clonidine test 689+/-395 vs 761+/-468, NS). Percent change in IGF-I and IGFBP-3 during the somatomedin generation test was not significantly affected by zinc supplementation (118% vs 136% and 57% vs 44%, respectively). There was no significant correlation between percentage increase in zinc levels and percentage increase in parameters tested. Height SDS or weight SDS did not improve significantly in 17 patients who continued on zinc supplementation for at least 6 months (6-12 months) (-2.59 vs -2.53 SDS and -1.80 vs -1.67 SDS, respectively). Zinc supplementation increased basal IGF-I, IGFBP-3, alkaline phosphatase and osteocalcin without changing GH response to clonidine. Zinc supplementation did not affect sensitivity to exogenous GH as tested by IGF-I and IGFBP-3 generation test. These results suggest a direct stimulatory effect of zinc on serum IGF-IGFBP-3, alkaline phosphatase and osteocalcin. Despite improvements in the above parameters, zinc supplementation to children with idiopathic short stature with normal serum zinc levels did not significantly change height or weight SDS during 6-12 months follow-up.     

The effects of pubertal status and glycemic control on the growth hormone-IGF-I axis in boys with insulin-dependent diabetes mellitus

Dysregulation of the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis in children and adolescents with insulin-dependent diabetes mellitus (IDDM) is well documented. Elevated levels of circulating GH, increased GH secretory amplitude, and decreased concentrations of IGF-I, IGFBP-3, and GHBP have been related to poor glycemic control. We proposed that pubertal maturation may be a more significant factor, potentially overriding the effects of metabolic control, especially during mid-puberty when the GH-IGF-I axis is maximally stimulated. We studied 24 male children and adolescents with IDDM over a 5 year period. Subjects were grouped both by pubertal stage (prepubertal vs mid-pubertal) and by level of glycemic control (hemoglobin A1 (<9%, 9-11.5%, and >11.5%). Twenty-four hour every 20 minute blood sampling for GH determination was analyzed using the Cluster algorithm, and static measures of IGF-I, IGFBP-3, and GHBP were obtained. When analyzed by pubertal status, we found no difference in the number of GH secretory peaks or the interval between concentration peaks. The sum of the peak heights and area under the curve were significantly greater in the mid-pubertal boys, as was the average GH nadir. Serum levels of IGF-I and IGFBP-3 were greater in the mid-pubertal boys, but levels of GHBP were higher in the prepubertal boys. When analyzed by level of glycemic control, we found no differences in the number of GH secretory peaks or interval between peaks among the 3 groups. However, the sum of the peak heights, area under the curve, and average GH nadir were all lower in the group with the intermediate level of glycemic control (HgbA1 9-11.5%); no differences were observed between the other 2 groups. This relationship persisted when the mid-pubertal subjects were analyzed separately. No differences were found among the 3 groups for levels of IGF-I, IGFBP-3, or GHBP. We conclude that normal increases in GH secretion and levels of IGF-I and IGFBP-3 occur during mid-puberty in boys with IDDM. A concomitant increase in average GH nadir may reflect an underlying effect of metabolic control. Greater GH secretion was observed in the groups with the lowest and highest levels of glycemic control. We speculate that this may be related to an increased incidence of severe hypoglycemic episodes in the group with the lowest levels of glycosylated hemoglobin, resulting in metabolic derangements similar to those with elevated glycosylated hemoglobin levels.     

Insulin-like growth factor binding protein-3 proteolysis and growth of athyreotic infants in the first weeks of life

To gain a better understanding of the growth of athyreotic newborns in the first weeks of life, we evaluated auxological parameters and determined the serum levels of growth hormone (GH), insulin-like growth factor I (IGF-I) and free IGF-I, and IGF-binding protein-3 (IGFBP-3) in 15 hypothyroid infants (10 females) at a mean age of 25 d of life, immediately before the beginning of L-thyroxine therapy, and at 3 and 6 mo of life. Fourteen normal infants (9 females) of the same age were studied as controls. IGFBP-3 proteolytic activity was evaluated in 8 patients and in 8 controls at 25 d and 6 mo of life. There was no significant difference concerning weight and length between the patients and controls at birth, 25 d, 3 and 6 mo of life. The blood GH, IGF-I and IGFBP-3 levels were significantly lower in patients at diagnosis than in controls of the same age (p < 0.01 for all parameters), as well as IGFBP-3 studied by Western blotting. At diagnosis, the patients' free IGF-I level was within the control range, but the free IGF-I percentage of total IGF-I was higher than in the controls (p < 0.01). IGFBP-3 proteolytic activity was found to be greater in the patients (p < 0.01). At 6 mo of life, after therapy, none of these parameters was different from those of the controls. CONCLUSION: Increased IGFBP-3 proteolytic activity in our patients at diagnosis, favouring IGF-I bioavailability, could account for normal free IGF-I levels and in turn for their normal growth pattern during the first weeks of life and before the start of treatment.     

