Evaluation of insulin-like growth factor (IGF)-I and IGF binding protein-3 generation test in short stature

BACKGROUND: Differentiation between growth hormone deficiency (GHD) and idiopathic short stature (ISS) based on GH tests and basal IGF-I and IGFBP-3 levels may be difficult. The aim of this study was to evaluate the role of pharmacological GH tests, IGF-I and IGFBP-3 generation test and height velocity off-treatment in the evaluation of GHD and ISS. METHODS: Thirty-three (17 M, 16 F) prepubertal short (height SDS < -2) children were divided into two groups: Group 1 (n = 19) with peak GH level <10 tg/l (GHD) and Group 2 (n = 14) GH > or =10 microg/l in two sex steroid primed pharmacological GH tests. Having excluded other diagnoses, Group 2 was regarded as having ISS. The generation test was performed concomitantly (0.1 IU/kg GH s.c. for 4 days) with IGF-I and IGFBP-3 measured on the 4th day in both groups. The patients were followed for a year for height velocity (HV). RESULTS: Group 1 and 2 had comparable height SDS (-2.3 +/- 0.4 and -2.3 +/- 0.3) at comparable ages (7.8 +/- 2.8 and 7.0 +/- 2.7 yr). Although the deltaIGF-I response was low (<2.0 nmol/l 115 ng/ ml]) in seven (37%) children in the GHD group, all GHD patients with low height velocity had adequate (> or =14 nmol/I [400 ng/ml]) deltaIGFBP-3 response. deltaIGFBP-3 in the generation test showed a negative correlation with HV (p = 0.021, r = -0.570) and also with basal IGFBP-3 (p <0.001, r = -0.743) in the GHD group. In the ISS group, deltaIGF-I and deltaIGFBP-3 responses were low in 31% and 7%, respectively, and the correlation between basal IGF-I, IGFBP-3 and HV and between delta values in the generation test were significantly positive, pointing to a difference in the growth response of these children. CONCLUSION: In the GHD group, based on pharmacological tests, an adequate deltaIGFBP-3 response in the generation test predicts poor height velocity at follow up and thus strengthens the diagnosis of true GHD.     

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.     

Linear growth, growth-hormone secretion and IGF-I generation in children with neglected hypothyroidism before and after thyroxine replacement

We studied growth hormone (GH) stimulation and insulin-like growth factor -I (IGF-I) generation tests in 15 children with neglected congenital hypothyroidism (CH) (age = 6.4 +/- 4.2 years) and measured their growth parameters for >1 years after starting thyroxine (T4) replacement. One year after treatment, height SDS (HtSDS) increased from -4.3 +/- 2.5 to -2.7 +/- 2.3. Peak GH response to clonidine increased from 3.2 +/- 1.2 ng ml(-1) to 7.62 +/- 1.38 ng ml(-1) after treatments. Basal and peak IGF-I response to GH increased from (34.66 +/- 17.3 ng ml(-1) and 58.4 +/- 36.99 ng ml(-1), respectively) before treatment to (130.6 +/- 97.8 ng ml(-1) and 193.75 +/- 122.5 ng ml(-1), respectively). HtSDS increments were correlated significantly with basal free T4 concentrations (r = 0.622, P < 0.01). In summary, after long period of hypothyroidism, T4 replacement produced significant, although incomplete, catch-up growth through a partial recovery of GH- IGF-I axis.     

Differential impact of simple childhood obesity on the components of the growth hormone-insulin-like growth factor (IGF)-IGF binding proteins axis

