Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency

BACKGROUND—Growth hormone insufficiency (GHI) is diagnosed conventionally by short stature and slow growth, and is confirmed by diminished peak GH response to a provocation test. Insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) have previously been considered individuallyOBJECTIVE—To test the hypothesis that the combined analysis of IGF-I and IGFBP-3 could act as a surrogate marker for the diagnosis of GHI.DESIGN—Reference ranges for IGF-I and IGFBP-3 were calculated using 521 normal individuals. A retrospective analysis was performed on 318 children referred for investigation of short stature.RESULTS—No significant difference was found between either the IGF-I or IGFBP-3 standard deviation scores (SDSs) in children with and without GHI. If the requirement were for both tests to be positive (< ?2 SDS) for a diagnosis of GHI, then 99% of children without GHI would be correctly identified; however, the sensitivity of the test was only 15%.CONCLUSIONS—Neither IGF-I nor IGFBP-3 alone is a marker for GHI. In addition, they cannot be used as an effective screening test in combination.     

Associations of IGF-I, IGFBP-1 and IGFBP-3 on intrauterine growth and early catch-up growth.

Fetal cord blood IGF-I, IGFBP-1 and IGFBP- 3 levels of appropriate-for-gestational-age (AGA) and intrauterine growth retardation (IUGR) babies are studied and followed up for 6-9 months, reevaluated for anthropometric measures and the effects of IGF-I, IGFBP-1 and IGFBP-3 on fetal growth and early catch-up growth is investigated. 23 AGA and 21 IUGR babies, totally 44 newborns, were included in the study protocol. IGF-I and IGFBP-3 levels were found to be high in AGAs with respect to IUGR babies and IGFBP-1 is found to be high in IUGR with respect to AGAs. IGF-I was significantly lower in IUGR babies without catch-up growth (group 2b) with respect to AGAs (group 1) and neonates with IUGR and catch-up growth (group 2a) and group 2a infants had higher IGF-I values than group 2b infants (p < 0.05). IGFBP-3 levels in group 1 were significantly higher than in the other two groups (p < 0.05), but not significantly different in group 2a with respect to group 2b (p > 0. 05). IGFBP-1 values showed no statistically significant difference with respect to the three different groups (p > 0.05). A good correlation was found between birth weight, postnatal weight and postnatal height and IGF-I and IGFBP-3 levels (p < 0.05) but not with IGFBP-1 levels. Aside from the height of the 3 groups of infants which were similar to each other after the follow-up period, IGF-I was significantly high in IUGR infants with catch-up growth with respect to IUGR infants without catch-up growth, indicating its importance in early catch-up growth of IUGR babies.     

Reevaluation of growth hormone deficiency during and after growth hormone (GH) treatment: diagnostic value of GH tests and IGF-I and IGFBP-3 measurements

Retesting of patients with growth hormone (GH) deficiency (GHD), especially those with idiopathic GHD, has yielded normalization of the results in several studies. The aim of this study was to reevaluate patients diagnosed as GHD at completion or reconfirm the diagnosis before completion of GH treatment by retesting with provocative tests, and to evaluate the value of IGF-I and IGFBP-3 levels in the diagnosis of GHD. Fifty (33 M, 17 F) patients with GHD (peak GH level <0.46 pmol/l (10 ng/ml]) in two pharmacological tests were retested and IGF-I and IGFBP-3 levels measured. The age of the patients at retest was 15.2+/-5.0 yr. Thirteen of 50 patients (26%) normalized their GH secretion. According to the initial diagnosis, 69% of those with partial GHD (peak GH level 0.32-0.46 pmol/l [7-10 ng/ml]), 43% with isolated GHD, 33% idiopathic and 11% of those with complete GHD (peak GH level <0.32 pmol/l [7 ng/ml]) normalized their GH level at retesting. None of the patients with multiple hormone deficiency and none with small pituitary on MRI normalized GH levels at retest. The sensitivities of IGF-I and of IGFBP-3 were 70% and 67%, respectively, and the specificities were 100%, when peak GH cutoff is taken as 0.46 pmol/l (10 ng/ml) for the diagnosis of GHD. The sensitivities of IGF-I and IGFBP-3 increased to 76.5% and 73.5% when the cutoff level for GHD is taken as 0.32 pmol/l (7 ng/ml). Those patients who normalized their GH levels at retest showed a satisfactory height velocity when GH therapy was discontinued. In conclusion, reevaluation of GH status may also be undertaken while patients are still on treatment as well as at completion of treatment, especially in patients with idiopathic, partial and isolated GHD, by retesting and by IGF-I and IGFBP-3 measurements. Lowering the cutoff level of GH peak at pharmacological tests to 0.32 pmol/l (7 ng/ml) will lower the number of false positive results in the diagnosis of GHD.     