Basal and stimulated levels of growth hormone, insulin-like growth factor-I (IGF-I), IGF-I binding and IGF-binding proteins in beta-thalassemia major

A significant percentage of children with beta-thalassemia major shows retardation in longitudinal growth as they progress towards puberty due to skeletal dysplasia, endocrine gland hypofunction or trace element deficiencies. The aim of this study was to evaluate GH/IGF-I secretion and action in prepubertal patients with beta-thalas-semia major. Eight prepubertal patients with short stature (group A) and seven prepubertal patients with normal stature (group B) were studied. Basal and stimulated (after administration of the hexapeptide Hexarelin) GH levels were measured with IRMA (Nichols); IGF-I and IGFBP-3 levels were measured with RIA (Nichols). IGF-I binding proteins (IGFBPs) were analyzed qualitatively with Western ligand blot. IGF-I binding to B-lymphocytes of the patients was also measured with competitive binding studies using human recombinant IGF-I and 125I-IGF-I (Amersham). Basal GH levels did not differ statistically between the groups. Peak GH levels after Hexarelin stimulation test were higher in group A (A: 27.9 +/- 15.6 ng/ml vs B: 9.1 +/- 4.7 ng/ml) (Wilcoxon test, p < 0.05). IGF-I levels in the two groups were low-normal and comparable (A: 168.0 +/- 81.6 ng/ml vs B: 126.6 +/- 25.5 ng/ml). IGFBP-3 levels were low in both groups (A: 1.21 +/- 0.27 microg/ml vs B: 1.08 +/- 0.20 microg/ml). Western ligand blot did not reveal any discernible difference in IGFBPs. However, IGF-I binding on B-lymphocytes was at least 20% lower in group A compared to group B (t-test, p < 0.01). IGF-I binding inversely correlated with peak GH levels (r = -0.54, p < 0.05). Patients in group A were older and chronological age correlated with IGF-I levels (r = 0.53, p < 0.05) whereas it inversely correlated with IGF-I binding (r = -0.63, p < 0.05). Moreover, patients in group A had higher ferritin levels. No correlation was found between ferritin levels, desferrioxamine dose/compliance or liver enzyme levels and the parameters of the GH axis studied. However, desferrioxamine dose x years correlated with IGFBP-3 (r = 0.56, p < 0.05) and correlated inversely with IGF-I binding (r = -0.74, p < 0.01). In conclusion, we have shown adequate GH secretion, higher secretive capacity after the administration of Hexarelin and lower IGF-I binding in prepubertal beta-thalassemic patients with short stature. Whatever the cause, reduced IGF-I action has to be considered when treating beta-thalassemic patients with short stature.     

一个Laron 综合征家系患者临床特点和生长激素受体基因突变分析

Laron 综合征是一种常染色体隐性遗传病,生长激素受体（GHR）基因缺陷是导致Laron 综合征的主要病因。Laron 综合征主要临床特征为生后严重的生长落后伴特殊面容,血生化特点为高生长激素(GH)、低胰岛素样生长因子- (IGF-I) 和低胰岛素样生长因子结合蛋白- (IGFBP-3)。该研究报道一家系2例Laron 综合征患者的临床特点及GHR基因突变。这两个病人为同胞姐弟。弟弟8岁,身高80.0 cm (-8.2 SDS),姐姐11岁,身高96.6 cm (-6.8 SDS)。他们出生体重和身长无特殊,自生后出现生长落后,身高明显落后于同龄正常儿童,并均呈现了典型Laron 综合征外貌特征：身材矮、肥胖、前额突出、大眼睛、塌鼻梁、头发稀软。这两个病人空腹血清GH值均明显高于正常儿童,空腹血清IGF-I明显低于同年龄同性别正常儿童,血浆IGFBP-3和生长激素结合蛋白（GHBP）低于检测线。其中1例（8岁男孩）胰岛素和可乐定刺激后GH峰值大于350 ng/mL,给予重组人生长激素治疗1年,身高由治疗前的80.0 cm 增加至83.3 cm。GHR基因序列测定结果显示2例患者均存在外显子4上第65位氨基酸的纯合突变S65H(TCA → CCA),为新发现的突变。Laron 综合征患者存在特殊的面貌特征,结合血GH、IGF-I、IGFBP-3和GHBP测定可以明确诊断。GHR基因外显子4上S65H突变可能是这两位Laron 综合征患者的致病原因。［中国当代儿科杂志,2007,9（4）：335-338］     

