Persistent short stature, other potential outcomes, and the effect of growth hormone treatment in children who are born small for gestational age.

To provide pediatric endocrinologists, general pediatricians, neonatologists, and primary care physicians with recommendations for the management of short children born small for gestational age (SGA). A 13-member independent panel of pediatric endocrinologists was convened to discuss relevant issues with respect to definition, diagnosis, and clinical management of short children born SGA. Panel members convened over a series of 3 meetings to thoroughly review, discuss, and come to consensus on the identification and treatment of short children who are born SGA. SGA is defined as birth weight and/or length at least 2 standard deviations (SDs) below the mean for gestational age (<or=-2 SD). Accurate gestational dating and measurement of birth weight and length are crucial for identifying children who are born SGA. Comprehensive pregnancy, perinatal, and immediate postnatal data may help to confirm the diagnosis. Maternal, placental, and fetal causes of SGA should be sought, although the cause is often not clear. Most children who are SGA experience catch-up growth and achieve a height >2 SD below the mean; this catch-up process is usually completed by the time they are 2 years of age. A child who is SGA and older than 3 years and has persistent short stature (ie, remaining at least 2 SD below the mean for chronologic age) is not likely to catch up and should be referred to a pediatrician who has expertise in endocrinology. Bone age is not a reliable predictor of height potential in children who are SGA. Nevertheless, a standard evaluation for short stature should be performed. A diagnosis of SGA does not exclude growth hormone (GH) deficiency, and GH assessment should be performed if there is clinical suspicion or biochemical evidence of GH deficiency. At baseline, insulin-like growth factor-I, insulin-like growth factor binding protein-3, fasting insulin, glucose, and lipid levels as well as blood pressure should be measured, and all aspects of SGA-not just stature-should be addressed with parents. The objectives of GH therapy in short children who are SGA are catch-up growth in early childhood, maintenance of normal growth in childhood, and achievement of normal adult height. GH therapy is effective and safe in short children who are born SGA and should be considered in those older than 2 to 3 years. There is long-term experience of improved growth using a dosage range from 0.24 to 0.48 mg/kg/wk. Higher GH doses (0.48 mg/kg/wk [0.2 IU/kg/d]) are more effective for the short term. Whether the higher GH dose is more efficacious than the lower dose in terms of adult height results is not yet known. Only adult height results of randomized dose-response studies will give a definite answer. Monitoring is necessary to ensure safety of medication. Children should be monitored for changes in glucose homeostasis, lipids, and blood pressure during therapy. The frequency and intensity of monitoring will vary depending on risk factors such as family history, obesity, and puberty.

The aim of this study was to quantify serum adiponectin concentrations in short children born small for gestational age (SGA) compared with those in children born appropriate for gestational age (AGA), and to assess the relationship between the serum levels of adiponectin and insulin-like growth factor binding protein-1 (IGFBP-1) known as a predictor of the development of type 2 diabetes mellitus and cardiovascular disease. Sixteen prepubertal short children born SGA and 20 short children born AGA, matched for age, body mass index, height, pubertal status, gestational age, bone age and midparental height, were included in the study. The serum levels of adiponectin, IGFBP-1, insulin and insulin-like growth factor-I (IGF-I) were measured in the fasting state. The levels of serum adiponectin were significantly lower in the SGA than in AGA children (10.5 +/- 4.2 vs. 13.9 +/- 5.1 micro g/ml, P < 0.05). The levels of serum IGFBP-1, insulin and IGF-I were all similar in both groups. Overall, there was a significant positive correlation between adiponectin and IGFBP-1 (r = 0.40, P < 0.05). Our results suggest that hypoadiponectinaemia in short SGA children without catch-up growth may reflect insulin resistance and imply a higher risk of developing type 2 diabetes mellitus. Additionally, adiponectin may be a more sensitive indicator for latent insulin resistance than IGFBP-1 in short SGA children.