Alterations in serum growth hormone (GH)/GH dependent ternary complex components (IGF-I, IGFBP-3, ALS, IGF-I/IGFBP-3 molar ratio) and the influence of these alterations on growth pattern in female rhythmic gymnasts

BACKGROUND AND AIM: Normal growth in children is regulated to a great extent through the actions of the GH/IGF-I axis, a system consisting of GH and its mediators (ternary complex) that modulate growth in many tissues. The ternary complex (IGF-I/IGFBP-3/ALS) provides an acute regulatory mechanism in which IGF-I may be mobilized from the circulating reservoir of 150 kDa complexes to the tissues. Acute exercise is known to be a stimulus for GH secretion. The beneficial effects of scheduled exercise on body composition are also well established. However, the impact of strenuous exercise on the pubertal development of child athletes is still not well understood. The first goal of this study was to assess the acute effects of high intensity exercise training on GH-dependent ternary complex components in female rhythmic gymnasts compared to age-matched healthy female controls with normal physical activity. The second goal was to explore the influence of these exercise-induced changes on skeletal and pubertal growth in the same group prospectively over a period of 4 years. SUBJECTS AND METHODS: Seventeen female rhythmic gymnasts, aged 11.4 +/- 0.9 years, who had 10 h per week intense exercise for at least 4 months volunteered to participate in this study. Anthropometric measurement of height (Height SDS for chronological age [HtSDS(CA)], parentally adjusted height, predicted adult height), bone age and weight (BMI) were made using standard techniques in gymnasts and controls (aged 12.5 +/- 3.0 years, n = 12). Gymnasts were followed up to 4 years to observe growth velocity and pubertal progression. In order to determine the acute impact of exercise on levels of GH and GH-dependent ternary complex component (IGF-I, IGFBP-3, ALS, IGF-I/IGFBP-3 molar ratio), blood samples were obtained from gymnasts after a routine 2-h high-intensity training program and then after a 2-day rest period. These results were compared with age-matched controls with no scheduled sports activity. RESULTS: Despite the significant increment in serum GH and GH-dependent components immediately following the exercise, serum GH/IGF-I levels showed a significant decrement (p < 0.01) after a 2-day rest in gymnasts, to a nadir as low as those of the control subjects' baseline levels (p < 0.01). There was no difference in anthropometric characteristics of gymnasts and controls except BMI; gymnasts were leaner than controls. During a 4-year follow up, there were no differences between the gymnasts and controls in regard to skeletal growth and reaching their predicted height. However, in gymnasts there was a delay in pubertal tempo but not in growth. CONCLUSION: Intense exercise induces an acute rise in GH levels, but this acute elevation rapidly normalizes after a 2-day rest in female rhythmic gymnasts. These fluctuations in serum GH and GH-dependent ternary complex components had no reflection on the skeletal growth patterns in gymnasts over the 4-year follow up but there was a delay in their pubertal progression.     

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.     

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.     

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.     

