The insulin-like growth factor-I response to growth hormone is increased in prepubertal children with obesity and tall stature

CONTEXT: Children with obesity [body mass index (BMI) > +2 sd score (SDS)] and children with constitutional tall stature [CTS; height > +2 SDS)] have normal-high serum IGF-I levels, associated with a low and broad range of GH secretion, respectively. This suggests increased sensitivity to GH, whereas children with idiopathic short stature (ISS; height < -2 SDS) are believed to have decreased GH sensitivity. OBJECTIVE, DESIGN, AND MAIN OUTCOME MEASURE: To compare the responsiveness to GH in 62 prepubertal children (43 females, 19 males) with obesity, CTS, or ISS and 26 controls (15 females, 11 males; height and BMI -2 to +2 SDS), we used an IGF-I generation test and studied the IGF-I concentration 24 h after a single injection of GH (2 mg/m2). PATIENTS: Twenty patients with obesity, 20 with CTS, 22 with ISS, and 26 controls were studied. The mean age was 8.3 +/- 2.9 yr, with no difference in age or gender between groups. RESULTS: Compared with controls, the mean IGF-I increment was 80% higher in obese children and 36% higher in tall children (P < 0.05 obese or tall vs. control children; P = 0.05 obese vs. tall children). Conversely, the IGF-I increment was similar in short compared with control children, despite a mean baseline IGF-I 62% lower in short children (P < 0.05 vs. controls). In all groups, the IGF-I increment was correlated with the BMI SDS or the fat mass percentage (r = 0.51-0.58, P < 0.05). CONCLUSION: Obese children tend to have greater GH responsiveness than tall children, and both have greater GH responsiveness than controls. GH responsiveness was similar in controls and short children, despite a lower baseline IGF-I in short children. Whether the differences in the IGF-I response to GH between these children reflect differences in the respective anabolic (growth promotion) and metabolic (i.e. insulin action modulation) roles of circulating IGF-I is unknown.     

Serum levels of free insulin-like growth factor (IGF)-I and IGF-binding protein-1 in prepubertal children with idiopathic short stature

The study was performed to evaluate the relationships among serum free and total insulin-like growth factor (IGF)-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and insulin concentrations in prepubertal children with idiopathic short stature (ISS). Eighteen children with ISS and 15 age-matched controls were included in the study. All short children had a height standard deviation score of more than 2 below the mean, and maximum stimulated GH levels greater than 10 microg/l after two standard provocation tests. The serum levels of free IGF-I were significantly lower in short children (1.6 +/- 0.3 microg/l) than in the controls (2.8 +/- 0.6 microg/l, P<0.05), while total IGF-I levels were slightly, but not significantly, lower in short children than in controls. The serum levels of IGFBP-1 were significantly higher in the ISS group (124.6 +/- 5.6 microg/l) than in controls (80.0 +/- 8.7 microg/l, P < 0.0001). The fasting insulin and IGFBP-3 levels were similar in both groups. A stepwise regression analysis for all subjects revealed that IGFBP-1 is the only independent predictor of log free IGF-I (R2 = 0.23, P<0.01). The present study shows that the serum levels of free IGF-1 are significantly lower and insulin-like growth factor-binding protein-1 levels are higher in prepubertal children with idiopathic short stature, as compared with age-matched controls. The high IGFBP-1 may contribute to growth retardation in a subgroup of idiopathic short stature through a decrease in free IGF-1.     

Novel application of IGF-I and IGFBP-3 generation tests in the diagnosis of growth hormone axis disturbances in children with beta-thalassaemia

OBJECTIVE: Children with beta-thalassaemia major (beta-thal) frequently have growth retardation in the presence of low serum IGF-I and a normal GH response to pharmacological stimulation suggesting that they have GH insensitivity (GHIS). This study was carried out to study the cause of their growth retardation. DESIGN: We studied IGF-I and IGFBP-3 generation after exogenous GH administration for four days, in 15 prepubertal controls (C) and 41 prepubertal beta-thal patients divided into three groups according to their growth status: (Group 1) 15 with normal growth (N-thal) (Group 2) 16 with decelerated growth (D-thal) and (Group 3) 10 with short stature (S-thal), in order to determine whether GHIS is the cause of their growth retardation. MEASUREMENTS: IGF-I and IGFBP-3 were measured daily, before and for 4 days after daily administration of 0.1 IU/kg hGH, in 3 groups of prepubertal beta-thal patients and normal controls. RESULTS: N-thal and C had similar basal serum IGF-I (142 +/- 52 and 196 +/- 56 ng/ml, respectively) and IGFBP-3 concentrations (2.07 +/- 0.49 and 2.66 +/- 0.41 mg/l, respectively) as well as a similar percent increase of IGF-I (101 +/- 23% and 104 +/- 37%, respectively) and IGFBP-3 (52 +/- 36%, and 38 +/- 14%, respectively) during the generation tests. S-thal and D-thal had significantly lower basal IGF-I and IGFBP-3 concentrations (85 +/- 42 and 101 +/- 36 ng/ml; and 1.60 +/- 0.49 and 1.79 +/- 0.52 mg/l, respectively) as compared to N-thal and C (P < 0.001 and P < 0.005, respectively), and a significantly higher percent increase of IGF-I and IGFBP-3 during the generation tests (249 +/- 43 and 161 +/- 76%; and 121 +/- 99 and 73 +/- 35%, respectively) as compared to N-thal and C (P < 0.0001 and P < 0.01, respectively). Twenty-five percent of the growth retarded patients had classic GH deficiency (GHD) and percent increases of IGF-I and IGFBP-3 in the generation tests (164 +/- 86% and 80 +/- 49%, respectively) which were similar to those of the remaining growth-retarded children. CONCLUSION: The greater percent increases of IGF-I and IGFBP-3 in the generation tests of the growth retarded beta-thal patients, both with and without GHD, strongly suggest impaired GH secretion rather than GHIS as the cause of their growth retardation. We conclude that the IGF-I and IGFBP-3 generation tests are useful tools for the study not only of GHIS but also of GH secretory disorders in patients with beta-thal and short stature that can easily be performed in an outpatient setting as an initial test to identify the patients that may benefit from GH therapy.     

