Clinical utility of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 measurements in paediatric practice

Measurements of serum insulin-like growth factor-I (IGF-I) and its major binding protein, IGFBP-3, are utilised in the routine clinical management of short children. In this review, the value of such measurements in the diagnosis of primary and secondary IGF-I deficiency is presented. The achievement of optimal growth while maintaining IGF-I within the normal range is the goal of GH treatment schedules used in a range of growth disorders, and thus data on IGF-I monitoring during initiation and maintenance phases of GH treatment are discussed. Comment is also made on the relationship between levels of IGF-I and IGFBP-3 in the population with regard to risks for cancer and cardiovascular disease.IGF-I and IGFBP-3 are important parameters to measure as one part of the process of managing short children. It is proposed that improving the clinical value of IGF measurement may involve measurement of specific prohormones and E-peptides, to get closer to the pool of GH dependent IGF-I.     

血清胰岛素样生长因子-I、瘦素水平及其与2～7岁小于胎龄儿生长关系的研究

目的探讨胰岛素样生长因子-I（IGF-I）和瘦素（leptin）在小于胎龄儿（SGA）儿童生长中的作用。方法选择符合纳入标准的60例儿童作为研究对象（SGA组），适于胎龄儿40例儿童作为对照组。分析两组儿童相关资料及血清IGF-I、leptin水平。结果①对照组和SGA组身高标准差得分（HtSDS）、体重标准差得分（WtSDS）差异有统计学意义（P均〈0．01）。②男女童血清IGF-I水平差异无显著性（P〉0．05）。③年龄分组比较对照组和SGA组的血清IGF-I水平差异无显著性（P〉0．05）。④当HtSDS、WtSDS均〈-2时，leptin与IGF-I存在较强的正相关关系（r=0．94，P〈0．01）；当HtSDS、WtSDS均〉0时两者不存在相关关系（r=0．46，P〉0．05）。结论①2～7岁组的SGA儿童生长落后于同龄正常儿童，但其血清IGF-I水平无明昆降低，特别是2～岁组，提示SGA儿童可能存在IGF-I抵抗。②在营养不良时血清IGF-I和瘦素水平呈正相关。     

Influence of iodine supplementation on serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) levels in severe iodine deficiency

Iodine deficiency is an important public health problem worldwide. In addition to severe consequences such as brain damage, developmental delay, deficits in hearing and learning, it also has a negative impact on growth. The negative impact of severe iodine deficiency (SID) on insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) was shown previously. In this study we aimed to analyze the impact of iodine supplementation on growth and growth factors of children with SID. One hundred and four children (63 boys and 41 girls) aged 5-15 years participated in the study. Height standard deviation scores (HSDS), and serum levels of IGF-I and IGFBP-3 were assessed both before and six months after a single dose of iodized oil. Serum levels of free thyroxine (FT4) and thyroid stimulating hormone (TSH) were also analysed to investigate the mechanisms by which alterations of iodine status may influence growth. Pubertal children had lower HSDS six months after iodine supplementation, while that of prepubertal children remained unchanged. IGF-I and IGFBP-3 levels decreased significantly and FT4 levels were suppressed six months after the supplementation, while TSH was normalized. These findings suggest a negative impact of iodine supplementation on growth factors in the short-term, which may be a direct effect of iodine repletion or an indirect effect caused by alterations in thyroid function. It may also be related to the method of supplementation used. Further studies are necessary to resolve these issues, as well as to examine the impact of iodine supplementation on growth in the long-term.     

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

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

Serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 levels in severe iodine deficiency

Iodine deficiency is an important public health problem worldwide. It is well known that it has severe consequences such as brain damage, developmental delay, deficits in hearing and learning and lower intellectual attainment. It also has a negative impact on growth. In this study, we aimed to address this issue and we assessed height standard deviation scores of children living in an area of severe iodine deficiency in comparison to those living in a mild iodine deficiency area. Serum levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), thyroxine (T4), and thyroid stimulating hormone (TSH) were also analyzed to investigate the mechanisms by which iodine depletion leads to growth failure. Pubertal children in a severe iodine deficient SID area had lower height standard deviation scores (HSDS), IGF-I and IGFBP-3 levels than those living in mild iodine deficient MID area. Similar findings could not be elucidated in the prepubertal age group. The major determinants of HSDS were age, IGF-I, IGFBP-3 and TSH. IGF-I and IGFBP-3 were negatively correlated with T4. These findings suggest that iodine deficiency has a negative impact on growth, as well as IGF-I and IGFBP-3 levels. This effect seems to be due to the derangements in thyroid hormone economy arising from iodine depletion. The degree of this impact may be related to the duration of iodine depletion or may be dependent on the developmental stage of the organism at the time of iodine depletion.     