Many aspects of hormonal regulation and mechanisms of normal infancy growth are poorly understood. The objective of this study was to establish the determinants of serum growth factor levels in infancy and their association with growth. A prospective, longitudinal, population-based birth cohort between 1997-2001 was studied. 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 were anthropometrical measurements (0, 3, 18, and 36 months) and serum samples (3 months). Height, weight, and serum IGF-I and IGF-binding protein-3 (IGFBP-3) were the main outcome measures. 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. 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.

This editorial refers to 'Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: association with adiponectin' by S. Watanabe et al., published in this issue on page 1214–1222. An area of research which has attracted attention during recent years and which has been subject to some controversy is the possible role of growth hormone (GH) and its mediator insulin-like growth factor I (IGF-I) in the development of cardiovascular disease (CVD) in general and in chronic heart failure (CHF) in particular. Possible pathophysiological mechanisms seem to involve direct CV actions of GH and IGF-I as well as indirect effects through changes in CV risk factors.1 Based on available evidence, the predominant hypothesis is that reduced IGF-I signalling might be harmful in patients with CHF. Importantly, in clinical studies investigating circulating levels of the different components of the GH/IGF-I system, it has not been possible to determine in a consistent way whether low IGF-I action is harmful in CHF. In the general population, low2 as well as high3 IGF-I levels have been identified as independent risk factors for the development of CHF. In cross-sectional studies of patients with prevalent CHF, low,4 unchanged,5 or high levels6 of IGF-I have been reported. Adding to the confusion, two prospective studies have reported that low levels of IGF-I were associated with increased mortality,4,7 a third study found an association between mortality and the IGF-I/GH ratio,8 and a fourth study found that IGF-I levels did not provide prognostic information about survival in CHF patients.5 The reason for these conflicting results is at present unclear. The complexity of the GH/IGF-I system, consisting of GH, IGF-I, different binding proteins, and regulatory hormones means that a large variety of different biochemical analyses can be used to estimate GH/IGF-I activity.9 It is unclear which measurements are superior for estimating the biological activity of GH/IGF-I in different tissues. Measurement of total levels of GH and IGF-I is still considered to be the principal biochemical marker. However, the clinical utility of a single measurement of GH is limited by its short half-life (about 18 min) and pulsatile secretion. In contrast, circulating IGF-I has a longer half-life (about 7–20 h) and exhibits only minor diurnal variations,9 implying that single measurements of IGF-I can be used for scientific purposes. Circulating IGF-I is primarily of hepatic origin, but importantly IGF-I is also produced locally in almost all other organs and tissues where IGF-I exerts autocrine/paracrine effects via the IGF-I receptor.9 Another issue that should be considered is the fact that less than 1% of IGF-I molecules circulate in a free non-protein bound form, the remaining molecules form complexes with a family of six different IGF-I binding proteins (IGFBP1–6) and acid labile subunit.9 To obtain an estimate of the biologically active fraction of total IGF-I, different assays for the measurement of free IGF-I have been developed, but their importance is not yet well established. Another analytical approach is to use the molar ratio between IGF-I /IGFBP3 as a rough estimate of the free biological active fraction of total IGF-I.10 In the current issue of the European Journal of Heart Failure, Watanabe et al.11 report new and interesting data on the prognostic information provided by the molar IGF-I/IGFBP3 ratio (the IGF-I axis) in a thoroughly examined cohort of Japanese patients with CHF. The authors observed higher total levels of IGF-I and IGFBP3 in patients compared with a matched control group. However, the increases were disproportionate in such a way that bioactive IGF-I as judged by the IGF-I/IGFBP3 ratio was actually reduced in the patients. Furthermore, the severity of CHF was inversely related to the IGF-I/IGFBP3 ratio predicting mortality and hospitalizations. Thus, these data suggest, to some extent, that