Standard and low-dose IGF-I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature

OBJECTIVE: Abnormalities in the GH-IGF-I axis, consistent with GH insensitivity (GHI), have been reported in some patients with idiopathic short stature (ISS). The standard IGF-I generation test (IGFGT) has not demonstrated mild GHI in subjects with ISS. The aim of this study was to investigate the GH-IGF-I axis in ISS by performing standard and novel low-dose IGFGTs together with determination of spontaneous GH secretion. PATIENTS AND METHODS: Twenty-one (17 male) prepubertal children with ISS, mean age 8.3 years (4.5-12.2), mean height -3.48 SD (-5.40 to -1.79), mean peak GH to provocation with glucagon/clonidine 32.3 mU/l (14.1-66.0) were studied. Serum IGF-I and IGFBP-3 levels were measured during standard (GH 0.033 mg/kg/day x 4) and low (GH 0.011 mg/kg/day x 4) dose IGFGTs at 0, 12, 36 and 84 h. The low-dose IGFGT was performed in seven naive GH-deficient patients (4 male), mean age 8.5 years (range 4.1-11.1). Determination of spontaneous 24-h GH secretion was performed in the 21 ISS patients. RESULTS: Basal IGF-I and IGFBP-3 standard deviation scores (SDS) in ISS patients were -1.39 (-2.4-1.16) and -0.45 (-1.13-0.38), respectively, IGF-I being lower than IGFBP-3 (P < 0.0001). IGF-I increased in the standard IGFGT at 12 h (P < 0.005), 36 h (P < 0.001) and 84 h (P < 0.001); maximal increment 1.54 (-0.32-3.48), and in the low-dose test at 12 h (P < 0.005), 36 h (P < 0.001) and 84 h (P < 0.005); maximal increment 0.53 (0.08 to -1.23). IGFBP-3 SDS increased in the standard IGFGT at 36 h (P < 0.01) and 84 h (P < 0.001); maximal increment 0.72 (-0.44-1.96), and in the low-dose test at 84 h (P < 0.005); maximal increment 0.33 (-0.08-0.87). Five/19 patients with an IGF-I response > 2 x coefficient of variation (CV) of assay in the standard test failed to respond in the low-dose test, suggestive of mild GHI. In GH-deficient patients, IGF-I increased at each time point (P < 0.05) and IGFBP-3 at 36 h (P < 0.05). Mean GH secretion, expressed in SDS, compared with 66 normal stature controls was: basal GH -0.48 (-0.84-0.93), height of GH peaks compared with zero -0.36 (-1.26-1.51) (both P < 0.05), total GH secretion -0.76 (-1.22-0.42), total GH secretion above baseline -0.67 (-1.21-0.94) (both P < 0.01). CONCLUSIONS: In children with ISS, basal IGF-I and IGFBP-3 SDS values were below the mean, IGF-I showing a greater response in both IGFGTs. In the standard IGFGT, the IGF-I increase at 36 h was equal to that at 84 h. The low-dose IGFGT, in combination with the standard test, may identify patients with mild GHI.     

Measurement of insulin-like growth factor I (IGF-I) responsiveness of fibroblasts of children with short stature: identification of a patient with IGF-I resistance

