A prospective study of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in 942 healthy infants: associations with birth weight, gender, growth velocity, and breastfeeding

CONTEXT: Many aspects of hormonal regulation and mechanisms of normal infancy growth are poorly understood. OBJECTIVE: The objective of this study was to establish the determinants of serum growth factor levels in infancy and their association with growth. DESIGN: A prospective, longitudinal, population-based birth cohort between 1997-2001 was studied. PARTICIPANTS: Study participants were 942 healthy appropriate weight for gestational age (AGA) infants (538 boys and 404 girls) and 49 small for gestational age (SGA) children (29 boys and 20 girls). Interventions: Interventions were anthropometrical measurements (0, 3, 18, and 36 months) and serum samples (3 months). MAIN OUTCOME MEASURES: Height, weight, and serum IGF-I and IGF-binding protein-3 (IGFBP-3) were the main outcome measures. RESULTS: IGF-I levels showed no gender difference [boys, 92 ng/ml (confidence interval, 49, 162); girls, 91 ng/ml (47, 149); P = 0.50]. IGFBP-3 levels were significantly higher in females [2174 ng/ml (1295, 3330)] than in males [2103 ng/ml (1266, 3143); P = 0.04]. Infants receiving breast milk had lower IGF-I levels [90 ng/ml (48, 154)] than infants receiving formula [n = 62; 97 ng/ml (58, 165)] or both [n = 123; 94 ng/ml (48, 169); P < 0.001]. IGF-I and IGFBP-3 levels were positively associated with weight gain and height gain from birth to 3 months of age in AGA, but not in SGA, children. SGA children had significantly lower IGF-I [88.0 ng/ml (28, 145); P = 0.05] and IGFBP-3 [1835 ng/ml (1180, 2793); P < 0.001] levels than AGA children. CONCLUSION: We found a significant, but weak, association between IGF-I and IGFBP-3 levels at 3 months and postnatal growth in AGA, but not SGA, children. Factors other than IGF-I must contribute to the regulation of normal postnatal growth, and these may differ between AGA and SGA children. IGFBP-3, but not IGF-I, showed a gender difference, which may reflect an influence of the postnatal activation of the pituitary-gonadal axis on binding protein levels.     

Reduced serum testosterone levels in infant boys conceived by intracytoplasmic sperm injection

CONTEXT: Concern has been raised for the health of the offspring conceived by assisted reproduction technologies. Basal reproductive hormones around 3 months of age reflect the pituitary-testicular axis, which is transiently active at this age. OBJECTIVES: We tested the hypothesis that transmission of impaired testicular function from father to son could be detected at 3 months of age in boys conceived by intracytoplasmic sperm injection (ICSI), which is predominantly used in the management of male infertility. DESIGN: We conducted a longitudinal prospective cohort study, including 125 boys conceived by ICSI, 124 boys conceived by in vitro fertilization (IVF), and 933 naturally conceived (NC) boys. INTERVENTION: Anthropometrical measurements were performed at birth and at 3 months of age; 58, 67, and 64% of ICSI, IVF, and NC boys, respectively, had a blood sample taken at 3 months. MAIN OUTCOME MEASURES: We measured serum levels of LH, FSH, SHBG, inhibin B, testosterone, as well as penile length. RESULTS: Serum testosterone levels were significantly lower in boys conceived by ICSI (2.4 nmol/liter; 0.2-4.9 nmol/liter) (median; 2.5th-97.5th percentiles) compared with NC boys (3.3 nmol/liter; 0.6-7.6 nmol/liter; P < 0.001), and the LH to testosterone ratio was increased (0.8; 0.2-7.9 vs. 0.5; 0.2-2.3, respectively; P = 0.001). Boys conceived by IVF because of female infertility factors had a normal serum testosterone and LH to testosterone ratio compared with controls. Adjusted analyses for confounders did not alter the results. CONCLUSIONS: Our results point toward a subtle impairment of Leydig cell function in boys conceived by ICSI, possibly inherited from their fathers. The clinical significance of our findings is uncertain. However, our findings should raise concern because ICSI is increasingly used to overcome male infertility.     

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.     