reduced IGF-I signalling might be a risk factor in patients with prevalent CHF. It is a new observation that increased protein binding of IGF-I is an important factor in this scenario. In contrast, another report has suggested that reduced IGFBP3 and IGFBP2 might represent independent risk factors in CHF.7 Thus, the importance of the different components of the IGF-I system in CHF remains unclear. There are several ways by which GH/IGF-I activity may be involved in the development of CVD. Importantly, the direct CV effects and modulation of risk factors seem to be influenced in different directions by the GH/IGF-I system, as illustrated by the increased risk of CVD in pituitary patients with GH deficiency and acromegaly.1 Concerning direct cardiac effects, different experimental in vitro and in vivo models have suggested that IGF-I increases cardiac contractility.1 The underlying mechanisms seem to involve an influx of calcium into the cardiomyocytes when the IGF-I receptor is activated.1 Furthermore, IGF-I has been shown to protect cardiomyocytes from apoptosis, supporting a beneficial effect of high endogenous IGF-I activity in CHF.12 On the other hand, high IGF-I activity might increase left ventricular mass with long-term detrimental effects on cardiac contractility.13 IGF-I and the IGF-I receptor have been detected in atherosclerotic lesions in humans, and it has been shown that IGF-I exerts proliferative actions on vascular smooth muscle cells in vitro. Therefore, it has been suggested that IGF-I might be a promoter of arterial lesions.14 However, in the past 10 years, there has been increased attention on the beneficial vascular effects of high GH/IGF-I activity.1 Direct actions of IGF-I on the endothelium have been proposed as possible protective mechanisms, for example, release of NO with subsequent vasodilatation.15 In addition, high GH/IGF-I activity might have a favourable effect on CV risk factors such as lipid metabolism and inflammation,1 and it has also been proposed that high levels of the anabolic hormone IGF-I could protect against the catabolic wasting processes which characterize severe CHF.16 Adiponectin is a polypeptide hormone exclusively secreted by adipocytes. Paradoxically, the secretion is inversely related to fat mass. It is well documented that high levels of circulating adiponectin have a favourable effect on metabolic processes and protect against derangements that lead to obesity, metabolic syndrome, atherosclerosis, and subsequent CVD.17 Therefore, it was an unexpected observation reported by Kistorp et al.18 that in patients with CHF, a high level of adiponectin seems to predict a poor outcome. As a possible mechanism, the authors suggested that in end-stage CHF, wasting with the loss of adipose tissue might lead to increased levels of adiponectin.18 The study by Watanabe et al.11 confirmed that high serum adiponectin seems to be associated with a poor prognosis in CHF. The inverse association between the IGF-I/IGFBP3 ratio and serum adiponectin was a new observation, suggesting that low IGF-I activity might contribute to increased levels of adiponectin in severely affected CHF patients. It is a novel hypothesis that the enigma of high adiponectin levels in CHF patients with poor prognosis might partly be due to low IGF-I activity. Studies of patients with GH disturbances suggest that GH/IGF-I activity can inversely influence secretion of adiponectin. In acromegalic patients, reduced levels of adiponectin have been reported,19 whereas patients with primary GH resistance (Laron dwarfs) have elevated levels of adiponectin despite marked adiposity.20 In summary, the interaction between the different components of the GH system and the CV structures and risk factors is undoubtedly very complex. After more than two decades of extensive research, the pathophysiological mechanisms linking the GH system to the development of CVD are still insufficiently elucidated. One important issue that still requires clarification is how to obtain the best estimate of in vivo GH and IGF-I activity based on in vitro biochemical analyses. As another obvious challenge, GH and IGF-I action exerts pleiotropic CV effects implying that the overall effect of a given GH/IGF-I stimulation is difficult to predict and may vary between different groups of patients depending on factors such as age and number of years with disease. Associate professor Lars Østergaard Kristensen, Department of Internal Medicine O, Herlev Hospital, University of Copenhagen is thanked for valuable suggestions to improve this editorial. Conflict of interest: none declared.