Two cases of insulin-dependent diabetes mellitus under insulin treatment with slow height velocity: Relationship of growth hormone-binding protein,metabolic control and growth

Inadequate blood sugar control in children with insulin-dependent diabetes mellitus (IDDM) sometimes results in low insulin-like growth factor-I (IGF-I) and sluggish height growth. High affinity growth hormone-binding protein (GHBP), which is identical to the extracellular domain of growth hormone (GH) receptor, is present in the human sera. We have determined GHBP activity in two cases of poorly controlled IDDM with low height velocity in relation to metabolic control in order to determine the mechanism of resistance to GH in this condition, as indicated by low levels of GH-dependent growth factor IGF-I in the face of high serum GH levels. GHBP activity was within the normal range in two cases of IDDM with slow height velocity, low IGF-I and high hemoglobin-A₁. In both cases, improved blood sugar control normalized IGF-I to result in accelerated height velocity without a major change in GHBP levels. These results may indicate either normal peripheral GH receptor or normal free portion of serum GH, and may suggest that the major defect in slow growth in poorly controlled diabetes is due to the post GH receptor.     

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.

     

Laron综合征家系患者生长激素受体基因突变分析

目的研究Laron综合征患者的临床特点及生长激素受体（GHR）的基因突变。方法对一家系中2例表现为身材明显落后的患儿进行研究，分别进行体格测量和GH-IGF—I轴功能测定。提取外周血白细胞基因组DNA，运用聚合酶链式反应（PCR）扩增GHR基因第2～9外显子及其两侧的侧翼序列，直接进行测序，将所测结果与正常人GHR基因序列进行对比，确定突变位点和突变类型。对突变基因均经2次测定证实。结果2例患儿自出生后身长明显落后于同龄儿童，呈现Laron综合征的独特面貌，空腹血清GH值均明显高于正常儿童。空腹血清IGF-I明显低于同年龄同性别正常儿童。血浆IGFBP-3和GHBP低于检测线。GHR基因序列测定结果显示2例患儿均存在外显子4上第65为氨基酸的纯合突变S65H，为新发现突变。结论Laron综合征患者存在典型的面貌特征，结合血GH、IGF-I、IGFBP-3和GHBP测定可以明确诊断。GHR基因外显子4上S65H突变可能是该Laron综合征患者的致病原因。     

Serum insulin-like growth factor-I (IGF-I), IGF-binding protein-3, and growth hormone levels in collodion babies: a case-control study

AIM: Because growth failure occurs in many collodion babies, we investigated serum growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels in collodion babies admitted to Gevher Nesibe Hospital, Kayseri, Turkey between 1999 and 2006. PATIENTS AND METHOD: The newborns diagnosed clinically as 'collodion baby' were included in the study group (group 1). Because collodion babies are usually born small for gestational age (SGA) and/or premature, a control group (group 2) was formed by selecting the first infant admitted immediately after each study infant who matched for gestational age (+/- 7 days) and birth weight (+/- 100 g). All infants' blood samples were collected within the first 2 h of life for measurements of serum GH, IGFBP-3 and IGF-I levels. RESULTS: Group 1 consisted of 23 collodion babies (13 males and 10 females) with gestational ages ranging from 32 to 42 weeks, and birth weights ranging from 1,300 to 3,600 g. Ten were born premature and 16 were SGA. Serum IGF-I and IGFBP-3 levels were lower but serum GH levels were higher in collodion babies than in controls. Birth weight was positively correlated with serum IGF-I (r = 0.310, p = 0.046) and IGFBP-3 (r = 0.389, p = 0.011) levels. Serum GH level was negatively correlated with birth weight (r = -0.376, p = 0.014), serum IGF-I (r = -0.567, p <0.001) and IGFBP-3 (r = -0.444, p = 0.003). CONCLUSION: Collodion babies had lower serum IGF-I and IGFBP-3 levels but higher serum GH levels than controls in the present case-control study. The underlying mechanism needs to be explored.     

Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity

Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 micrograms/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly (p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs.     

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) concentrations compared to stimulated growth hormone (GH) in the evaluation of children treated for malignancy

OBJECTIVE: The aim of this investigation was to evaluate the utility of IGF-I and IGFBP-3 determinations in screening for GH deficiency (GHD) in children previously submitted to treatment for childhood malignancy. PATIENTS AND METHODS: We compared the GH responses to two pharmacological tests (arginine and levo-dopa) with the IGF-I and IGFBP-3 levels in 48 patients (29 boys) who had undergone bone marrow transplantation (BMT) (36 patients) or treatment for a solid cranial tumor (12 patients). RESULTS: 22 patients (45.8%) showed GHD (i.e. GH peak < 8 ng/ml in both tests), and only three (13.6%) of the GHD patients had concomitant low IGF-I levels (i.e. -2 SD below the normal mean) and only one (4.5%) an abnormal IGFBP-3 value (i.e. -2 SD below the normal mean). Among the 26 children with normal GH secretion, 21 (80.8%) also showed normal IGF-I and IGFBP-3 levels, three (11.5%) had a concomitant low IGF-I value and two (7.7%) a concomitant low IGFBP-3 value. A significant correlation was found between GH secretion and age at diagnosis (r = 0.26, P < 0.05), and between IGF-I and IGFBP-3 (r = 0.52, P < 0.0001), but not between GH and IGF-I or IGFBP-3. Comparing the growth pattern of these patients from diagnosis to the first year after therapy or BMT, we found that while individual height changes did not correlate with the GH peak, a significant correlation was found between height SDS decrease and IGF-I (r = 0.31, P < 0.05) or IGFBP-3 SDS (r = 0.37, P < 0.01). CONCLUSION: Our results indicate that the cut-off of -2 SD for IGF-I and IGFBP-3 was insensitive in screening for GHD. A normal value did not exclude a subnormal GH response to provocative tests and therefore although IGF-I and IGFBP-3 levels may be indicators of the growth pattern, they cannot be used alone as a tool for identifying GHD children after treatment for childhood malignancy.     

Relationship between serum growth hormone binding protein levels and height in young men

The biochemical mediators responsible for variations in stature among normal subjects are largely unknown. To obtain some initial information about potential endocrine factors, we measured the serum concentrations of GH, IGF-1, IGFBP-3 and GHBP in healthy young men shorter than 159 cm and taller than 187 cm. We studied 14 volleyball and basketball players (tall group), and 14 jockey students from a horse racetrack (short group). A careful medical history was taken, including dietary intake, and physical examination with special attention to the possible presence of genetic stigmata was performed. Serum prealbumin was determined as an index of nutritional status. A buccal smear was performed to exclude Klinefelter's syndrome. The BMI and serum prealbumin levels were comparable in both groups of individuals. The nutritional survey, however, revealed that the tall subjects had a higher intake of calories (42.2+/-11.2 vs. 30.1+/-15.15 kcal/kg, p<0.05), and protein (1.5+/-0.6 vs. 0.8+/-0.4 mg/kg, p<0.01). Serum concentrations of GHBP did not differ in the two groups (0.95+/-0.37 nmol/l in the tall, and 0.95+/-0.53 nmol/l in the short group), and did not correlate with height, serum IGF-I levels, or BMI. We observed a significant difference in the serum concentrations of IGF-I in the two groups of individuals (42.02+/-9.37 nmol/l in the tall and 31.79+/-3.18 nmol/l in the short group, p<0.05), and this growth factor showed a positive correlation with height (r = 0.5, p<0.01). These preliminary findings suggest that final height differences in young men do not appear to be mediated by variations in GHBP concentrations.     