Short children with familial short stature show enhancement of somatotroph secretion but normal IGF-I levels

The aim of the present study was to evaluate the GH status in children with familial, idiopathic short stature (FSS). To this goal we evaluated the GH response to GHRH (1 microg/kg iv) + arginine (ARG) (0.5 g/kg iv) test which is one of the most potent and reproducible provocative tests of somatotroph secretion, in 67 children with FSS [50 boys and 17 girls, age 10.8+/-0.4 yr, pubertal stages I-III, height between -3.6 and -1.6 standard deviation score (SDS), target height <10 degrees centile, normality of both spontaneous and stimulated GH secretion as well as of IGF-I levels]. The results in FSS were compared with those in groups of children of normal height (NHC) (42 NHC, 35 boys and 7 girls, age 12.0+/-0.5 yr, pubertal stages I-III, height between -1.3 and 1.4 SDS, height velocity standard deviation score (HVSDS)>25 degrees centile, GH peak >20 microg/l after GHRH+ARG test, mean GH concentration [mGHc]>3 microg/l) and children with organic GH deficiency (GHD) (38 GHD, 29 boys and 9 girls, age 11.2+/-3.7 yr, pubertal stages I-III, height between -5.7 and -1.3 SDS, GH peak <20 microg/l after GHRH +ARG test, mGHc <3 mg/l). Basal IGF-I levels and mGHc were also evaluated in each group over 8 nocturnal hours. IGF-I levels in FSS (209.2+/-15.6 microg/l) were similar to those in NHC (237.2+/-17.2 microg/l) and both were higher (p<0.0001) than those in GHD (72.0+/-4.0 microg/l). The GH response to GHRH +ARG test in FSS (peak: 66.4+/-5.6 microg/l) was very marked and higher (p<0.01) than that in NHC (53.3+/-4.5 microg/l) which, in turn, was higher (p<0.01) than in GHD (8.2+/-0.8 microg/l). Similarly, the mGHc in FSS was higher than in NHC (6.7+/-0.5 microg/l vs 5.1+/-0.7 microg/l, p<0.05) which, in turn, was higher than in GHD (1.5+/-0.2 microg/l, p<0.0001). In conclusion, our present study demonstrates that short children with FSS show enhancement of both basal and stimulated GH secretion but normal IGF-I levels. These findings suggest that increased somatotroph function would be devoted to maintain normal IGF-I levels thus reflecting a slight impairment of peripheral GH sensitivity in FSS.     

小于胎龄儿青春前期线性生长方式与血清胰岛素水平关系的研究

目的 探讨小于胎龄儿(small for gestational age,SGA)出生后生长追赶状态与血清胰岛素水平的关系.方法 青春前期30例有生长追赶SGA(catch-up growth SGA,CUG-SGA组)、37例无生长追赶SGA(NCUG-SGA组)和42例适于胎龄儿(appropriate for gestational age,AGA组),测定空腹血糖、空腹胰岛素(FINS)和血清胰岛素样生长因子I(IGF-I).结果 (1)与NCUG-SGA和AGA组比较,CUG-SGA组FINS和稳态模型评估的胰岛素抵抗指数(HOMA-IR)显著为高(P<0.01或P<0.05),而NCUG-SGA组与AGA组则无显著性差异(P>0.05).CUG-SGA组血清IGF-I水平较NCUG-SGA组显著为高[(212.61±17.81对137.40±14.66)ng/ml,P=0.001],但与AGA组无显著性差异(P=0.095).(2)SGA组HOMA-IR与年龄、身高标准差分值增值(AHtSDS)和体重指数分别正相关;≤6岁SGA组FINS与△HtSDS呈正相关,>6岁组FINS与体重标准差分值增值呈正相关.结论 生后早期胰岛素可能以生长因子角色参与了SGA儿的生长追赶;胰岛素抵抗程度与生长追赶程度相随.