It is generally recognized that children born small-for-gestational age (SGA) have a 5–7 times higher risk of short stature than children born at normal size. It has been suggested that the programming of the endocrine axes occurs during critical phases of fetal development and is affected by intrauterine growth retardation. This study was undertaken to characterize the postnatal growth pattern and the final height of children born SGA, as part of a population- based study (n = 3,650), from birth to final height, and to evaluate the hormonal status in another group of prepubertal children born SGA (n = 134) without postnatal catch-up growth. The majority (88%) of ‘healthy’ full-term singleton SGA infants achieved catch-up growth during the first 2 years of life, and most of the increase in height occurred by 2 months of age. The SGA children who remained short at 2 years of age had a higher risk of short stature later in life. The risk of having a short final height (<–2 SDS) was five times higher for children with a low birth weight and seven times higher for those with a low birth length in comparison with children with a normal birth size. Moreover, about 20% of all children of short stature were born SGA. As a group, children born SGA will have a final height, expressed in SDS, as they had during the prepubertal years. This is in contrast to children, who became short postnatally. During puberty, these short children will have a mean height gain of 0.6 SDS for girls and 0.7 SDS for boys. The mean estimated secretion rate for growth hormone (GH) was lower in the short children born SGA compared with the reference groups born at an appropriate size for gestational age, of either short (p < 0.05) or normal stature (p < 0.001). Moreover, in the youngest children born SGA (2–6 years of age) a different pattern of GH secretion was found, with a high basal GH level, low peak amplitude, and high peak frequency. The majority of the children born SGA had levels of GH-binding protein within the range previously reported for normal children. However, the levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3) and leptin were significantly reduced compared with the reference values (p < 0.001, p < 0.01 and p < 0.001, respectively). In conclusion, the low spontaneous GH secretion rate and a disturbed GH secretion pattern, together with low serum levels of IGF-I, IGFBP-3 and leptin, might contribute to the reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood.

BackgroundGrowth hormone (GH) treatment has become a frequently applied growth promoting therapy in short children born small for gestational age (SGA). Children born SGA have a higher risk of developing attention deficit hyperactivity disorder (ADHD). Treatment of ADHD with methylphenidate (MP) has greatly increased in recent years, therefore more children are being treated with GH and MP simultaneously. Some studies have found an association between MP treatment and growth deceleration, but data are contradictory.ObjectiveTo explore the effects of MP treatment on growth in GH-treated short SGA childrenMethodsAnthropometric measurements were performed in 78 GH-treated short SGA children (mean age 10.6 yr), 39 of whom were also treated with MP (SGA-GH/MP). The SGA-GH/MP group was compared to 39 SGA-GH treated subjects. They were matched for sex, age and height at start of GH, height SDS at start of MP treatment and target height SDS. Serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels were yearly determined. Growth, serum IGF-I and IGFBP-3 levels during the first three years of treatment were analyzed using repeated measures regression analysis.ResultsThe SGA-GH/MP group had a lower height gain during the first 3 years than the SGA-GH subjects, only significant between 6 and 12 months of MP treatment. After 3 years of MP treatment, the height gain was 0.2 SDS (±0.1 SD) lower in the SGA-GH/MP group (P = 0.17). Adult height was not significantly different between the SGA-GH/MP and SGA-GH group (−1.9 SDS and −1.9 SDS respectively, P = 0.46). Moreover, during the first 3 years of MP treatment IGF-I and IGFBP-3 measurements were similar in both groups.ConclusionMP has some negative effect on growth during the first years in short SGA children treated with GH, but adult height is not affected.