Simple childhood obesity is characterized by normal or even accelerated growth in spite of reduced growth hormone (GH) secretion. There are conflicting reports on the effects of obesity upon components of the GH-insulin-like growth factor-I (IGF-I)-IGF binding proteins (IGFBPs) system. In the present study we aimed to determine GH, IGF-I, IGFBP-3 and IGFBP-2 as well as some of the less explored components of this axis (IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments, and total acid labile subunit [ALS]) in 22 obese and 17 age-matched control children. We also evaluated not only total GH binding protein (GHBP) serum levels but also GHBP bound to GH (complexed) in both groups. Obese and control groups strongly differed in BMI (obese: 4.7 +/- 0.36 vs control: 0.37 +/- 0.25 SDS, p <0.0001). In the obese group, we found lower GH serum levels, but normal serum levels of GH-GHBP complex, IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Obese children presented higher total circulating GHBP (6.0 +/- 0.44 vs 2.9 +/- 0.29 nmol/l, p <0.001) and insulin levels (10.5 +/- 1.5 vs 5.1 +/- 0.8 mU/l, p <0.001), while IGFBP-2 (4.6 +/- 0.5 vs 6.6 +/- 0.7%, p <0.05) and the ratio IGFBP-2/IGF-I (0.032 +/- 0.019 vs 0.095 +/- 0.01, p = 0.013) were lower than in controls. BMI and insulin were directly, and IGFBP-2 serum levels inversely, correlated to total GHBP serum levels when multiple regression analysis was performed (r = 0.74, p <0.001). By stepwise regression analysis, insulin (r = -0.37, p <0.05) and BMI (r = -0.52, p <0.01) inversely determined IGFBP-2. In summary, obese children present normal growth in spite of reduced GH secretion, probably because the combination of increased total GHBP and normal GH-GHBP complex serum levels (suggesting increased GH receptor [GHR] number and a normal serum GH reservoir, respectively) allow for the achievement of normal levels of IGF-I, IGFBP-3, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Reduced IGFBP-2 serum levels and a lower ratio of IGFBP-2/IGF-I in obese children may suggest an increase of tissue IGF-I bioavailability, thus promoting its action. Normal IGF-I and GH availability may be contributing to maintain normal growth in obese children.     

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

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

Growth hormone secretion in patients with constitutional delay of growth and pubertal development

Growth hormone levels were measured every 30 minutes during sleep over 9 hours in 20 prepubertal patients with constitutional delay of growth and puberty (CGD) and in 10 age-matched controls, all of whom had had normal GH responses to an orally administered dose of clonidine. We found no significant difference in the mean 9-hour overnight GH concentration between groups (4.5 +/- 1.8 ng/ml (mean +/- SD) in the CGD group, 4.4 +/- 2.8 ng/ml in the control group). Total GH output (258 +/- 99 U vs 222 +/- 135 U), total number of nocturnal GH pulses (3.6 +/- 0.8 vs 3.3 +/- 1.3), mean peak GH response during nocturnal sampling (13 +/- 1.2 ng/ml vs 13.2 +/- 1.3 ng/ml), and basal somatomedin C concentrations were not different in the children with growth delay and controls. We conclude that prepubertal patients with constitutional delay of growth and puberty secrete GH normally and do not seem to have any abnormality in GH regulation.     

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

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

Spontaneous and provoked growth hormone (GH) secretion and insulin-like growth factor I (IGF-I) concentration in patients with beta thalassaemia and delayed growth

Growth retardation in children with thalassaemia major is multifactorial. We studied the growth hormone (GH) response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP3), and ferritin, and evaluated the spontaneous nocturnal (12 h) GH secretion in prepubertal patients with thalassaemia and age-matched children with constitutional short stature (CSS) (height SDS < -2, but normal GH response to provocation). The anatomy of the hypothalamic pituitary area was studied in patients with abnormal GH secretion using MRI scanning. Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (8.8 +/- 2.3 micrograms/l and 8.2 +/- 3.1 micrograms/l respectively) than did controls (17.6 +/- 2.7 micrograms/l and 15.7 +/- 3.7 micrograms/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP3 (68.5 +/- 19 ng/ml and 1.22 +/- 0.27 mg/l respectively) compared to controls (153 +/- 42 ng/ml and 2.16 +/- 0.37 mg/l respectively). Seven of the thalassaemic children had a GH peak response of < 7 micrograms/l after provocation. Those with a normal GH response after provocation also had significantly lower IGF-I and IGFBP3 concentrations than controls. Analysis of their spontaneous nocturnal GH secretion revealed lower mean (2.9 +/- 1.77 micrograms/l) and integrated (2.53 +/- 1.6 micrograms/l) concentrations compared to controls (4.9 +/- 0.29 micrograms/l and 5.6 +/- 0.52 micrograms/l respectively). Five of them had mean nocturnal GH concentration < 2 micrograms/l and four had maximum nocturnal peak below 10 micrograms/l. These data denoted defective spontaneous GH secretion in some of these patients. MRI studies revealed complete empty sella (n = 2), marked diminution of the pituitary size (n = 4), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 7) in those patients with defective GH secretion (n = 9). Serum ferritin concentration was correlated significantly with the circulating IGF-I (r = -0.47, p < 0.01) and IGFBP3 (r = -0.43, p < 0.01) concentrations. These data prove a high prevalence of defective GH secretion in thalassaemic children associated with structural abnormality of their pituitary gland.     