Somatomedins are important mediators of GH action on skeletal tissues. A possible cause of growth failure, therefore, is impaired somatomedin (Sm) responsiveness of the target tissues. To investigate Sm responsiveness, we studied fibroblasts from 11 normal-statured individuals and 9 patients with short stature. Five of the short patients had normal serum GH and normal or increased Sm levels and, therefore, are considered possibly to be Sm resistant. The other short patients include 2 with Laron-type dwarfism and 2 with GH resistance of undefined type. As a measure of Sm responsiveness, we determined the ability of insulin-like growth factor I (IGF-I; Sm-C) to stimulate uptake of [3H]alpha-aminoisobutyric acid by fibroblasts. The mean ED50 of the 11 normal fibroblast cell lines was 3.2 +/- 0.9 (+/- SD) ng/ml. Fibroblasts from 8 of the 9 short-statured patients had ED50 values within the normal range. This included 2 fibroblast lines isolated from children with Laron-type dwarfism. Fibroblasts from 1 patient, however, were significantly less sensitive to IGF-I in 9 separate assays, with an ED50 of 10.7 +/- 1.8 ng/ml. Fibroblasts from the mother of the patient had an ED50 of 5.0 +/- 1.4 ng/ml, and fibroblasts from the father had an ED50 of 4.3 +/- 0.7 ng/ml, both above the normal mean. Measurements of [125I]IGF-I binding by suspended fibroblasts from this patient and her parents failed to demonstrate significant abnormalities in either the number of binding sites or the affinity of binding. We conclude that the ability of IGF-I to stimulate [3H]alpha-aminoisobutyric acid uptake by human fibroblasts provides a useful method of identifying short children with Sm resistance. Of five patients with clinical evidence of possible Sm resistance, fibroblasts from one consistently were hyporesponsive to IGF-I. Cells from two patients with Laron-type dwarfism were normally responsive to IGF-I.     

Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 response to growth hormone is impaired in HIV-infected children

To better characterize the somatotropic axis in HIV-infected children the circadian rhythm of growth hormone (GH), and basal and stimulated (by an insulin-like growth factor I [IGF-I] generation test) plasma levels of IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3), were evaluated in 16 children (9 boys and 7 girls; age range, 7-11 years) with HIV infection. All patients were free from active opportunistic infection or liver disease at the time of the study. Sixteen age- and sex-matched healthy children (10 boys and 6 girls; age range, 7-11 years) served as control subjects. GH rhythmometric data were analyzed by single and population mean cosinor analysis. As regards the IGF-I generation test, biosynthetic human GH (hGH, 0.1 IU/kg, 0.033 mg/kg) was administered subcutaneously for 4 days and blood samples were taken from fasting subjects at baseline and on the morning after the last GH injection for measurement of IGF-I and IGFBP-3. Plasma GH levels fell within normal limits in the HIV-seropositive patients and were similar to those of healthy children (1.31 +/- 1.18 vs. 1.57 +/- 1.16 microg/liter, respectively; mean +/- SD). The population mean cosinor analysis shows that the GH circadian rhythm reached statistical significance both in the HIV-seropositive children and in the control group. Despite this, the IGF-I and IGFBP-3 levels were significantly lower in HIV-infected children than in the control group (75.6 +/- 57.2 vs. 233.3 +/- 52.5 ng/ml, p < 0.001 and 2.09 +/- 0.17 vs. 3.89 +/- 0.24 mg/liter, p < 0.01, respectively; mean +/- SD); moreover, the response of IGF-I and IGFBP-3 to the IGF-I generation test was significantly lower in HIV-infected children than in the control group (86.3 +/- 55.8 vs. 257.5 +/- 53.4 ng/ml, p < 0.001 and 3.14 +/- 0.43 mg/liter, p < 0.01, respectively; mean +/- SD). It appears that circadian GH secretion is normal in children with HIV infection, but the response to exogenous GH with regard to IGF-I and IGFBP-3 production is impaired, indicating a degree of GH insensitivity in such children.     

Growth hormone (GH) secretion in children with Noonan syndrome: frequently abnormal without consequences for growth or response to GH treatment

The role of GH insufficiency in the pathogenesis of short stature in Noonan syndrome is unclear. Cross-sectional study. Seventeen patients with Noonan syndrome (13 boys, 4 girls; aged 4.8-13.3 (mean 9.2) years) and short stature before start of GH treatment. Spontaneous 12-h overnight GH secretion by continuous sampling analysed using Pulsar, plasma IGF-I and IGFBP-3 levels, and 24-h urinary GH excretion were measured at start of GH treatment. A glucagon stimulation test was performed. Height and height velocity were monitored before and after 1 year of GH treatment. IGF-I and IGFBP-3 were remeasured after 1 year of GH treatment. Nine of the 17 children had a mean overnight GH concentration below the lower limit of the normal range. In six of the 17 patients, overnight GH profiles showed high trough GH concentrations. Glucagon stimulation tests were normal in 16 of the 17 patients. Mean IGF-I level was below normal (-0.4 SD). None of the parameters regarding GH secretion obtained from the overnight profile or provocative test was related to height or height velocity, nor to first year response to GH treatment. IGF-I and IGFBP-3 did not correlate with any of the GH secretion data. IGF-I and IGFBP-3 were related to height and height velocity at the start of GH treatment (r = 0.53 (P < 0.01) and r = 0.61 (P < 0.03) respectively). Rises in IGF-I and IGFBP-3 under GH treatment were related to the increment in height velocity (r = 0.70 (P < 0.01) and r = 0.71 (P < 0.02) respectively). Abnormalities in GH secretion are frequent in patients with Noonan syndrome and short stature. These abnormalities were not related to auxology at start of or response to GH treatment. Clinically GH insufficiency is not important in Noonan syndrome and monitoring spontaneous GH secretion is not necessary before the start of GH treatment.     