Monthly measurements of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in healthy prepubertal children: characterization and relationship with growth: the 1-year growth study

The usefulness of measurements of IGF-I or IGF-binding protein-3 (IGFBP-3) in the clinical management of growth disorders is dependent on the extent of physiologic variation in their concentrations. Our purpose was therefore to investigate the longitudinal intraindividual variation in serum concentration of IGF-I and IGFBP-3 in healthy prepubertal children. Monthly serum samples and auxologic measurements were taken over a period of 1 y from 65 prepubertal children (38 boys, 27 girls; mean age 9.1 y, range 7.8-10.8). Concentrations of IGF-I and IGFBP-3 were measured by RIA. The mean (+/-SD) serum concentration of IGF-I in the children was 165 +/- 42.0 microg/L, with a mean coefficient of variation (CV) of 13.9% around the annual mean serum concentration for each child. The corresponding mean concentration of IGFBP-3 was 3273 +/- 604.5 microg/L, and the mean CV for each child was 9.7%. These monthly longitudinal variations in IGF-I and IGFBP-3 were parallel to changes in longitudinal growth. Short-term changes (1 mo) in IGF-I were positively correlated with changes in weight (r(s) = 0.42, p < 0.0005) and body mass index (r(s) = 0.45, p < 0.0005), and negatively correlated with minor intercurrent illnesses (-0.32; p < 0.05). Seasonal fluctuations also occurred, with short term changes in IGF-I (1 mo) and IGFBP-3 (3 mo), increasing with increasing outdoor temperatures (r(s) = 0.30, p < 0.05 and r(s) = 0.39, p < 0.005, respectively). We conclude, that there are significant changes in both IGF-I and IGFBP-3 that occur in association with growth, and that IGF-I is more sensitive than IGFBP-3 to short-term changes in weight, body mass index, and intercurrent illnesses. Physiologic short-term changes must therefore be taken into consideration when using serum levels of IGF-I or IGFBP-3 in the evaluation of the short or slowly growing child.     

Is there heterozygote expression of growth hormone receptor deficiency?

Expression of heterozygosity for the defect in the growth hormone (GH) receptor has been proposed to be reflected in stature, and in GH binding protein (GHBP) and insulin-like growth factor I (IGF-I) levels in parents and other relatives of patients with GH receptor deficiency (GHRD; Laron syndrome). The Ecuadorean population with GHRD, in which heterozygosity can be accurately determined in clinically unaffected relatives of probands, offers a unique opportunity to consider this issue. It has previously been demonstrated that 17 parents heterozygous for the Ecuadorean mutation of the GH receptor differed little in biochemical measures (GHBP, IGF-I, IGF-II, IGFBP-2 and IGFBP-3) from Ecuadorean controls. Mean height SDS of 24 non-carrier siblings (−1.3 ± 0.95 SD) and 41 heterozygote siblings or offspring of probands (−1.8 ± 1.15) did not differ significantly ( p = 0.08). Thus, although there may be slight heterozygote expression of the defective gene for the GH receptor, there is no rationale for counselling based on such minimal variation.     

Diagnostic significance of urinary growth hormone measurements in children with growth failure: correlation between serum and urine growth hormone

Twelve-h overnight urine and serum samples obtained simultaneously at 20-min intervals were assayed for growth hormone (GH). Ninety-one children, 5 to 16 y (Tanner stage 1 to 3) participated; group 1 were healthy children, group 2 were children with organic GH deficiency, and group 3 had idiopathic growth failure and normal GH stimulation tests. Serum pool GH concentrations in group 1 were similar to those in group 3 (3.3 +/- 0.3 versus 3.4 +/- 0.2 micrograms/L); group 2 had significantly lower GH concentrations (1.6 +/- 0.2 micrograms/L). Plasma IGF-I levels were significantly greater in groups 1 (14.2 +/- 2.6 nmol/L, p less than 0.001) than in groups 2 and 3 (2.6 +/- 0.5 and 5.5 +/- 0.7 nmol/L, respectively). Urinary GH (mean +/- SEM) standardized for body weight (micrograms/kg) in group 1 (0.31 +/- 0.02) was significantly greater than in group 2 (0.14 +/- 0.01) and group 3 (0.20 +/- 0.01). However, when expressed as microgram/mol creatinine, the output of GH was similar in group 1 (4.0 +/- 0.3) and group 3 (3.4 +/- 0.3); both groups had significantly greater output compared to group 2 (1.3 +/- 0.2). Urinary IGF-I (nmol/kg) in group 1 (0.22 +/- 0.02) was significantly greater than in group 2 (0.12 +/- 0.01) or group 3 (0.07 +/- 0.01). Urinary GH correlated with serum pool GH concentration (r = 0.64, p less than 0.001). Although urinary GH output reflects endogenous GH secretion, the overlap between groups 1 and 3 precludes using urinary GH measurements as a diagnostic test for GH deficiency in children with idiopathic growth failure.     