The diagnosis of childhood growth hormone insufficiency and growth hormone resistance

Growth hormone insufficiency (GHI) is an uncommon though treatable cause of retarded growth velocity and short stature in childhood, the diagnosis generally requiring the demonstration of a subnormal growth hormone (GH) response to a physiological or pharmacological stimulus. Physiological and pharmacological GH release is a continuous variable and the relationship between spontaneous GH secretion and height velocity is asymptotic. Cut-off points for defining GH insufficiency are largely derived from adult observations, but have been extrapolated to children, for whom normative data are relatively scanty. There is no absolute cut-off that discriminates between normal and abnormal GH response. Moreover, poor reproducibility, sensitivity and specificity of the many dynamic tests available, particularly when performed in the very young child or in early adolescence, together with the confounding effects of assay performance, further weaken the diagnostic efficiency of biochemical investigations. Between 20-40% of children retested at the completion of GH therapy demonstrate a normal GH response to a provocative stimulus. Such limitations mitigate against over-reliance on GH provocation tests in diagnosis, and further emphasize the importance of careful auxology in evaluating the short child.     

The contributions of plasma IGF-I, IGFBP-3 and leptin to growth in extremely premature infants during the first two years

We determined the contributions of IGF-I, IGFBP-3 and leptin to growth in extremely premature infants over the first two years. Weight (Wt), crown-to heel length (CHL), plasma IGF-I, IGFBP-3 and leptin were measured in infants (gestation 24-33 wk) at birth (n = 54), expected date of delivery (EDD) and 6, 12 and 24 mo post-EDD (n = 29). Area under the curve (AUC) for hormone levels was calculated over 4 periods: birth-EDD, EDD-200 d, EDD-350 d and EDD-700 d. IGFBP-3, but not IGF-I or leptin, on day 1 correlated with birth Wt SD scores (SDS) (r = 0.46, p = 0.002) and CHL SDS (r = 0.41, p = 0.01). Wt SDS at EDD correlated with AUC IGF-I, IGFBP-3 and leptin (birth-EDD), but leptin was the best predictor in multiple regression (r = 0.65, p < 0.0001). Wt at EDD + 700 d correlated with AUC leptin (EDD-700 d) (r = 0.62, p = 0.002). CHL SDS at EDD correlated with AUC IGFBP-3 and leptin (birth-EDD), but IGFBP-3 was the best predictor (r = 0.55, p < 0.0001). CHL at EDD + 700 d correlated with AUC IGF-I and IGFBP-3 (EDD-700 d), but IGFBP-3 was the best predictor (r = 0.47, p = 0.01). Wt and CHL at birth were associated with IGFBP-3 levels in these infants. Wt at EDD and EDD + 700 d was predicted by concurrent leptin output while linear growth at EDD and EDD + 700 d was predicted by IGFBP-3 output.     

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.     

Circular IGFBP-3 level affected by the gene transfer of different growth hormone isoforms

To evaluate whether through gene transfer, which growth hormone (GH) isoform can influence the circulation IGFBP-3 level, mice were injected three times with the human cytomegalovirus (CMV) mediated mammalian expression vector encoding different GH isoform gene. Then blood samples were drawn and the ELISA method was used to determine the circulation concentration of IGFBP-3. It was found that the 22 kDa GH gene could increase IGFBP-3 levels to 1.94 microg/ mL whereas 20 kDa GH, 17 kDa GH and 5 kDa GH genes did not play a role in the circulation expression of IGFBP-3.     