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.     

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

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

Diagnosis of idiopathic growth hormone deficiency: contributions of data on the acid-labile subunit, insulin-like growth factor (IGF)-I and-II, and IGF binding protein-3

The diagnosis of non-organic growth hormone (GH) deficiency (GHD) remains difficult. OBJECTIVE: To evaluate the value of measuring plasma insulin-like growth factor (IGF)-I and -II, IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS) as criteria for diagnosing GHD. PATIENTS: 120 prepubertal patients having at least one of the main auxological criteria defined by the GH Research Society for initiating GH exploration were classified as (1) certain GHD (n = 40), (2) transient GHD (n = 18), (3) idiopathic short stature (n = 27), or (4) extreme short stature (n = 35). RESULTS: All the patients with certain GHD had low (< or = -2 z-score) plasma concentrations of IGF-I and ALS, but only 35.1% had low IGF-II, and 48.6% had low IGFBP-3. All the patients but three (83.3%) with transient GHD had low IGF-I, but only 44.4% had low ALS, and only one had low IGF-II or IGFBP-3. The data for patients with idiopathic and extreme short stature and normal GH peak were similar to each other and to those for patients with transient GHD, except that IGF-I was less frequently low (49.2%, p <0.05). CONCLUSIONS: All the patients with certain GHD had both IGF-I and ALS z-scores < or = -2, unlike those with transient GHD, and idiopathic or extreme short stature. Almost all the patients with short stature and normal GH peak had normal serum IGF-II and IGFBP-3 concentrations.     

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.     

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 individually OBJECTIVE: 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.     

Effect of growth hormone therapy on bone metabolism of growth hormone deficient children

The effects of human growth hormone (hGH) therapy on biochemical markers of bone metabolism were studied in 17 children (10 boys and 7girls, aged 3.7–13.1 years old) with idiopathic GH deficiency, before and 1 and 6 months after GH therapy (0.5–0.7 IU/kg weekly, SC). Serum levels of calcium, phosphate, alkaline phosphatase, osteocalcin, parathyroid hormone, 1,25 dihydroxyvitamin D, insulin-like growth factor I (IGF-I) and renal phosphate per 100 ml glomerular filtrate (TPO₄/GFR) were assessed. During therapy with hGH, a significant decrease of serum calcium levels and increases of phosphate, osteocalcin, parathyroid hormone 1,25 dihydroxyvitamin D and IGF-I were observed. TPO₄/GFR was also significantly increased. Growth response (increment in HV) was positively related with changes in alkaline phosphatase and IGF-I levels after 6 months of hGH therapy. There was also a significant positive correlation between increment in HV and increment in TPO₄/GFR after 1 month of GH therapy, whereas no correlation between HV and changes in osteocalcin levels was found. Conclusion GH treatment significantly influences mineral metabolism and the measurement of TPO₄/GFR after 1 month of GH therapy may serve as a useful predictor of growth response to hGH therapy in GH-deficient children. Received: 16 August 1996 / Accepted: 5 February 1997     

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.     