Abstract：

Objective To evaluate the association between two different linear growth patterns with the levels of serum insulin in children bem small for gestational age(SGA).Methods Serum fasting glucose,fasting insulin,and insulin-like growth factor-I(IGF-I)concentrations were determined in 30 catch-up growth(CUG)children bern SGA [CUG-SGA,16 females,14males,(6.62±0.66)year],37 non-catch-up growth(NCUG)children born SGA[NCUG-SGA,15 females,22 males,(5.97±0.56)year],and42 appropriate for gestational age(AGA)children with normal height[AGA,16females,26males,(7.05±0.39)year].Results (1) Basal fasting insulin and homeostasis model assessment for insulin resistance(HOMA-IR)were significantly higher in CUG-SGA group than in NCUG-SGA and AGA group(P<0.01 or P<0.05).But there was no difference in fasting insulin between NCUG-SGA group and AGA group.IGF-I levels in CUG-SGA were significantly higher than in NCUG-SGA group[(212.61±17.81 vs 137.40±14.66)ng/ml,P=0.001],but showed no difference from AGA group(P=0.095).(2)In the SGA group,HOMA-IR showed positive correlation with age,△height SDS,and current body mass index.Fasting insulin showed positive correlation with △height SDS(r=0.500,P=0.002)in≤6 year group as well as with △weight SDS(r=0.496,P=0.030)in>6 year group.Conclusions Insulin as a growth factor may participate in postnatal catch-up growth accompanied with increased insulin resistance in SGA children.     

Effects of exercise training on insulin-like growth factor-I expression in the skeletal muscle of non-cachectic patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with progressive muscle atrophy and reduced local expression of insulin-like growth factor I (IGF-I). DESIGN: The present study was designed to test the hypothesis that the local deficiency of IGF-I in the skeletal muscle of patients with CHF would respond to a 6-months aerobic training intervention. Therefore, 18 patients [mean age 52.4 (SD 4.8) years, left ventricular ejection function (LVEF) 27 (SD 6)%] were prospectively randomized to either 6 months of training or sedentary lifestyle. METHODS: Serum levels of growth hormone (GH) were measured by immunofluorometric assay, IGF-I by competitive solid phase immunoassay. IGF-I expression was assessed in vastus lateralis biopsies by real-time PCR. RESULTS: Exercise training led to a significant increase in peak oxygen uptake by 26% [from 20.3 (SD 3.3) ml/kg per min to 25.5 (SD 5.7) ml/kg per min, P=0.003 versus control]. Local expression of IGF-I increased significantly after exercise training by 81% [from 6.3 (SE 0.8) to 11.4 (SE 1.4) relative units, P=0.007 versus control] while IGF-I receptor expression was reduced by 33% [from 20.0 (SE 2.1) to 13.8 (SE 1.7) relative units, P=0.008 versus control]. Serum growth hormone (GH) rose modestly from 0.12 (SE 0.07) to 0.65 (SE 0.37) ng/ml in the training group (P=0.043 versus baseline), however, this change was not significant compared to the control group (P=0.848). IGF-I serum levels remained virtually unchanged. CONCLUSIONS: Exercise training improves local IGF-I expression without significant changes of systemic parameters of the GH/IGF-I axis. These findings indicate that exercise training has the therapeutic potential to attenuate peripheral skeletal muscle alterations in particular with respect to local IGF-I expression in patients with moderate CHF.     

Effect of overnight constant infusion of human growth hormone (GH)-releasing hormone-(1-44) on 24-hour GH secretion in children with partial GH deficiency

A continuous infusion (0.5 or 1 microgram/kg X h) of GH-releasing factor-(1-44) [GHRH-(1-44)] was administered from 2000-0800 h to 16 children with GH deficiency, defined as a maximum peak plasma GH less than 11 ng/ml in response to 2 provocative tests [first test; mean, 7.4 +/- 2.6 (+/- SD) ng/ml; second test; mean, 8.4 +/- 2.4 ng/ml]. Eight were boys and 8 girls; their average age was 10 yr, 5 months; and growth was retarded in all [mean, -3 +/- 0.6 (+/- SD)]. Polygraphic monitoring was carried out during the night, and blood samples for plasma GH measurements were drawn every 20 min during the night and the following day. A control study had been carried out in the preceding months with the same children. During GHRH infusion, a significant increase in nocturnal GH secretion occurred; the mean maximum peak increased from 17.5 +/- 3.4 (+/- SD) to 38.7 +/- 3.2 ng/ml, the mean area under the curve from 2243 +/- 459 to 5348 +/- 710 ng/ml, the mean integrated concentration from 4.2 +/- 0.8 to 9.9 +/- 1.3 ng/ml X min, and the mean number of peaks above 5 ng/ml from 2.7 +/- 0.3 to 4.7 +/- 0.4. During GHRH infusion, the 16 children had 2 peaks during the first 4 h of sleep and a third peak at the end of the night. Plasma GH levels the day after the infusions were not significantly increased. We conclude that continuous nocturnal GHRH infusion increases pulsatile sleep GH secretion throughout the night in children with partial GH deficiency.     

Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis

To test the hypothesis that the relative insulin resistance of puberty is associated with changes in IGF-I levels, we compared IGF-I, IGF binding protein-3 (IGFBP-3), and IGFBP-1 levels to insulin resistance [M(lbm), milligrams glucose used per kilogram of lean body mass (LBM) per minute] measured during euglycemic, hyperinsulinemic clamp studies in 342 children and adolescents. IGF-I levels rose and fell during the Tanner stages of puberty in a pattern that closely followed the rise and fall of insulin resistance. IGF-I levels were significantly related to M(lbm) in boys (P = 0.0006) and girls (P = 0.02). IGF-I was significantly related to fasting insulin levels only in girls (P = 0.006; boys, P = 0.26), and this relation was significantly influenced in girls by body fat (P = 0.007), with the strongest association between IGF-I and fasting insulin seen in thin girls. IGFBP-1 correlated negatively with insulin resistance in both boys (P = 0.0004) and girls (P = 0.04), whereas IGFBP-3 correlated positively with insulin resistance in boys (P = 0.0004) but not girls (P = 0.85). These data suggest that the GH/IGF-I axis is an important contributor to the insulin resistance of puberty.     

Growth hormone suppression after an oral glucose load in children

BACKGROUND: GH nonsuppression after oral glucose is diagnostic for GH excess, but normative data are lacking in children. Adult data cannot be extrapolated to children given the pubertal increase in GH concentration. In addition, because GH levels are higher in pubertal girls than boys, nadir GH may differ across gender. OBJECTIVE: Our objective was to determine whether nadir GH during an oral glucose tolerance test (OGTT) is gender and pubertal stage specific. We hypothesized that nadir GH would be higher in girls, and at the pubertal stage known to correspond with peak height velocity (Tanner 2-3 in girls and Tanner 3-4 in boys) and maximal GH concentrations. SUBJECTS/ METHODS: A 2-h OGTT using 2.35 g/kg oral glucose (maximum 100 g) was performed in 64 girls and 43 boys, 9-17 yr (10th-90th percentiles for body mass index). Girls were grouped as group 1 (Tanner 1), group 2 (Tanner 2-3), and group 3 (Tanner 4-5), and boys as group 1 (Tanner 1-2), group 2 (Tanner 3-4), and group 3 (Tanner 5). RESULTS: Nadir GH was higher in girls than boys, and in group 2 girls and boys than the other two groups. The upper limit for nadir GH was highest in group 2 girls (1.57 ng/ml), and lower for the other two groups of girls (0.64 ng/ml), and for boys (0.50 ng/ml). All but one girl, and all boys suppressed to less than 1.0 ng/ml. There were 16 girls and five boys who had a nadir GH of more than 0.3 ng/ml. CONCLUSION: GH suppression after oral glucose is gender and pubertal stage specific.     

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.     

Oxandrolone in constitutionally delayed growth, a longitudinal study up to final height

Twenty-seven prepubertal boys and 9 prepubertal girls with constitutionally delayed growth were treated with the anabolic steroid oxandrolone for 12 months and followed until they reached final height. Sixteen boys were treated with a mean dose of 0.12 mg/kg.day [low dose (LD)] and 11 boys with a mean dose of 0.22 mg/kg.day [high dose (HD)]. The girls were treated with a mean dose of 0.1 mg/kg.day. Thirteen boys and 9 girls served as controls. On oxandrolone the mean height velocity increased from 4.0 to 8.6 (boys, LD), from 4.3 to 8.9 (boys, HD), and from 4.3 to 8.3 cm/yr (girls). The immediate posttreatment height velocity was significantly higher than the pretreatment height velocity (P less than 0.05), regardless of whether the patients had entered puberty. On oxandrolone the mean ratios of change in bone age/change in chronological age were 2.0 (boys, LD), 2.3 (boys, HD), and 2.0 yr/yr (girls) and continued to be accelerated during the 6 months after treatment. Height predictions at the onset of treatment and after 6 months off treatment were calculated by three different methods: Bayley-Pinneau (BP), Roche-Wainer-Thissen (RWT), and Tanner Mark II (T II). In the boys (LD) mean height predictions increased significantly by the methods of BP (3.3 cm) and RWT (2.9 cm), but not by the method of T II (0.6 cm). In the boys (HD) no significant change in height predictions was noted. In the girls mean height predictions remained unchanged by BP and RWT, but decreased significantly by T II (-2.5 cm). The difference between final height and initial height prediction was taken as a measure of the influence of the treatment on adult height. In all three treatment groups the difference between final height and initial height prediction, calculated with all three methods, did not differ from the control group. We conclude that oxandrolone treatment for 1 yr has no effect on adult height. In spite of this, the use of an anabolic steroid such as oxandrolone may still have value, as an increase in height velocity and an earlier onset of puberty may benefit short children suffering from psychological problems due to delay of growth and development.     