Short stature with normal growth hormone and elevated IGF-I

We report on a Japanese girl with short stature, malar hypoplasia, up-slanting palpebral fissures, blue sclerae and thin, stiff and slightly brownish hair. Short stature started in utero and her psychomotor development was normal. Menarche appeared at 13 years 8 months. Height at 14 years 5 months was 132 cm (–4.6 SD). Her growth hormone (GH) sleep pattern and responses to insulin,l-dopa, arginine, propranolol-glucagon and growth hormone-releasing hormone were normal. Plasma insulin-like growth factor I (IGF-I) was high (2170–4860 units/l) and increased from 4860 to 7080 units/l 20 h after biosynthetic GH injection. Gel infiltration patterns of the free and protein-bound IGF-I in plasma from the patient were not different from the controls; IGF-I fraction of the high and low molecular weight binding protein and the non-protein bound fraction were 75.5%, 15.8% and 8.7%, respectively. IGF-I from the patient showed normal bioactivities when determined by [³⁵S]sulphate and [³H]thymidine uptake into cultured rat chondrocytes, and by [³H]thymidine and [³H]-aminoisobutyric acid uptake into the patient's skin fibroblasts. IGF-I binding to cultured skin fibroblasts from the patient was comparable to that of controls. These results suggest that tissue specific defects of IGF-I receptors may be the cause of increased IGF-I levels in the patient.     

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     

Ghrelin, IGF-I and IGFBP-3 levels in children with type 1 diabetes mellitus

There is a strong relationship between ghrelin, insulin, glucose and IGF-I/IGFBP-3 metabolism. This aim of this study was to investigate ghrelin level, and its relationship with IGF-I and IGFBP-3 levels in children with type 1 diabetes mellitus (DM1). Twenty-seven children with DM1 and 25 healthy controls were investigated. Ghrelin levels were similar, and IGF-I and IGFBP-3 levels were lower, in prepubertal and pubertal patients compared to controls. In the patient group, ghrelin levels were negatively correlated with chronological age, height, weight, pubertal status and IGF-I, but had no correlation with fasting glucose, HbA1c, insulin dose, duration of insulin therapy, and IGFBP-3 levels. Similar ghrelin levels in patients compared to controls may suggest that ghrelin levels remain unchanged in children with DM1, or that altered ghrelin levels at diagnosis recover as a consequence of insulin therapy. The lack of correlation of serum ghrelin levels with fasting plasma glucose, HbA1c and insulin dose suggests that ghrelin level is not affected by these parameters. Decreased IGF-I level and its negative correlation with ghrelin are compatible with previous findings.     

Effect of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-3

OBJECTIVE: To examine the effect of carbamezapine and valproate on bone mineral density (BMD), IGF-I and IGFBP-3 levels in children. METHODS: The effects of at least 2 years valproic acid and carbamazepine therapy on BMD were evaluated in a cross-sectional and retrospective study. All children were ambulatory, prepubertal, and had normal activity and nutritionally adequate diets. Ambulatory epileptic patients were divided into two groups. Thirty-three patients (group 1; 17 boys, 16 girls; mean age: 8.8 +/- 2.0 years) were treated with valproic acid and 33 patients were treated with carbamazepine (group 2; 20 boys, 13 girls; mean age: 9.7 +/- 1.6 years). The control group consisted of 22 healthy children (13 boys, 9 girls; mean age: 8.9 +/- 2.3 years), who were age- and sex-matched with the patient groups. Children with metabolic bone disease, growth and neurological impairment, signs of malnutrition, or any chronic disease were excluded from the study. RESULTS: BMD values at lumbar spine in both the carbamazepine (-1.69 +/- 0.85 mean L1-4 BMD z-scores, mean 35.5 +/- 12.8 months treatment, and 19,478.6 +/- 6,301.3 mg/kg cumulative dose) and valproic acid (-1.28 +/- 0.80 mean L1-4 BMD z-scores, mean 33.7 +/- 15.0 months treatment, and 22,852.4 +/- 12,477.4 mg/kg cumulative dose) groups were significantly lower than that of the control group (-0.23 +/- 0.87 mean L1-4 BMD z-score). Serum ALP and PTH levels were significantly higher in the carbamazepine-treated group (65.4 +/- 21.1 pg/ml, 767 +/- 267 U/l, respectively) than those of the valproic acid-treated (39.1 +/- 12.8 pg/ml, 561 +/- 166 U/l, respectively) and control groups (36.3 +/- 4.9 pg/ml, 487 +/- 82 U/l, respectively). Serum 25-hydroxyvitamin D of the carbamazepine-treated group (9.8 +/- 3.2 microg/l) was significantly lower than the other groups (15.1 +/- 3.5, 16.6 +/- 4.7 microg/l, respectively). There were eight and 13 patients with plasma intact PTH above reference values in groups 1 and 2, respectively. Valproic acid and carbamazepine therapy results in a hyperparathyroid state and altered vitamin D metabolism, respectively. CONCLUSION: BMD values at lumbar spine were significantly reduced in both carbamezapine and valproic acid treated groups. Valproic acid and carbamazepine therapy do not change IGF-I and IGFBP-3 levels. Altering the hepatic conversion of vitamin D may be the mechanism of carbamazepine-associated reduction in BMD, but the mechanism of decreased BMD in valproate therapy remains unclear.     