The relationship between ovarian structure and serum insulin, insulin-like growth factor-I (IGF-I) and its binding protein (IGFBP-1 and IGFBP-3) levels in premature pubarche

The aim of this study was to determine serum insulin, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-1 and IGFBP-3) levels and their relationship with androgen levels and ovarian structure in 23 girls with premature pubarche (PP). Fasting levels of testosterone, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), androstenedione (delta4A), sex hormone binding globulin (SHBG), glucose (G), insulin (I), IGF-I, IGFBP-1, IGFBP-3 were measured. Androgens or steroid hormone levels > 3 SD of normal postpubertal levels were considered as an exaggerated response to the ACTH test. The fasting I to G ratio (FIGR) was calculated and FIGR > 22 was suggestive of insulin resistance (IR). A pelvic ultrasound (US) was carried out and the ovarian structure was divided into five classes (c): c1--homogeneous, c2--microcystic, c3--multicystic, c4--polycystic and c5--follicular. The girls with PP were divided into two groups according to the main ovarian classes observed: PPc1 (n = 6) and PPc2 (n = 15). The FIGR showed IR in 44% of patients. The androgens, SHBG, G, I, FIGR, IGF-I and IGFBP-1 levels were similar among the groups (PPc1 vs PPc2). An exaggerated response to ACTH was more common and IGFBP-3 levels were higher in the PPc2 than in the PPc1 group (p = 0.04). Regression analysis revealed that I was correlated with DHEAS (r = -0.43, p = 0.04) and IGFBP-1 (r = -0.51, p = 0.01); IGF-I was correlated with DHEA (r = -0.42, p = 0.05), delta4A (r = -0.47, p = 0.02), SHBG (r = -0.43, p = 0.04), IGFBP-1 (r = -0.61, p = 0.002) and IGFBP-3 (r = 0.56, p = 0.005); IGFBP-1 was correlated with SHBG (r = 0.56, p = 0.005). These findings suggest that there might be interactions between the insulin-IGF-I-IGFBPs system and hyperandrogenism. However, the possible causal role of adrenal androgen hypersecretion on the insulin-IGF-I-IGFBPs axis and ovarian structure in girls with PP remains to be established. Since studies reveal that IGFBP-3 levels could be a negative predictor for insulin sensitivity throughout puberty, we hypothesize that girls with PP and microcystic ovaries are at risk of developing IR in the course of normal puberty.     

Serum insulin-like growth factor-I (IGF-I), IGF-binding protein-3, and growth hormone levels in collodion babies: a case-control study

AIM: Because growth failure occurs in many collodion babies, we investigated serum growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels in collodion babies admitted to Gevher Nesibe Hospital, Kayseri, Turkey between 1999 and 2006. PATIENTS AND METHOD: The newborns diagnosed clinically as 'collodion baby' were included in the study group (group 1). Because collodion babies are usually born small for gestational age (SGA) and/or premature, a control group (group 2) was formed by selecting the first infant admitted immediately after each study infant who matched for gestational age (+/- 7 days) and birth weight (+/- 100 g). All infants' blood samples were collected within the first 2 h of life for measurements of serum GH, IGFBP-3 and IGF-I levels. RESULTS: Group 1 consisted of 23 collodion babies (13 males and 10 females) with gestational ages ranging from 32 to 42 weeks, and birth weights ranging from 1,300 to 3,600 g. Ten were born premature and 16 were SGA. Serum IGF-I and IGFBP-3 levels were lower but serum GH levels were higher in collodion babies than in controls. Birth weight was positively correlated with serum IGF-I (r = 0.310, p = 0.046) and IGFBP-3 (r = 0.389, p = 0.011) levels. Serum GH level was negatively correlated with birth weight (r = -0.376, p = 0.014), serum IGF-I (r = -0.567, p <0.001) and IGFBP-3 (r = -0.444, p = 0.003). CONCLUSION: Collodion babies had lower serum IGF-I and IGFBP-3 levels but higher serum GH levels than controls in the present case-control study. The underlying mechanism needs to be explored.     

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.     