Effects of the IGF-I/IGFBP-3 complex on GH and ghrelin nocturnal concentrations in low birth weight children

OBJECTIVE: There is limited information regarding the effects of IGF-I and/or IGFBP-3 on circulating ghrelin concentrations. To determine the effects of IGF-I on GH and ghrelin concentrations, we examined the GH and ghrelin nocturnal profiles before and after the administration of the IGF-I/-IGFBP-3 complex (Iplex) to low birth weight children. DESIGN: The children were studied on two separate occasions, the first under basal conditions, and the second time after the sc administration of 1 mg/kg of Iplex at 2100 h. Blood samples for determination of GH and ghrelin were obtained every 20 min between 2300 h and 0700 h, while the children were sleeping. In each patient, we calculated the mean GH and ghrelin area under the curve (GH AUC and GHR AUC), both under basal conditions and after the administration of the IGF-I/IGFBP-3 complex. SETTING: The study was performed at a University Research Centre located at a General Hospital in Santiago, Chile. PATIENTS: Twenty prepubertal children (11 boys and 9 girls), born after a full-term pregnancy with a birth weight below 2.8 kg were studied at a mean +/- SEM age of 7.3 +/- 0.5 years (range 4-11 years). Their mean height was -1.8 +/- 0.3 standard deviation score (SDS) and their mean BMI was 0.1 +/- 0.2 SDS at the time of the study. MAIN OUTCOME AND RESULTS: Mean nocturnal GH AUC exhibited a significant decrease (2903 +/- 185 vs 1860 +/- 122 ng/ml min, P < 0.01), whereas mean GHR AUC showed a significant increase after administration of the IGF-I/IGFBP-3 complex (68 +/- 16 vs 288 +/- 36 ng/ml min, P < 0.01). CONCLUSIONS: These findings indicate that the IGF-I/IGFBP-3 complex appears to have opposite effects on circulating GH and ghrelin concentrations in low birth weight children, suggesting that, in addition to its known negative feed-back effect on GH, IGF-I and/or IGFBP-3 may have a positive feed-back effect on ghrelin.     

Growth hormone (GH) provocative testing frequently does not reflect endogenous GH secretion

GH secretion was studied in 73 children with classical GH deficiency or GH neurosecretory dysfunction (GHND), intrinsic short stature, or normal stature. The GH-deficient group was defined by a peak GH secretory response below 10 ng/ml to all provocative tests (arginine, L-dopa, insulin hypoglycemia, and clonidine). GHND was defined by a mean serum 24-h GH concentration below 3 ng/ml, with a normal response (greater than or equal to 10 ng/ml) to provocative testing. Twenty-one GH-deficient children, 21 children with GHND, and 18 short control children underwent provocative GH testing and a 24-h study with GH sampling every 20 min. A group of 13 normal stature control children also underwent 24-h GH sampling. The mean stimulated peak serum GH level [4.7 +/- 0.6 (+/- SEM) ng/ml] in the GH-deficient group was significantly below that in the GHND (19.5 +/- 1.7 ng/ml) and short control groups (24.0 +/- 3.5 ng/ml; P less than 0.01). The mean 24-h serum GH concentration was reduced in GH-deficient (1.5 +/- 0.2 ng/ml) and GHND (2.0 +/- 0.1 ng/ml) children compared to those in short (5.6 +/- 0.5 ng/ml) and normal stature (5.8 +/- 0.8 ng/ml) control children (P less than 0.01). Peak GH concentrations after provocative testing correlated poorly with 24-h mean concentrations in GH-deficient, GHND, and short control children (r = 0.38, 0.23, and 0.41, respectively; P = NS for all groups). Mean serum GH concentrations from blood sampling intervals of 12 h (day/night; 0800-2000/2000-0800 h, respectively) or even 6 h (day; 0900-1500 h) were statistically different in GHND or GH-deficient groups compared to those in control children; however, there was significantly more overlap for individual children using the 6- and 12-h daytime intervals than for the 24-h data. Plasma somatomedin-C/insulin-like growth factor I correlated with mean 24-h GH concentration endogenous secretion (r = 0.7; P less than 0.001). These data suggest that provocative GH testing frequently does not correlate with endogenous GH secretion.     

Do growth hormone (GH) serial sampling,insulin‐like growth factor‐I (IGF‐I) or auxological measurements have an advantage over GH stimulation testing in predicting the linear growth response to GH therapy?