Noonan's syndrome: abnormalities of the growth hormone/IGF-I axis and the response to treatment with human biosynthetic growth hormone

Auxological and endocrine data from 6 children (3 male, 3 female) aged 8.5-12.8 years with Noonan's syndrome and the results of treatment with human biosynthetic growth hormone (hGH) are presented. All the children were short (Ht SDS -3.5 to -2.3) and height velocity SDS ranged between -1.76 and +0.03. The maximum plasma growth hormone (GH) response to standard provocation tests ranged from 17 to 52 mU/l, yet, plasma insulin-like growth factor I (IGF-I) concentrations were low or low normal. Overnight GH secretory profiles were normal in all but 2 children who had disordered pulsatility with high trough concentrations. In 5 children who have completed one year of hGH therapy mean height velocity increased from 4.8 to 7.4 cm/year and the height velocity SDS ranged from +0.2 to +3.75. This improvement was associated with an increase in plasma IGF-I in three subjects. These results suggest that a defect of the GH/IGF-I axis may be present in some children with Noonan's syndrome and hGH therapy may have a role in the management of the short stature in these children.     

Insulin-like growth factor-I (IGF-I) ameliorates and IGF binding protein-1 (IGFBP-1) exacerbates the effects of undernutrition on brain growth during early postnatal life: studies in IGF-I and IGFBP-1 transgenic mice

Insulin-like growth factor-I (IGF-I) plays an important role in the stimulation of postnatal brain growth. In transgenic (Tg) mice, IGF-I overexpression stimulates postnatal brain growth, whereas decreased IGF-I availability caused by ectopic brain expression of IGF binding protein-1 [(IGFBP-1), an inhibitor of IGF-I action] retards postnatal brain growth. Because undernutrition during early postnatal development profoundly retards growth and maturation of the brain in rodents, we sought to determine the influence of IGF-I on undernutrition-induced brain growth retardation. Caloric restriction was imposed on IGF-I Tg mice, IGFBP-1 Tg mice, and their non-Tg littermates by separating half of each litter from their dams during the suckling period, postnatal d 1 to 21. Undernutrition reduced the brain growth of each group of mice, but the growth of undernourished IGF-I Tg mice was comparable to that of well-fed control mice (increased 4.13- and 4.22-fold, respectively) and greater than that of undernourished control mice (increased 3.45-fold), whereas undernourished IGFBP-1 Tg mice exhibited less growth (increased 3.15-fold) than undernourished control mice. When the effects of undernutrition were examined in specific brain regions of each group, the same pattern was observed, and IGF-I was found to be more effective in preserving the growth of the regions with the highest transgene expression (cerebral cortex, hippocampus, and diencephalon). Despite undernutrition, IGF-I transgene expression stimulated overgrowth of these regions as well as that of the posterior medial barrel subfield, a somatosensory area of the cerebral cortex in which IGF-I may be especially important in development. These data indicate that IGF-I can ameliorate the brain growth retardation caused by undernutrition imposed during development, although it is unclear whether IGF-I directly opposes the impact of undernutrition or acts independently of nutritional status. Nonetheless, these findings raise the possibility that the relatively high IGF-I expression during early postnatal life may be responsible for sparing the brain from the full impact of undernutrition during this time in development.