Epidemiological studies have shown that the metabolic syndrome, a combination of type 2 diabetes mellitus, hypertension, dyslipidaemia and a high body mass index (BMI), occurs more frequently among adults who were born with a low birth weight. Because insulin is thought to play a key role in the pathogenesis of this syndrome we investigated insulin sensitivity and risk factors for cardiovascular disease in short prepubertal children born small for gestational age (SGA). Frequently sampled intravenous glucose tolerance tests (FSIGT) were performed in 28 short prepubertal children born SGA. Short stature was defined as a height < -2SD. SGA was defined as a birth length and/or a birth weight for gestational age < -2SD. Twelve short children born appropriate for gestational age (AGA) were used as controls for the FSIGT's results only. AGA was defined as a birth weight and/or birth length for gestational age > -2SD. In short SGA children, blood pressure (BP), fasting levels of serum free fatty acids (FFA), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) were measured and compared to reference values. Mean insulin sensitivity (Si) level in short SGA children was significantly reduced to 38% of the mean Si level measured in short AGA controls (P = 0.004). Mean acute insulin response (AIR) was significantly higher in SGA children compared to short AGA controls (P < 0.001). Differences in Si and AIR between the two groups remained significant after adjusting for age and BMI (P < 0.001 and P = 0.003, respectively). The mean (SD) systolic BP SDS was 1.3 (1,1), being significantly higher than zero. Mean fasting serum levels of FFA, TC, TG, HDL and LDL were all within the normal range. However, 6 of the 28 SGA children had serum FFA levels above the normal range. Cardiovascular risk factors could statistically be represented in two clusters. Both clusters played a significant role in the development of insulin insensitivity (1/Si). Although the metabolic syndrome has been described in adulthood, our study showed that risk factors for the development of type 2 diabetes mellitus and cardiovascular disease are already present during childhood in short prepubertal children born SGA, suggesting a pretype 2 diabetes mellitus phenotype.

Intrauterine growth retardation, or being small for gestational age (SGA), has a life-long impact on a fetus's potential for development and survival. The incidence and relative risk of short stature in children born SGA were studied using a Swedish healthy full-term (37-43 wk of gestation) singleton birth cohort (n = 3650) from Göteborg, followed from birth to final height at about 18 y of age. Most infants, defined as SGA on the basis of a birth length less than -2 standard deviation scores (SDS) below the mean (SGAL infants), showed catch-up growth during the first 6 mo after birth, and by 1 y only 13.4% of the SGAL infants were below -2 SDS in height. This percentage decreased further during childhood to reach a value of 7.9% at 18 y of age. Although most SGAL infants have catch-up growth in early life, those who do not constitute 21% of short, prepubertal children. At 18 y of age, 22% of the total short population were short at birth (< -2 SDS), whereas when birth weight was used to define SGA, only 14% of the 18-y-old short population were light at birth. SGAL infants were found to have a 7-fold higher risk for short final stature (relative risk, 7.1; 95% confidence interval, 3.7-13.6) in comparison with the non-SGAL group. In a multiple linear regression analysis, both birth length and mid-parental height were found to be significantly related to the magnitude of catch-up growth from birth to 18 y of age. Neither the length of gestation nor birth weight showed such a relationship. It is concluded that the vast majority (> 86%) of "healthy" full-term singleton SGAL infants will achieve catch-up in height during the first 6-12 mo of life, and that this is almost independent of whether birth weight or birth length is used to define SGA. Of the remaining, non-catch-up SGA infants, about 50% remain short in final height, and thus constitute a high risk group for persistent short stature.