OBJECTIVE: To compare the relative utility of GH secretion via pharmacological stimulation, overnight serial sampling, IGF-I levels and auxological variables as predictors of change in height standard deviation score (deltaHt SDS) during GH treatment. DESIGN: A multicentre observational study. PATIENTS: Prepubertal children (n = 825) with idiopathic growth failure who were subsequently treated with GH were divided into two groups, based on their maximum GH response to pharmacological stimulation testing: (1) idiopathic GH deficiency (IGHD), defined by a maximum GH response < 10 microg/l (n = 300); and (2) idiopathic short stature (ISS), with a maximum GH response > or = 10 microg/l (n = 525) (GH conversion factor: 3 IU = 1 mg). MEASUREMENTS: Overnight spontaneous GH secretion was measured in all patients. The following characteristics of spontaneous GH secretion were studied: maximum or peak GH, mean peak GH, number of GH peaks, pooled GH, mean GH, and approximate entropy of GH secretion. RESULTS: Although children with IGHD had lower indices of spontaneous GH secretion, there were no differences between IGHD and ISS groups in baseline Ht SDS, growth rate or IGF-I level. The dose and duration of GH therapy were similar. There was no statistically significant difference in the mean (+/- SD) change in Ht SDS (deltaHt SDS) in the two groups (IGHD 1.3 +/- 0.9 and ISS 1.2 +/- 0.8). Measures of spontaneous secretion, such as peak GH, mean of GH peaks, mean area under GH peaks, and mean GH, as well as IGF-I concentrations, were all statistically significantly correlated with deltaHt SDS in IGHD children (P < 0.0001). A significant correlation was also observed for pooled GH (P = 0.002) and approximate entropy (P = 0.01). Children with the most severe ISS (Ht SDS < -3.33) demonstrated a more disorganized pattern of GH secretion compared to children who were not as short (Ht SDS -2.33 to -1.64), as indicated by a higher approximate entropy (0.673 +/- 0.193 vs. 0.607 +/- 0.161, P < 0.004). This increased disorder in GH secretion was accompanied by lower IGF-I levels (104 +/- 99 microg/l vs. 137 +/- 74 microg/l, P < 0.001), even though pooled GH concentrations were indistinguishable between the two groups (2.2 +/- 1.3 microg/l vs. 2.0 +/- 1.0 microg/l). Children with IGHD demonstrated lower approximate entropy than did those with ISS (0.551 +/- 0.235 vs. 0.631 +/- 0.182, P < 0.0001). Duration of GH treatment, height deficit and genetic potential (midparental Ht SDS) were the most important variables influencing deltaHt SDS in children receiving GH therapy. Maximum stimulated GH, IGF-I and indices of spontaneous GH secretion also correlated with deltaHt SDS, but their relative importance varied among diagnostic groups. CONCLUSIONS: Patients with GH deficiency demonstrate a reduced capacity for GH secretion, while those with idiopathic short stature exhibit a more disorderly and less functional secretory pattern. Although effective in predicting a response to GH treatment in patients with severe GH deficiency, overnight serial sampling is less practical than other methods currently available. In addition, serial sampling was less useful as a predictor of growth response to exogenous GH in patients with idiopathic short stature.     

Suppression of the growth hormone (GH) response to clonidine and GH-releasing hormone by exogenous GH

GH release in response to clonidine and human GH-releasing hormone-(1-44) (hGHRH-44) was assessed in 11 boys (aged 7-14 yr) with short stature, who had normal GH secretion. The response to these 2 provocative stimuli was repeated after, respectively, 2 and 3 days of treatment with human GH (0.1 U/kg, im). Exogenous GH significantly blunted the response to both clonidine [the mean 2-h integrated serum GH concentration falling from 1050 +/- 350 (+/- SEM) to 749 +/- 297 ng/ml X min; P = 0.03] and hGHRH-44, the 2-h integrated GH concentration falling from 1553 +/- 358 to 547 +/- 202 ng/ml X min; (P = 0.03). Plasma insulin-like growth factor (IGF-II) concentrations did not change after GH administration. In contrast, plasma IGF-I (somatomedin-C) concentrations increased from 97 +/- 16 ng/ml before administration of GH to 142 +/- 32 ng/ml (P = 0.05) after two days and 149 +/- 23 ng/ml (P less than 0.01) after the third treatment day. However, no correlation was found between the changes in response to clonidine or hGHRH-44 and changes in circulating levels of IGF-I. Our data confirm the existence of GH-dependent feedback inhibition of GH release during childhood and suggest that this inhibition operates, at least in part, at the level of the pituitary. While participation of the IGFs/somatomedins in this feedback loop cannot be excluded, the inhibitory effects of exogenous GH do not depend directly on circulating plasma IGF-I or IGF-II levels.     

IGF-I, IGFBP-3 and ALS generation test in Turner syndrome.

OBJECTIVES: The pathophysiology of the short stature in girls with Turner syndrome (TS) is not well understood. The "IGF-I generation test" is used to assess the sensitivity to growth hormone. We compared the biochemical response to four days of growth hormone of TS and controls. STUDY DESIGN: Pre-pubertal TS were recruited to participate in the study. Their siblings served as controls. IGF-I, IGFBP-3 and ALS were measured before and 5 days after using hGH (0.05mg/kg/day). Student-t test was used to compare the differences in their responses. RESULTS: Eleven TS (mean age of 8.5+/-2.4) and 11 siblings (6 females and 5 males) (mean age of 7.0+/-2.0) participated in the study. The basal serum levels of IGF-I, IGFBP-3 and ALS were normal and not different between groups (p=0.62 for IGF-I, p=0.91 for IGFBP-3 and p=0.51 for ALS). The IGF-I generation test was positive in all controls and in 10/11 TS. The IGFBP-3 generation test was positive in 6/11 controls and 4/11 TS. After hGH the mean IGFBP-3 was lower in TS than in controls (p=0.08). The ALS response to hGH was not uniform between groups. CONCLUSIONS: The IGF-I and ALS generation test results were not different between controls and TS. The IGFBP-3 results were higher in the control group but more than 50% of tested children did not pass. The IGF-I/IGFBP-3 generation tests, as presently done, did not help in the understanding of the short stature in TS. The use of different GH dosages and number of doses need to be investigated.     