Growth enhancement by dopaminergic therapy in children with intrauterine growth retardation

In a previous study we reported stimulation of growth velocity in hypopituitary children by dopaminergic therapy (DA), i.e. either L-dopa or bromocriptine. The purpose of the present study was to determine if DA stimulated endogenous GH release and growth in children with intrauterine growth retardation (IUGR), who also had microcephaly and psychomotor retardation. The effect of DA on serum LH, FSH, gonadal steroids, cortisol, T4, and TSH also was examined. Six prepubertal children [four girls and two boys; bone age (BA), 1.5-4 yr] with IUGR were divided into two study groups. Group I (n = 3) received L-dopa (15 mg/kg) orally every 6 h for 6 months. Group II (n = 3) received bromocriptine (1.25 mg) orally every 12 h for 6 months. At the end of the 6 months of DA therapy, both groups received human GH (hGH) (0.1 IU/kg) im thrice weekly for 6 months. The growth rate in group I was 6.5 +/- 0.1 (+/-SD) cm/yr after 6 months of DA compared with a pretreatment growth rate of 4.1 +/- 0.7 cm/yr. Individual increments ranged from 38-80%. All three children achieved normal growth rates for their BA. Similarly, the growth rate in group II increased to 7.7 +/- 0.9 cm/yr from a pretreatment growth velocity of 4.2 +/- 1.6 cm/yr. The growth increments of group II ranged from 43-133%. Two children of group II achieved normal growth rates for their BA, and all had a significant increase in height (P less than 0.05). Four of the six children achieved normal growth velocities after 6 months of hGH therapy. Five of the six children significantly increased their mean hGH responses to L-dopa or bromocriptine during chronic DA therapy compared with the pretreatment period. Maximum serum hGH values in group I increased from a pretreatment mean (and range) of 12 +/- 4 (+/-SE) ng/ml (5-18 ng/ml) to 46 +/- 12 ng/ml (21-64 ng/ml). The maximum hGH concentrations in group II increased from a pretreatment mean and range of 21 +/- 7 ng/ml (11-34 ng/ml) to 48 +/- 4 (42-56 ng/ml). Also, four of the six children had correspondingly increased somatomedin-C concentrations after DA therapy. The findings of this preliminary study indicate that dopaminergic therapy, i.e. L-dopa or bromocriptine, induced linear growth in patients with a form of IUGR associated with microcephaly and psychomotor retardation. DA therapy perhaps may be useful in treating other various forms of IUGR.     

Insulin-like growth factor-I and growth in height, leg length, and trunk length between ages 5 and 10 years

OBJECTIVE: IGF-I, a major regulator of childhood growth, is also associated with the risk of several cancers in adult life. Adult height and particularly leg length are also associated with cancer risk. Prepubertal growth is more in leg than trunk length, and it has been suggested that leg length might be a biomarker of childhood IGF-I. However, there is little information on the association between childhood IGF-I and subsequent leg and trunk growth. In this study, we investigated the association of IGF-I measured at 5 and 7-8 yr with growth in height and the components of height (leg and trunk length) from 5 yr to 9-10 yr. PARTICIPANTS: A total of 675 children participated in the Avon Longitudinal Study of Parents and Children. RESULTS: IGF-I was strongly positively associated with growth in height in both sexes. Among boys, IGF-I was strongly associated with subsequent growth in both leg and trunk length, but there was no evidence that IGF-I was more strongly associated with one component of growth than the other. Among girls, IGF-I was strongly positively associated with growth in trunk but not leg length, although there was only weak evidence that these two associations differed in strength (P = 0.058). CONCLUSIONS: These results support the contention that the associations between height and cancer may be mediated by variation in childhood IGF-I. However, they provide no evidence to support the hypothesis that leg length is a better biomarker of childhood IGF-I levels than trunk length.     