Although short children who were born small for gestational age (SGA) seem to have normal body proportions, objective data both before and during growth hormone (GH) treatment are very limited. Therefore, we investigated in a large group of short children who were born SGA the effects of GH treatment versus no treatment on head circumference (HC) and body proportions. Furthermore, we studied differences in linear growth and HC between SGA children who were born with a low birth length and birth weight (SGA(L+W)) and SGA children who were born with a low birth length only (SGA(L)). An open-labeled, GH-controlled, multicenter study was conducted for 3 years. Non-GH-deficient short SGA children (n = 87), with a mean age (standard deviation) of 5.9 (1.5) years, were randomized to either a GH group (n = 61), receiving GH in a dose of 33 microg/kg/day, or an untreated control group (n = 26). Height; weight; HC; sitting height; armspan; and hand, tibial, and foot size were measured and expressed as standard deviation score (SDS) adjusting for gender and age. At baseline, all anthropometric measurements, except HC SDS, were significantly lower compared with -2 SDS. During GH treatment, all anthropometric measurements normalized in accordance to the normalization of height SDS. At the start of the study, mean HC SDS was significantly lower in SGA(L+W) children compared with SGA(L) children. It is interesting that most (14 of 16) children with an HC SDS less than -2.00 had been born SGA(L+W). During GH treatment, the 3-year increase in height, HC, and other anthropometric measurements was comparable between SGA(L+W) and SGA(L) children. In both SGA(L+W) and SGA(L) control subjects, no changes in SDSs of height, HC, and other anthropometric measurements were found during the 3-year follow-up period. Untreated short SGA children have normal body proportions with the exception of HC, which is relatively large in many of these children. SGA(L+W) children still had a smaller HC at the age of 5.9 years compared with SGA(L) children. Three years of GH treatment induced a proportionate growth resulting in a normalization of height and other anthropometric measurements, including HC, in contrast to untreated SGA control subjects.

To determine the independent contributions to infant birth size of insulin-like growth factor I (IGF-I) and leptin measured in umbilical cord plasma. Umbilical cord blood was collected in 12 804 consecutive deliveries, and cord plasma from 585 singleton infants born at term after uncomplicated pregnancies was analyzed for leptin, IGF-I, and 2 IGF-binding proteins (IGFBP-1 and IGFBP-3). In multivariable analyses, we assessed maternal and infant covariates of leptin and IGF-I, and we evaluated the independent contribution of cord levels of leptin and IGF-I on infant birth size. Cord plasma levels of IGF-I were lower in women who reported smoking at the beginning of pregnancy compared with nonsmokers. In female infants, levels of IGF-I and leptin were higher than in male infants after adjustment for ponderal index and maternal factors. We found a strong parallel increase in umbilical IGF-I and leptin with increasing birth weight and birth length. For IGFBP-1, there was an opposite pattern: IGFBP-1 increased with decreasing birth size. The multivariable analysis, adjusted for length of gestation and maternal age, parity, prepregnancy weight, smoking during pregnancy, and offspring sex, showed that IGF-I and leptin, independent of each other, were associated with birth weight and birth length. Levels of IGF-I and leptin in umbilical cord plasma were higher in girls than in boys, but in both sexes, these 2 factors contributed independently and positively to birth weight and length. For IGFBP-1, high levels were associated with low birth weight and reduced length. If intrauterine growth is related to the risk of developing adult diseases, IGF-I, IGFBP-1, and leptin may be involved in the underlying processes.1131-1135 insulin like growth factors, leptin, umbilical cord plasma, birth weight.