Growth hormone bioactivity and immunoactivity in tall children.

In subjects with constitutional tall stature, both low and high GH response to stimulation tests have been observed when measured by commercial kits. To investigate the reason for these conflicting results, we evaluated growth hormone (GH) secretion using different assays as well as GH-binding protein and insulin-like growth factor-I (IGF-I) concentrations in tall children. Serum samples were collected from 22 prepubertal constitutionally tall children, aged 2.87-13.25 years, during two pharmacological tests to evaluate serum GH levels measured by both immunofluorometric assay (IFMA) and the Nb2 cell bioassay. Serum IGF-I values were evaluated by RIA. Circulating low affinity (LA) and high affinity (HA) GH-binding proteins (GHBPs) were evaluated by FPLC gel filtration. Considering the highest serum GH levels as measured by IFMA, the 22 tall subjects were divided into two groups: group A including 16 children with blunted serum GH peak levels (5.78+/-0.68 ng/ml) and group B including 6 subjects with normal serum GH peak values (15.73+/-1.56 ng/ml). No differences were observed in serum GH peak levels as measured by the Nb2 cell bioassay between group A (14.77+/-1.54 ng/ml) and group B (16.03+/-1.96 ng/ml), and between both groups and 11 age-and sex-matched controls (12.25+/-1.19 ng/ml). In group A, the Nb2 cell bioassay/IFMA ratio of serum GH peak levels (0.29+/-0.08) was significantly higher (p<0.05) than in group B (0.07+/-0.01). No differences were found in serum LA-GHBP and HA-GHBP as well as in IGF-I concentrations between the 16 patients of group A and the 6 of group B. Likewise, no difference in auxological parameters was found between the two groups. The biological activity of GH evaluated using the Nb2 cell bioassay is similar in tall children with a low GH response as measured by IFMA in comparison with those with a normal GH response, and is in agreement with both the auxological data and serum IGF-I concentrations.     

重组人生长激素治疗不同生长激素分泌状态青春前期矮小患儿追赶性生长模式分析

目的 比较不同生长激素(GH)分泌状态矮小患儿重组人生长激素(rhGH)治疗后的初始追赶性生长模式,初步探讨其机制.方法 回顾性分析62例青春前期不同GH分泌状态矮小患儿对rhGH治疗1年半的追赶性生长模式并定期监测体格指标、促生长素轴的血清指标和骨龄.结果 各组在初始追赶性生长的幅度相似,特发性矮小(ISS)组比完全性生长激素缺乏症(GHD)组更早出现生长减速,并与生长激素结合蛋白(GHBP)水平降低和胰岛素样生长因子结合蛋白3的标准差分数(SDS)增值较小显著相关.GH激发峰值(Ghmax)>7μg/L的部分性GHD组与ISS组有类同的生长追赶的模式.结论 GH受体的降调节和受体后效应的降低可能是ISS组较早出现生长减速的机制.以Ghmaxμg/L作为GHD诊断的界值并相应选择rhGH治疗剂量有更充分的依据和临床意义.     

Growth hormone, IGF-I and its binding proteins (IGFBP-1 and -3) in adult uraemic patients undergoing peritoneal dialysis and haemodialysis