Linear growth and zinc supplementation in children with short stature

Physical growth retardation is an early and prominent feature of zinc deficiency, but the effect of zinc supplementation in children is still not completely clear. This study investigated the impact of zinc supplementation on linear growth, growth velocity, IGF-I levels, and skeletal maturation of short children during and after mineral supplementation. The study was designed as a double-blind, randomized, controlled trial of zinc supplementation during a 6-month period, with a subsequent 6-month follow-up. Anthropometric data were collected at 0, 6, and 12 months. Measurements included plasma Zn, IGF-I, height, weight, triceps skinfold thickness, and body mass index. Eighteen healthy pre-pubertal short children (z-score -2.0) 7 to 10 years old with normal GH and IGF-I levels were randomized to two groups, one with zinc supplementation (5 mg/kg/d of ZnSO4) and the other with placebo. In the first 6 months, only height velocity increased significantly, 5.99+/-0.80 cm/yr vs 5.05+/-0.85 cm/yr (p=0.03). After 12 months, height velocity returned to the initial values, 3.92+/-0.59 cm/yr vs 4.19+/-1.08 cm/yr (p=0.29). This study indicates that zinc supplementation increased growth velocity, but these effects did not persist after supplementation was discontinued.     

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.     

Correlation between pituitary growth hormone reserve and degree of growth failure in children with short stature

The correlation between a releasable pituitary growth hormone (GH) pool and degree of growth failure was examined in 30 children with GH deficiency (group I) and 19 children with normal short stature (group II). Based on the responsiveness of GH to GH-releasing hormone (GHRH), group I, with low GH responses (below 7 ng/ml) to both insulin and arginine, was classified into three subgroups; I_a (peak value less than 10 ng/ml, n=19), I_b (10–20 ng/ml, n=5) and I_c (above 20 ng/ml, n=6). Group II, with a GH response above 10 ng/ml to either insulin or arginine, was also divided into II_a (below 20 ng/ml, n=5) and II_b (above 20 ng/ml, n=14). Body length and growth velocity in I_a and I_b were significantly reduced vs I_c; bone age in I_a was retarded vs I_c; plasma somatomedin C (Sm-C) levels in I_a and I_b were decreased vs I_c, who had almost normal levels (0.90±0.55 U/ml). The incidence of other combined pituitary hormone deficiencies and previous perinatal distress was definitely high in I_a and I_b, but zero in I_c. In group II also, body length and growth velocity were significantly decreased in II_a vs II_b (P<0.01). These results indicate that [1] the pituitary reserve of GH estimated by GHRH is a good reflection of the degree of growth failure in GH-deficient children as well as in those of normal short stature, [2] hypothalamic GHRH deficiency tends to have a milder effect on growth retardation than pituitary GH deficiency, and [3] normal short children with a diminished GH reserve may be potential candidates for the GH treatment.Abbreviations ACTH adrenocorticotropin - LH luteinizing hormone - LH-RH luteinizing hormone-releasing hormone - GH growth hormone - GHRH growth hormone-releasing hormone - Sm-C somatomedin C - TRH thyrotropin-releasing hormone - TSH thyrotropin     

Novel growth hormone receptor mutation in a Chinese patient with Laron syndrome

Laron syndrome, growth hormone (GH) insensitivity syndrome, caused by a mutation of the GH receptor (GHR) gene, is extremely rare in the Chinese population. We report a Chinese girl diagnosed with Laron syndrome at age 1.9 years with height -4.9 SDS, basal GH 344 mIU/ml, IGF-I <12 ng/ml, IGFBP-3 <0.2 mg/ml, and undetectable GHBP. A novel mutation of the GHR, not previously described, was identified at the donor splice site of intron 6.     

Oral clonidine: an effective growth hormone provocative test

Twenty normal statured healthy children (8 M; 12 F) aged 9-16 years were subjected to growth hormone (GH) provocative tests. The mean basal GH level was 2.0 +/- 0.42 ng/ml (+/- SEM). The mean peak levels of GH were 11.9 +/- 2.19 ng/ml (+/- SEM) after exercise, 9.82 +/- 2.81 ng/ml (+/- SEM) after insulin and 15.2 +/- 2.54 ng/ml (+/- SEM) after oral clonidine. A significant rise (peak level greater than 7 ng/ml) of serum GH was found in 70, 80 and 85% of children after exercise, insulin and oral clonidine tests, respectively. The observation in the present study indicates that oral clonidine test, a safer, easier and more economical test than insulin hypoglycemia, is equally potent and can be done in out patients.