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目的探讨生长激素-胰岛素样生长因子(GH-IGF)轴在先天性心脏病患儿中的变化。方法2004年1~10月在广西医科大学一附院经超声心动图或手术确诊的先天性心脏病患儿50例,应用ELISA方法检测50例患儿及20名健康小儿血中生长激素结合蛋白(GHBP),应用免疫放射分析检测血中胰岛素样生长因子-1(IGF-1)及胰岛素样生长因子结合蛋白-3(IGFBP-3)。结果先天性心脏病患儿血清IGF-1、IGFBP-3质量浓度下降,有紫绀及心衰者下降更为显著;GHBP浓度在有紫绀及心功能不全的患儿中下降。结论先天性心脏病患儿GH-IGF轴发生紊乱,存在生长激素抵抗或不敏感。GHR下调可能是生长激素抵抗或不敏感的分子机制之一。     

Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity

Burren CP, Wanek D, Mohan S, Cohen P, Guevara-Aguirre J, Rosenfeld RG. Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity. Acta Pædiatr 1999; Suppl 428: 185–91. Stockholm. ISSN 0803–5326
Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 ug/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly ( p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs. □ Growth hormone, growth hormone insensitivity, insulin-like growth factor I, insulin-like growth factor binding protein     

Relationship of insulin-like growth factor-I, insulin-like growth factor binding protein-3, insulin, growth hormone in cord blood and maternal factors with birth height and birthweight

BACKGROUND: To determine whether the following factors are related to birthweight or birth height, we measured insulin-like growth factor (IGF)-I, insulin-like growth factor binding protein (IGFBP)-3, insulin and growth hormone (GH) levels in cord blood and also observed the relationship between birthweight, birth height and maternal factors. METHODS: One hundred and ninety-four cord bloods were collected, 106 from males and 88 from females. Three newborns were small for gestational age (SGA), 168 were appropriate (AGA) and 23 were large (LGA); 21 newborns were preterm and 172 were term. RESULTS: Levels of IGF-I and IGFBP-3, measured by enzyme-linked immunosorbent assay, were significantly lower in preterm babies (35.3 +/- 15.1 and 1025.6 +/- 562.8 ng/mL, respectively) than in term babies (61.6 +/- 39.5 and 1252.6 +/- 403.2 ng/mL, respectively; P < 0.01), but neither insulin nor GH levels, measured by radioimmunoassay, showed any significant difference between the two groups (P > 0.05). Among term babies, IGF-I and IGFBP-3 levels were significantly higher in the LGA group (96.1 +/- 34.1 and 1544.7 +/- 418.1 ng/mL, respectively) than in the AGA group (56.4 +/- 37.6 and 1212.8 +/- 383.4 ng/mL, respectively; P < 0.01). Levels of IGF-I and IGFBP-3 showed significant correlation with birthweight and length, respectively (P < 0.01), although GH and insulin levels did not (P > 0.05). There was a significant correlation between IGF-I and IGFBP-3 levels (P < 0.01, r = 0.64), but IGF-I and IGFBP-3 levels showed no relationship with GH or insulin levels. Birthweight correlated significantly with prepartum maternal weight, maternal weight gain and maternal height (P < 0.05), but birth length correlated significantly only with maternal height (P < 0.05). CONCLUSIONS: Our results suggest that fetal growth depends on fetal levels of IGF-I and IGFBP-3 and maternal factors, not on insulin or GH. Levels of IGF-I and IGFBP-3 may not be regulated by insulin alone, but by the complex interactions between several factors, such as insulin, GH and maternal factors.     

Clinical utility of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 measurements in paediatric practice

Measurements of serum insulin-like growth factor-I (IGF-I) and its major binding protein, IGFBP-3, are utilised in the routine clinical management of short children. In this review, the value of such measurements in the diagnosis of primary and secondary IGF-I deficiency is presented. The achievement of optimal growth while maintaining IGF-I within the normal range is the goal of GH treatment schedules used in a range of growth disorders, and thus data on IGF-I monitoring during initiation and maintenance phases of GH treatment are discussed. Comment is also made on the relationship between levels of IGF-I and IGFBP-3 in the population with regard to risks for cancer and cardiovascular disease.IGF-I and IGFBP-3 are important parameters to measure as one part of the process of managing short children. It is proposed that improving the clinical value of IGF measurement may involve measurement of specific prohormones and E-peptides, to get closer to the pool of GH dependent IGF-I.