Plasma leptin levels of large for gestational age and small for gestational age infants

The hormone leptin produced in the adipose tissue is involved in the regulation of body weight. This study investigates whether plasma leptin levels are related to an infant's birthweight, and whether the levels change with feeding. We measured plasma leptin levels from infants who were large for gestational age (n = 21), small for gestational age (n = 21), and appropriate for gestational age (n = 20). Two blood samples were collected before and after breastfeeding from each infant and plasma leptin concentrations were determined by radioimmunoassay. Leptin concentration was found to be increased in large for gestational age infants and to be decreased in small for gestational age infants compared with the level in appropriate for gestational age infants. There was a positive correlation between plasma leptin levels and both the infants' birthweights and the body mass indexes. Plasma leptin concentrations were found to be decreased during fasting and to be increased after feeding (p < 0.01). It is concluded that the plasma leptin levels correlate with the size of adipose tissue mass and are related to the nutritional status.     

Association between serum leptin and anthropometric parameters at birth and at 15th day of life in infants born asymmetrically small for gestational age

The aim of this study was to investigate changes in skinfold measurements taken at three sites, mid-arm circumference and umbilical circumference during the first 15 days of life; and to evaluate relationships between anthropometric measurements and umbilical cord blood serum leptin levels in infants born small for gestational age (SGA) and appropriate for gestational age (AGA) infants. Of 50 newborn infants, 25 were SGA and 25 were AGA. Neonates' weight, mid-arm circumference (MAC), umbilical circumference (UC), and triceps, subscapular and periumbilical skinfold thicknesses were measured (Holtain callipers) immediately after delivery. Anthropometric parameters were measured again at 15th days of age. At birth, mean birth weight, mean skinfold thickness, MAC and UC measurements in the AGA group were significantly higher than those of the SGA group. These differences were also found on the 15th day. Birth weight correlated with all skinfold thicknesses, MAC and UC at birth. Weight at 15th day of life correlated with skinfold thicknesses, MAC and UC at 15th day of life. Cord blood leptin level was significantly lower in the SGA than in the AGA infants. This difference continued on the 15th day. When cord blood leptin level was compared with that of the 15th day, we found that leptin levels in the cord blood were significantly higher. There were significantly positive correlations between leptin levels and birth weight and skinfold thicknesses when the infants were all grouped together. When the newborns were grouped according to birth weight, there were positive correlations between cord blood serum leptin levels and these parameters in the AGA group, but no correlation in the SGA group. At the 15th day of life serum leptin levels correlated with weight, subscapular and triceps skinfold thickness in the AGA group, but only with triceps skinfold thickness in the SGA group.     

Breastfeeding and catch-up growth in infants born small for gestational age

Postnatal growth was prospectively measured from birth to 1 y in 54 term infants born small for gestational age (SGA), fed either breast milk or a standard term infant formula. Breastfeeding was associated with a 0.36 and 0.64 standard deviation (SD) increase in weight at 2 weeks and 3 months of age. respectively, which persisted beyond the breastfeeding period (0.64 SD at 1 y). Breastfed infants also showed greater catch-up growth in head circumference [SD score (SDS) 0.53 higher at 3 months], and greater body length gain (SDS 0.68 higher at 6 months). This increased growth was independent of potentially confounding obstetric, social and demographic factors. Our findings suggest that breastfeeding may promote faster growth in infants compromised by poor growth in utero. SGA infants may be programmed for a number of adverse outcomes; the possibility that such events are altered by choice of postnatal diet is a key issue for future research.     

Leptin, insulin-like growth factor (IGF)-I and IGF binding protein-3 levels in children with constitutional delay of growth

This study was planned in order to investigate the role of insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) and leptin, the product of the ob gene synthesized by fat tissue cells, in constitutional delay of growth and puberty (CDGP) which is the most frequent cause of short stature in children. This study was conducted on 80 children with CDGP aged 6-15 years, and 60 healthy children served as controls. Serum IGF-I, IGFBP-3, insulin and plasma leptin levels were measured by immunoradiometric assay. Mean IGF-I and leptin levels were significantly lower in the CDGP group compared with the controls, but the mean IGFBP-3 level was not different in the two groups. Mean leptin levels were 3.72 +/- 2.29 in CDGP and 4.68 +/- 3.08 in the control group (p <0.05). There was a statistically significant relationship between leptin levels and height, weight, and body mass index. Leptin levels were also correlated with chronological age, bone age and height age. When evaluated according to pubertal status, a significant difference was found in IGF-I, leptin and IGFBP-3 levels between prepubertal and pubertal groups. Leptin levels were significantly different in the prepubertal CDGP group compared with controls but in the pubertal CDGP group only IGF-I levels were significantly different from controls. As the weight of children with CDGP was lower than in the control group, it is postulated that the reason for short stature and pubertal delay may be this decrease in weight which is also the cause of low levels of leptin and IGF-I.     

Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3 and insulin in obese children.

In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are diminished. However, this diminished GH secretion does not result in decreased somatic growth in obese children. Although the increased insulin level, low insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as being involved, the exact mechanism has not yet been established. We investigated serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39 non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I, free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not significantly different from those in the control group. A positive correlation was found between body mass index (BMI) and IGF-I in the obese children (r = 0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p < 0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p = 0.05) in the obese children. We concluded that normal growth in obese children might be maintained through normal IGF-I and increased IGFBP-3 levels, which are stimulated by increased insulin levels or nutritional factors or by increased responsiveness to GH.     

Serum zinc, insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels in children with type 1 diabetes mellitus

BACKGROUND: Growth is impaired during the course of diabetes mellitus (DM). Derangement of the growth hormone/insulin-like growth factor (IGF) axis, insulinopenia and zinc deficiency are the possible causative factors of this impairment. Zn supplementation is proven to attenuate hyperglycemia in mice but its use to ameliorate impaired height is still a matter of discussion. OBJECTIVE: To investigate serum Zn, IGF-I and IGF binding protein-3 (IGFBP-3) levels and to emphasize the potential beneficial effects of Zn supplementation for the prevention of growth failure in children with type 1 DM (DM1). Patients and Methods: Twenty-eight patients with DM1 and 15 control children were included in the study. Zn levels were measured by flame atomic absorption spectrophotometry; IGF-I and IGFBP-3 levels were measured by immunoradiometric assay. RESULTS: Mean serum Zn levels were significantly lower in diabetic children taken as a whole and as their pubertal subgroup compared to the controls. Mean serum IGF-I and IGFBP-3 levels were significantly lower in both prepubertal and pubertal diabetic groups compared to those of control groups. CONCLUSION: From the results of our study, it can be hypothesized that serum Zn levels should be closely monitored during the course of DM1 and supplementation may be given to patients, especially at the time of puberty. This hypothesis needs to be confirmed by further studies.     

Reduced levels of growth hormone, insulin-like growth factor-I and binding protein-3 in patients with shunted hydrocephalus

OBJECTIVE: Children with hydrocephalus are characterised by slow linear growth in prepuberty, accelerated physical maturation during puberty, and reduced final height. We aimed to study the possible roles of growth hormone, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) in this growth pattern. STUDY DESIGN: One hundred and fourteen patients with shunted hydrocephalus (62 males) aged 5 to 20 years, of whom 17 had spina bifida (six males), and 73 healthy controls (38 males) were studied. Anthropometric measures, body mass index, and body fat mass were assessed and the stage of puberty was determined. Serum growth hormone and plasma IGF-I and IGFBP-3 concentrations were measured. RESULTS: The patients comprised 44 (26 males) who were prepubertal and 70 (36 males) pubertal or postpubertal, while 32 of the controls (19 males) were prepubertal and 41 (19 males) pubertal or postpubertal. The prepubertal children with hydrocephalus had lower IGF-I (p = 0.002) and IGFBP-3 concentrations (p < 0.001) than the controls, and the pubertal children had four times lower basal growth hormone concentrations (p < 0.001). There was a correlation between height SD score and IGF-I levels in the total patient population (r = 0.23; p = 0.01). Peripheral IGF-I concentrations peaked at pubertal stages 2-3 in the female patients and at stage 4 in the controls. The prepubertal patients on antiepileptic treatment, carbamazepine in most cases (73%), had higher IGF-I (p = 0.01) and IGFBP-3 concentrations (p = 0.03) than those who had never been treated with antiepileptic drugs, but still lower IGFBP-3 levels than the controls (p = 0.01). CONCLUSION: Based on these findings, it can be concluded that reduced growth hormone secretion may contribute to the pattern of slow linear growth and reduced final height observed in these patients.     