Normal somatomedin-C/insulin-like growth factor I binding and action in cultured human fibroblasts from Turner syndrome

Growth retardation is a major manifestation of Turner syndrome (TS). Since plasma growth hormone and somatomedin-C/insulin-like growth factor I (SM-C/IGF-I) levels are generally normal, growth failure has been ascribed to peripheral defects in SM-C/IGF-I receptors or action. We have measured the binding of [125I]SM-C/IGF-I to cultured fibroblast monolayers derived from patients with Turner syndrome, and have evaluated SM-C/IGF-I stimulation of both [3H]thymidine incorporation and cell replication. When compared to fibroblasts from normal adults, newborns, and age-matched children, no significant differences were observed in specific binding of [125I]SM-C/IGF-I to fibroblast monolayers, and displacement curves demonstrated similar receptor affinities for all groups. Similarly, equivalent SM-C/IGF-I stimulation of [3H]thymidine incorporation was seen in both Turner and control fibroblasts. In the absence of serum, SM-C/IGF-I, at a concentration of 10-25 ng/ml, stimulated thymidine incorporation 3.7-11.8-fold in Turner fibroblasts and 1.9-9.8-fold in control cells. In combination with 1.0% human hypopituitary serum (HHS), SM-C/IGF-I stimulated thymidine incorporation 20-70-fold in all cell lines. Cell replication in both TS and control cells was increased 90% by the combination of SM-C/IGF-I + 0.5% HHS, and 140% by SM-C/IGF-I + 0.5% HHS + dexamethasone. We conclude that TS fibroblasts have normal SM-C/IGF-I receptors and sensitivity, and are capable of enhanced DNA synthesis and replication following SM-C/IGF-I stimulation.     

Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study

CONTEXT: Weight-based dosing of GH is the standard of care for short children, although IGF-I is thought to be the main mediator of GH actions on growth. OBJECTIVE: The objective of the study was to test whether IGF-I levels achieved during GH therapy are determinants of the growth responses to GH treatment. DESIGN: This was a 2-yr, open-label, randomized, IGF-I concentration-controlled trial. Prepubertal short children [n = 172, mean age 7.53 yr, mean height sd score (HT-SDS) -2.64] with low IGF-I levels (mean IGF-I SDS -3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF((low)) group, n = 70] or the upper limit of the normal range [+2 SDS, IGF((high)) group, n = 68] or to a comparison group of conventional GH dose of 40 microg/kg/d (n = 34). SETTING: The study was conducted in a multicenter, outpatient setting. PRIMARY OUTCOME MEASURE: Change in HT-SDS over 2 yr was measured. RESULTS: One hundred forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6-9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF((low)), and IGF((high)), respectively, with IGF((high)) showing significantly greater linear growth response (P < 0.001, compared with the other two groups). The IGF((high)) arm required higher doses (>2.5 times) than the IGF((low)) arm, and these GH doses were highly variable (20-346 microg/kg/d). Multivariate analyses suggested that the rise in the IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. CONCLUSION: IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I targets results in improved growth responses, although at higher average GH doses.     

Inhibin A,inhibin B,follicle-stimulating hormone,luteinizing hormone,estradiol, and sex hormone-binding globulin levels in 473 healthy infant girls

The early postnatal regulation of reproductive hormones seems to be more complex in girls than in boys. The aim of this study was to describe inhibins A and B, FSH, LH, estradiol, and SHBG in a large prospective cohort of 473 unselected, healthy, 3-month-old girls. In full term, appropriate-for- gestational-age girls (n = 355) hormones showed a marked interindividual variation, with concentrations up to pubertal values [medians (95% confidence intervals): inhibin B, 82 pg/ml (<20-175); FSH, 3.8 IU/liter (1.2-18.8); LH, 0.07 IU/liter (<0.05-1.07); estradiol, 31 pM (<18-83); SHBG, 137 nM (72-260)]. In 38%, FSH levels exceeded 4.5 IU/liter. Weight at 3 months had significant inverse relationships with estradiol and SHBG (P = 0.048 and P = 0.001, respectively). Gestational age was negatively correlated to estradiol (P = 0.001), with a similar trend for LH, FSH, and inhibin B. Inhibin B was higher in premature girls [126 pg/ml (<20-265)] than in term [80 pg/ml (<20-181), P = 0.002] and postmature girls [59 pg/ml (<20-152), P = 0.012]. Likewise, estradiol levels in prematures were higher than in mature girls [51 pM (<18-128) vs. 31 pM (<18-85), P = 0.009]. Estradiol was also higher in small-for-gestational-age than in appropriate-for-gestational-age girls (P = 0.046), with inhibin B and LH, but not FSH, showing a similar trend. In conclusion, reproductive hormones showed a large variation, and concentrations corresponded to those observed in puberty. Our findings support the concept of a minipuberty in infant girls similar to that in boys.     