OBJECTIVE: The GH/IGF axis is altered in chronic renal failure (CRF). CRF patients usually show normal or high serum concentrations of GH and IGF-I, whereas all IGF binding proteins (IGFBP-1 to -6), except IGFBP-5, considerably increase with declining renal function. The aims of the present study were to quantify serum concentrations of GH, IGF-I, IGFBP-1 and IGFBP-3 in a group of patients with CRF, and determine whether there were differences according to the type of dialysis, that is, peritoneal dialysis (PD) and haemodialysis (HD). DESIGN: A cross-sectional study in the setting of a dialysis unit of a general hospital. PATIENTS AND MEASUREMENTS: We studied 108 dialysis patients treated by PD (n = 54, 32 males and 22 females, mean age 61.0 +/- 1.4 years) or HD (n = 54, 31 males and 23 females, age 62.6 +/- 1.5 years). A group of 42 healthy subjects of similar age, sex and body mass index (BMI) served as the control group. Baseline serum concentrations of GH, insulin, IGF-I, IGFBP-1 and IGFBP-3 were measured in all patients and control subjects. RESULTS: Fasting serum concentrations of IGF-I and its binding proteins (IGFBP-1 and IGFBP-3) were significantly higher in dialysis patients than in subjects with normal renal function. IGF-I (248.9 +/- 23.4 vs. 205.5 +/- 15.5 micro g/l, NS), IGFBP-3 (5.6 +/- 0.4 vs. 5.5 +/- 0.2 mg/l, NS) and IGFBP-1 (36.1 +/- 5.9 vs. 44.1 +/- 6.5 micro g/l, NS) concentrations were similar in both groups of dialysis (PD vs. HD) patients. However, GH (2.3 +/- 0.3 vs. 1.1 +/- 0.1 micro g/l, P < 0.001) and insulin (40.4 +/- 4.5 vs. 30.1 +/- 3.1 micro U/ml, P < 0.05) levels were significantly higher in the PD group than in the HD group. Both groups of dialysis patients showed significantly higher levels of insulin than healthy subjects (14.7 +/- 1.9 micro U/ml, P < 0.0001 and P < 0.01 for PD and HD, respectively). In both groups of dialysis patients, IGF-I correlated inversely with IGFBP-1 (PD group r = -0.46, P = 0.0006; HD group r = -0.57, P = 0.0001) and directly with IGFBP-3 (PD group r = 0.44, P = 0.001; HD group r = 0.73, P = 0.001). No correlation between insulin and IGFBP-1 was found in any of the groups studied. CONCLUSIONS: These findings demonstrate that adult dialysis patients have elevated IGF-I, IGFBP-1 and IGFBP-3 serum concentrations compared with subjects with normal renal function. Only GH and insulin show statistically significant differences in relation to type of dialysis. Finally, the negative correlation between IGF-I and IGFBP-1 and the positive correlation between IGF-I and IGFBP-3 are maintained in both groups of adult dialysis patients.     

Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.     

Serum IGF-I and IGFBP-3 levels for the assessment of disease activity of acromegaly

To assess the disease activity of acromegaly in patients, we measured the changes in serum growth hormone (GH) levels during oral glucose tolerance test and the basal serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP-3) in 29 acromegalic patients and 30 health persons served as normal controls. Based on the clinical and laboratory criteria, acromegaly was in an active state of disease in 18 patients and was inactive in the other 11 patients. Basal serum IGF-I levels were 177+/-116 ng/ml (mean+/-SD), 250+/-135 ng/ml and 810+/-297 ng/ml in the normal subjects, the inactive and active acromegalic patients, respectively. Basal serum IGFBP-3 levels were 1.71+/-1.29 microg/ml, 2.98+/-0.96 microg/ml and 6.82+/-1.31 microg/ml in the normal controls, the inactive and active acromegalic patients, respectively. Serum levels of IGF-I and IGFBP-3 significantly correlated with each other in the normal subjects as well as the patients. Both IGF-I and IGFBP-3 levels were significantly higher in the group of patients with active acromegaly than inactive acromegalic patients and the normal subjects but there was not statistically difference between the normal controls and the inactive acromegalics. While serum IGF-I levels presented considerable overlapping instances among the three groups, the serum IGFBP-3 of inactive patients and the normal controls could rarely reach 4.44 ng/ml, the lowest value of the active acromegalics. The serum IGF-I and IGFBP-3 levels declined with increased age in normal controls, but not in the patients with acromegaly. There was no sex predilection of serum IGF-I and IGFBP-3 found in our study. The results of this study indicated that the serum IGFBP-3 level is an important laboratory parameter for assessing growth hormone function in humans, and might be a more reliable discrimination for the disease activity of acromegaly than the serum IGF-I is.     

Effects of recombinant human insulin-like growth factor (IGF)-I and estrogen administration on IGF-I,IGF binding protein (IGFBP)-2, and IGFBP-3 in anorexia nervosa: a randomized-controlled study

Administration of recombinant human (rh) IGF-I has been shown to have positive effects on bone density in anorexia nervosa, but the effects of rhIGF-I and estrogen on IGF binding protein (IGFBP)-2 and IGFBP-3 in anorexia nervosa are not known. Sixty-five osteopenic women with anorexia nervosa were randomized to rhIGF-I (30 micro g/kg sc twice daily) alone (n = 15), daily ethinyl estradiol (Ovcon 35) with rhIGF-I (n = 15), estradiol and placebo (n = 15), or placebo (n = 14) for 9 months. Subjects were 25.6 +/- 0.8 yr of age, low weight (body mass index 16.6 +/- 0.2 kg/m(2)) and osteopenic (T scores -2.06 +/- 0.09 for spine and -1.76 +/- 0.13 for hip). IGFBP-3 correlated with total hip bone density (r = 0.47, P = 0.0002) and was a significant predictor of hip bone density (P = 0.010) independent of IGF-I and body mass index in a multivariate regression model. During therapy, IGFBP-2 increased by 48 +/- 19 ng/ml in response to rhIGF-I and decreased by -38 +/- 22 ng/ml in response to placebo (P = 0.011). IGFBP-3 decreased (-895 +/- 120 ng/ml) in response to rhIGF-I but showed a minimal change (-53 +/- 99 ng/ml) in response to placebo (P < 0.0001). In contrast, no significant effect of estrogen was seen on IGF-I, IGFBP-2 or IGFBP-3. Among patients receiving rhIGF-I, the change in IGFBP-2 was inversely associated with the change in total hip bone density (R = -0.47, P = 0.013). In conclusion, our data suggest that chronic rhIGF-I administration increases IGF-I and IGFBP-2 and decreases IGFBP-3 in women with anorexia nervosa. IGFBP-2 and IGFBP-3 may be important determinants of bone density in this population.     