宫内发育迟缓与胰岛素样生长因子及其结合蛋白关系研究

为了解脐血中胰岛素样生长因子_I(IGF -I)、胰岛素样生长因子结合蛋白_3(IGFBP_3)的水平变化与胎儿期生长的关系 ,将86例新生儿脐血标本分为宫内发育迟缓 (IUGR ,即小于胎龄儿 )组 (22例 )及适于胎龄儿 (AGA)组 (64例 )两组 ,采用竞争性放射免疫分析法 (RIA)测定IGF_1水平、非竞争性免疫放射分析法 (IRMA)测定IGF BP_3水平。结果显示 ,与AGA组相比 ,IUGR组脐血中IGF_1和IGFBP_3水平显著降低 (P均<0.01) ;IGF_1、IGFBP_3水平均随胎龄及出生体重增加而增加 (P均<0.01) ;IGFBP_3与IGF_1呈正相关 (P<0.01)。提示IUGR与IGF_1及其结合蛋白降低密切相关 ;脐血中IGF_1、IGFBP_3水平与胎龄及出生体重呈正相关     

Maternal insulin-like growth factor binding protein-1, body mass index, and fetal growth

AIM: To examine the hypothesis that the maternal insulin-like growth factor system may constrain fetal growth. METHODS: A prospective observational study of maternal serum insulin-like growth factor binding protein-1 (IGFBP-1) and fetal growth was undertaken in neonates with birthweights below the 5th centile. They had been classified either as having fetal growth restriction (FGR) due to placental dysfunction (increased umbilical artery Doppler pulsatility index (PI); n = 25) or as being small for gestational age (SGA; normal umbilical artery PI, growth velocity and amniotic fluid; n = 27). Eighty nine controls had normal birthweights (5th-95th centile), umbilical artery PI, growth velocity, and amniotic fluid. IGFBP-1 was measured by radioimmunoassay. RESULTS: Among the controls, there was no significant correlation between IGFBP-1 and birthweight after allowing for body mass index (BMI). Maternal BMI was high in FGR and after adjusting for this, IGFBP-1 was increased (109 ng/ml) compared with SGA babies (69 ng/ml) and controls (57 ng/ml) and correlated with the umbilical artery PI. CONCLUSIONS: Maternal IGFBP-1 is probably not part of normal placental function. Its increase in FGR could be the cause or consequence of impaired placental perfusion, but high IGFBP-1 concentrations might further reduce the availability of maternal IGF-I to the placenta. This could worsen placental function and so adversely affect fetal growth.     

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.     

Developmental pattern of fetal growth hormone,insulin-like growth factor I,growth hormone binding protein and insulin-like growth factor binding protein-3

AIMS—To evaluate the developmental pattern of fetal growth hormone (GH), insulin-like growth factor I (IGF-I), GH binding protein (GHBP) and IGF binding protein-3 (IGF-3); to determine the implications for fetal growth.
METHODS—Serum GH, IGF-I, GHBP and IGFBP-3 were measured in 53 fetuses, 41 aged 20-26 weeks (group A) and 12 aged 31-38 weeks (group B). Fetal blood samples were obtained by direct puncture of the umbilical vein in utero. Fetal blood samples were taken to rule out β thalassaemia, chromosome alterations, mother to fetus transmissible infections, and for maternal rhesus factor. GHBP was determined by gel filtration chromatography of serum incubated overnight with ¹²⁵I-GH. GH, IGF-I and IGFBP-3 were determined by radioimmunoassay.
RESULTS—Fetal serum GH concentrations in group A (median 29 µg/l, range 11-92) were significantly higher (P<0.01) than those of group B (median 16.7 µg/l, range 4.5-29). IGF-I in group A (median 20 µg/l, range 4.1-53.3) was significantly lower (P<0.01) than in group B (median 75.2 µg/l, range 27.8-122.3). Similarly, IGFBP-3 concentrations in group A (median 950 µg/l, range 580-1260) were significantly lower than those of group B (median 1920 µg/l, range 1070-1770). There was no significant difference between GHBP values in group A (median 8.6%, range 6.6-12.6) and group B (median 8.3%, range 6-14.3). Gestational age correlated positively with IGF-I concentrations (P<0.0001) and IGFBP-3 (P<0.0001) and negatively with GH (P<0.0001). GHBP values did not correlate with gestational age. Multiple regression analysis showed a negative correlation between GH:IGF-I ratio and fetal growth indices
CONCLUSIONS—The simultaneous evaluation of fetal GH, IGF-I, IGFBP-3 and GHBP suggests that the GH-IGF-I axis might already be functional in utero. The progressive improvement in the efficiency of this axis in the last part of gestation does not seem to be due to an increase in GH receptors.