Effect of sex hormone administration on circulating ghrelin levels in peripubertal children

BACKGROUND: Ghrelin levels gradually decrease throughout childhood and with advancing pubertal stage. The change during puberty is more pronounced in boys than girls. OBJECTIVE: The objective of the study was to investigate whether the pubertal drop in ghrelin secretion is modified by the increase in sex hormones. PATIENTS AND METHODS: Ghrelin levels were measured in 34 short peripubertal children (17 boys and 17 girls) aged 8-12.5 yr before and after sex hormone priming for GH stimulation testing. RESULTS: In boys, priming with testosterone increased testosterone to pubertal levels (23.7 +/- 7.1 nmol/liter), which in turn induced a marked decrease in ghrelin (from 1615.8 +/- 418.6 to 1390.0 +/- 352.0 pg/ml) and leptin (from 8.0 +/- 4.5 to 5.8 +/- 3.2 ng/ml) and an increase in IGF-I (from 162.7 +/- 52.8 to 291.1 +/- 101.6 ng/ml) (P < 0.001 for all parameters). In girls, priming with estrogen led to a supraphysiological increase in estradiol levels (1313.8 +/- 438.0 pmol/liter), which had no effect on ghrelin, leptin, or IGF-I. There was no correlation between ghrelin levels and levels of sex hormones, leptin, or body mass index in either boys or girls. CONCLUSIONS: A pharmacological increase in sex hormones is associated with a marked decline in circulating levels of ghrelin in boys but not girls. Additional longitudinal studies through puberty are needed to elucidate the physiological interaction between sex hormones and ghrelin.     

Free/dissociable insulin-like growth factor (IGF)-I, not total IGF-I, correlates with growth response during growth hormone treatment in children born small for gestational age

CONTEXT: IGF-I plays an important role in pre- and postnatal growth. Its serum levels are regulated by metabolic and genetic factors. Mean total IGF-I in short, small for gestational age (SGA) children is reduced, but within the normal range. Free/dissociable IGF-I is the bioactive form of IGF-I. Objectives: The aim of the study was to investigate changes in free IGF-I during GH treatment in short SGA children and to evaluate whether free IGF-I levels contribute to predicting first-year growth response and/or adult height. DESIGN, SETTING, AND INTERVENTION: We conducted a randomized, double-blind GH dose-response study with a GH dose of either 1 mg/m(2).d (group A) or 2 mg/m(2).d (group B). Free IGF-I, total IGF-I, and IGF binding protein (IGFBP)-3 were determined at baseline, after 1 and 5 yr, at stop, and 6 months after GH discontinuation. PATIENTS: We studied 73 (46 male) short SGA children (36 group A) with a baseline mean age of 7.7 (2.2) yr and a mean GH duration of 8.2 (2.1) yr. MAIN OUTCOME MEASURES: Untreated SGA children had a mean free IGF-I sd score (SDS) of -0.2 (1.2), not related to total IGF-I. During GH therapy, free IGF-I significantly increased to 1.6 (0.7) SDS, as did total IGF-I and IGFBP-3 [2.0 (0.8) and 1.3 (0.9), respectively]. Multiple regression analysis showed that baseline free IGF-I and IGFBP-3 were negatively correlated with adult height SDS, whereas baseline bone age delay, target height SDS, baseline height SDS, and GH dose were positively correlated. Free IGF-I was also negatively correlated with first-year growth response. CONCLUSIONS: Circulating baseline free IGF-I and IGFBP-3 were better predictors for adult height in GH-treated SGA children than total IGF-I, or total IGF-I to IGFBP-3 ratio. This suggests a possible role for free IGF-I measurement in predicting the effect of GH therapy in short SGA children.     

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation.

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment.     

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.