The role of IGF binding protein-3 as a parameter of activity in acromegalic patients.

OBJECTIVE: The production of insulin-like growth factor binding protein-3 (IGFBP-3), the main IGF-I binding protein, is regulated by GH, and its serum levels are increased in acromegaly. We investigated its potential value as a parameter of acromegaly activity or remission in comparison with IGF-I, taking GH suppression below 2 microg/l after glucose load as the normal standard. METHODS: Data from 40 acromegalic patients (12 males and 28 females, aged 28 to 79 years) were obtained retrospectively from stored samples. From these, 145 pairs of IGF-I/IGFBP-3 values were collected; in 67 of them, simultaneous measurement of GH after glucose loading allowed their classification as active or inactive acromegaly. Relationships between IGF-I, IGFBP-3 and GH after glucose load were assessed, as well as differences between IGF-I and IGFBP-3 levels in active and inactive acromegaly. RESULTS: Significant positive correlation between IGF-I and IGFBP-3 in 145 samples was observed (r=0.49, P<0. 0001). As for the 67 samples in which activity or remission could be defined in terms of GH after glucose load, 50 were active and 17 inactive. Both IGF-I and IGFBP-3 significantly correlated with minimum GH (r=0.53, P<0.0001 and r=0.41, P<0.001 respectively). For both parameters, significant differences of means between active and inactive cases were observed (623+/-296 vs 300+/-108 ng/ml, P<0.0001 for IGF-I, and 4.1+/-1.3 vs 3.2+/-0.9 microg/ml, P<0.006 for IGFBP-3). Yet, when comparing in individual cases their classification as active or inactive with the finding of normal or increased IGF-I and IGFBP-3, among active cases 16% appeared as normal according to IGF-I, and 50% appeared as normal in terms of IGFBP-3. Among inactive cases, 23.5% appeared as active according to IGF-I, while 17.5% appeared as active in terms of IGFBP-3. CONCLUSION: Even though IGFBP-3 reflects GH secretion, it offers no advantage over IGF-I in the assessment of acromegaly, and it may underestimate disease activity in acromegalic patients.     

Low plasma ghrelin level in gastrectomized patients is accompanied by enhanced sensitivity to the ghrelin-induced growth hormone release

Ghrelin is a brain-gut peptide with potent GH-releasing activities. It has been suggested that the majority of circulating ghrelin originates from the stomach, with a smaller portion from the small intestine. Gastrectomy (GASTRX) significantly reduces circulating ghrelin concentrations. The implication of decreased circulating ghrelin on the somatotropic axis post GASTRX has not been studied. Therefore, we aimed to investigate the somatotropic axis in 10 gastrectomized patients who underwent total GASTRX for various reasons at least 2 yr ago. At baseline circulating total ghrelin, GH, IGF-I, and IGF binding protein (IGFBP)-3 levels were measured. The GH stimulation test consisted of an insulin-induced hypoglycemia, ghrelin in two iv bolus doses (0.1 and 1 microg/kg), and a GHRH test. GH sensitivity was assessed by an IGF-I generation test. All the tests were performed 2 wk apart. At baseline serum ghrelin levels were reduced by 55% in GASTRX patients, compared with the control group (P < 0.05). IGF-I (P < 0.05) and IGFBP-3 (P < 0.01) levels were also significantly lower than in controls. GH response to the insulin-induced hypoglycemia test in both GASTRX and control subjects was of similar magnitude, whereas circulating plasma ghrelin levels in GASTRX patients were not modified during hypoglycemia. Both doses (0.1 and 1.0 microg/kg) of ghrelin stimulated GH release significantly more in GASTRX than control subjects, respectively (peak mean GH +/- se: 18.2 +/- 5.6 vs. 5.4 +/- 1.3 microg/liter, P < 0.03; and 58.7 +/- 7.5 vs. 35.3 +/- 1.9 microg/liter, P < 0.01). There was no difference in GHRH-induced GH response between GASTRX patients and control subjects (P > 0.05). Concomitantly, increased increments in IGF-I and IGFBP-3 to a single bolus of GH were found (P < 0.03). In conclusion, our data suggest that low circulating ghrelin levels, found in GASTRX patients, are accompanied by enhanced ghrelin sensitivity with respect to GH response. This is associated with increased GH responsiveness. GASTRX is a state of acquired chronic hypoghrelinemia that may require replacement with ghrelin, and it is tempting to speculate that this may affect the GH-IGF-IGFBP axis.