The relationship between GH, insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin may be critical to the understanding of variation in early growth, especially in the small for gestational age (SGA) baby. To investigate these relationships, we have undertaken 12-h hormone profiles in 26 babies (13 SGA) at a median of 4.5 days of age. GH levels were measured every 10 min; insulin and IGFBP-1 were measured every 20 min. Mean levels of these hormones and IGF-I levels (from a single sample) were related to size at birth. The GH data were analyzed by Pulsar and time series analysis to characterize hormone pulsatility and relationship with feeds. IGF-I levels correlated with birth weight and length (r2 = 0.47; P = 0.004, and r2 = 0.5; P = 0.0005, respectively, after allowing for gestation), whereas mean GH levels were negatively related to birth size (r2 = -0.18; P = 0.04 and r2 = -0.2; P = 0.03 for weight and length, respectively). No direct relationship between mean GH levels and IGF-I was identified. IGF-I levels were higher in appropriate for gestational age (AGA; mean +/- SD, 82+/-61 ng/mL) than in SGA (34+/-22 ng/mL; P = 0.03) babies. Baseline (mean +/- SD, 25.9+/-11.9), mean (33.9+/-14.0), and peak (45.0+/-18.1 microg/L) GH levels were higher in SGA than in AGA babies [17.1+/-8.2 (P = 0.04), 22.5+/-10.4 (P = 0.03), and 30.7+/-15.4 microg/L (P = 0.04), respectively]. Mean IGFBP-1 levels were also higher in SGA than AGA babies (157.4+/-90.7 vs. 62.7+/-43.8 ng/mL; P = 0.01). A positive correlation was identified between changes in insulin and coincident pulses of GH (r = 0.147; P < 0.01), whereas there was an inverse relationship between insulin and IGFBP-1, with a lag time 120 min (r = -0.33; P < 0.0001). In conclusion, these studies indicate that the GH-IGF-I axis is closely related to feeding in the newborn. In SGA babies, low IGF-I and elevated IGFBP-1 reflect the slow growth, but elevated GH and rapid GH pulsatility may be a signal for lipolysis.

Background: Primary goal of growth hormone (GH) treatment for short children is to achieve an adult height in the normal range. Different GH treatment strategies to achieve this goal include titration of GH dose according to serum insulin-like growth factor I (IGF-I) concentrations. However, IGF-I levels do not always correlate well with the growth response. The purpose of this study is to identify the factors affecting IGF-I concentration in each disease and to correct the related factors and then to identify the relationship between IGF-1 and treatment response. Methods: In this study, data of pre-pubertal children with idiopathic growth hormone deficiency (IGHD), organic GHD (OGHD), Turner syndrome (TS), small for gestational age (SGA) who were treated with recombinant human GH more than one year were obtained from the LGS Database. The LGS has been progressing since 2012 and is an open-label, multicenter, prospective, and retrospective observational study. Results: Among 2,021 registered in LGS, the subjects were 366 except for the violation of selection criteria. Among them, IGHD was 252, 16 OGHD, 31 TS, and 67 SGA. The mean age of IGHD was 6.02, and the mean bone age was 4.49 years. OGHD was 7.38, 5.74, TS was 7.13, 6.52, and SGA was 5.61, 4.96 years. The height SDS according to chronologic age was -2.76 in IGHD group, OGHD -2.33, TS -2.9, SGA -2.57. In the IGHD and SGA group, IGF-I level has a positive correlation with weight and BMI (weight; r=0.0071 in IGHD, r=0.0009 in SGA, BMI; r=0.0411 in IGHD, r=0.003 in SGA). IGF-I showed a negative correlation with chronological age in the IGHD group (r=0.0411) and mid-parental height in the SGA group (r=0.0069). There was no significant relationship between pretreatment IGF-I level and growth response. However, in the IGHD group, the growth response was significantly higher when the change in IGF-I SDS value was 1 or more (P=0.0013). Conclusion: This study is the first study using LGS data to identify factors affecting IGF-I levels in Korean children with short stature and the relationship with treatment response. IGF-I levels were positively correlated with body weight in IGHD and SGA groups. There was no significant relationship between pre-treatment IGF-I levels and post-treatment growth response. In conclusion, IGF-I concentrations should be used as a tool for treatment compliance rather than for efficacy determination.

Objective: Insulin-like growth factor I (IGF-I) is necessary for normal growth and development in infants. Recent research suggested that IGF-I deficiency is associated with the development of oxygen-induced retinopathy of prematurity (1). We hypothesized that low IGF-I levels might be a risk factor for oxygen-induced pulmonary damage in preterm infants, which leads to chronic lung disease (CLD) of prematurity.Methods: We measured growth hormone (GH) secretory patterns and levels of IGF-I and IGF binding protein 3 (IGFBP-3) in 34 preterm infants (gestational age(GA): 25–32 weeks, weights 526-1985 grams) at risk to develop chronic lung disease. Measurements were performed in clinically stable infants, requiring respiratory support. Between the 4th and 12th day of life, 6 h (with hourly intervals) and 24 h (with 6 h intervals) blood samples were taken for the determination of GH. In addition, IGF-I and IGFBP-3 levels were measured in the first blood sample. Results were adjusted for GA and birth weight SD score (BWSDS).Results: No significant differences in GH concentration were found between the different time points studied either in the 6 h or 24 h profiles; GH concentration between infants who developed CLD vs no CLD was not different (mean GH respectively 77±11 vs 79±8 mg/l, p=0.86, adjusted p= 0.56). IGF-I levels were significantly lower in CLD vs no CLD infants even adjusted for GA and BWSDS (respectively 1.3±0.1 vs 1.9±0.2 nmol/l, p=0.02, adjusted p=0.04). IGFBP-3 levels were not different between both groups (CLD 0.60±0.04 mg/l vs no CLD 0.71±0.05 mg/l, p=0.11, adjusted p=0.94).Conclusion: Our results support the hypothesis that IGF-1 deficiency may increase the risk to develop CLD. Since GH levels do not differ between infants who develop CLD and those who do not, differences in IGF-I levels may be explained by a relative GH resistance. Alternatively, levels of IGF-I may be lower due to a decreased production in preterm infants. With respect to the relationship between IGF-I and the development of serious sequelae associated with prematurity (1) our findings are comparable with observations by others). We therefore suggest that IGF-I may play an important role in the development of chronic lung disease of prematurity.

Weight-based dosing of growth hormone (GH) is the standard of therapy in short children although insulin-like growth factor-I (IGF-I) is a major mediator of GH actions on growth. Objective: to test whether the IGF-I levels achieved during GH therapy are determinants of the growth responses to GH therapy. This was a two-year open-label, randomized IGF-I concentration-controlled trial. Prepubertal short children [n = 172; mean age 7.53 years; 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 mg/kg/day (n = 34). The multicenter study was performed in the outpatient centers. The primary outcome measure was to determine changes in HT-SDS during 2-year therapy. One hundred and 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 two other groups). The IGF-I(high) arm required higher doses ( > 2.5 times) than the IGF-I(low) arm, and these GH doses were highly variable (20-346 mg/kg/day). Multivariate analyses suggest that the rise in IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. 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 target results in improved growth responses, although at higher average GH doses.

Epidemiological studies have indicated that high serum levels of GH and IGF-I are associated with long-term risks. The objective of the study was to evaluate the changes in serum levels of GH during overnight profiles, IGF-I, and IGF binding protein 3 (IGFBP-3) in short small for gestational age (SGA) children during GH treatment with two doses. Thirty-six prepubertal short SGA children were the subjects of this study. Subjects received 1 (group A) or 2 (group B) mg GH/m(2).d. At baseline and after 6 months of GH treatment, overnight GH profiles were performed, and serum IGF-I and IGFBP-3 levels were measured. After 6 months, group B had significantly higher GH levels during the profile (mean, maximum, and area under the curve above zero line) than group A (P < 0.009). In group B, maximum GH levels increased from 43.9-161 mU/liter (P < 0.0002), and in group A, from 57.2-104 mU/liter (P = 0.002). During the profile (i.e. 12 h per day), children of group B had mean GH levels of 64.4 vs. 34.8 mU/liter in group A (P = 0.001). The IGF-I and IGF-I to IGFBP-3 ratio sd scores increased significantly in both groups, but were higher in group B than A [1.5 vs. 0.2 (P = 0.002) and 1.4 vs. 0.3 (P = 0.007), respectively]. In group B, 74% of the children had IGF-I levels in the highest quintile during GH treatment compared with 19% in group A. Our study shows that high-dose GH treatment in short SGA children results in high serum GH and IGF-I levels in most children. We recommend monitoring IGF-I levels during GH therapy to ensure that these remain within the normal range.