Study of insulin-like growth factor I in human obesity.

In obesity there is a decrease in basal and stimulated GH secretion. IGF-I, which has negative feedback effects on GH secretion, could be the initial mediator of such alterations. We studied IGF-I levels in obese subjects and their relationship to the obesity level and GH secretion. We determined plasma IGF-I, basal and stimulated GH in 30 normal and 30 obese women and related these variables to obesity indices (body mass index, BMI, and % overweight). Baseline plasma GH values were 1.2 +/- 0.3 and 2.3 +/- 0.6 micrograms/l in obese subjects and controls, respectively (NS). Mean peak GH secretion after stimuli were 11.2 +/- 1.4 and 34.4 +/- 5.6 micrograms/l in obese subjects and controls, respectively (p less than 0.001). Plasma IGF-I were 1.0 +/- 0.1 U/ml and 0.7 +/- 0.1 U/l in obese subjects and controls, respectively (NS). There was a significant negative correlation between plasma IGF-I and age (r = -0.55, p less than 0.001) and a significant negative correlation between mean peak GH secretion and weight (r = -0.60, p less than 0.001), BMI (r = -0.64, p less than 0.001) and percentage of ideal body weight (r = -0.67, p less than 0.001). We did not find any correlation between IGF-I and indices of overweight. These data suggest that the reduced GH secretion found in obesity is not related to a negative feedback inhibition by elevated levels of IGF-I and that adiposity is not associated with a decline in IGF-I levels. We confirm the existence of a negative correlation between GH secretion and obesity indices.     

Adult height in patients treated for isolated growth hormone deficiency: role of birth weight

To evaluate the effect of growth hormone (GH) administration on adult height (AH) in two groups of isolated GH-deficient (IGHD) children born either small (birth weight below -2 SD) or appropriate (birth weight above -2 SD) for gestational age (GA). Out of 35 prepubertal IGHD children, 14 small for GA (SGA, group A) and 21 appropriate for GA (AGA, group B) were examined. All patients received continuous GH treatment at a median dose of 0.028 mg/kg/day (range 0.023-0.032) in group A and 0.024 (range 0.023-0.028) in group B. GH treatment was administered for a period of 67.0 months (range 42.37-96.05) in group A and 54.31 months (range 47.14-69.31) in group B. All children were measured using a Harpenden stadiometer every 6 months until they reached AH (growth velocity <1 cm/year). The patients underwent a retesting a few months after stopping GH therapy. A significant difference was found between group A and B as expected for birth weight SD, -2.70 (range -2.87 to -2.29) and -0.73 (range -1.30 to 0.14) respectively (p < 0.000001) and interestingly also for body mass index SDS (BMI SDS) at retesting, 0.08 (range 0.30 to -1.51) and 0.61 (range 0.73 to -1.10) respectively (p < 0.04). We observed no significant differences between groups A and B in height (expressed as the SDS for chronological age, height SDS) at diagnosis (p = 0.75), height SDS at start of puberty (p = 0.51), height SDS at retesting (p = 0.50), target height SDS (TH SDS) (p = 0.47), AH SDS (p = 0.92), corrected height SDS (height SDS - TH SDS) (p = 0.60), BMI SDS at diagnosis (p = 0.25), GH dosage (p = 0.34) and therapy duration (p = 0.52). GH treatment with a standard dose in short IGHD children leads to a normalization of AH without any significant difference between SGA and AGA patients.     

Relationship of testicular growth and size to age, body weight and onset of puberty in Menz ram lambs

Scrotal circumference as an index of testes size, along with body weight, wither height, heart girth and body condition score were measured fortnightly for 114 Menz ram lambs from weaning (91+/-7 SD days) until puberty, which was defined as age at first collection of an ejaculate with 50 x 10(6) spermatozoa and 10% motility. The animals were maintained on poor (n=28), low (n=29), medium (n=29) or high (n=28) levels of nutrition through grazing and supplementation. Further, half the lambs in each group were drenched for endoparasites. Daily gains in live weight, wither height, heart girth and scrotal circumference were 48.5+/-1.6 g, 0.05+/-0.01 cm, 0.07+/-0.01 cm and 0.07+/-0.03 cm, respectively for the period from weaning to puberty and varied with level of nutrition (P<0.05 to 0.001) but not with drenching or its interaction with nutrition level (P>0.10). Scrotal circumference increased linearly and was strongly correlated with age, body weight, wither height, and heart girth (r = 0.83 to 0.85, P<0.001), and lamb weight could be predicted by the equation: 6.35 + 0.53 scrotal circumference (R(2) = 0.73). Mean age, body weight and condition score at puberty were 288+/-6 days, 19.3+/-0.4 kg and 2.6+/-0.06, respectively, and varied due to season of birth, level of nutrition and weaning weight (P<0.01 to 0.001). The nutrition level also influenced (P<0.001) scrotal circumference at puberty, averaging 21.5+/-0.3 cm. It was concluded that postweaning nutrition management had a strong influence on lamb weight gain, which in turn was related to testicular growth and puberty onset in Menz ram lambs. The suitability of scrotal size measurement as a criterion for early selection of tropical ram lambs is emphasised.     

Effect of parental anthropometric parameters on neonatal birth weight and birth length

Data on 550 healthy pregnant women, 550 healthy fathers and their healthy term neonates born from singleton pregnancies (37(+0) through 41(+6) week) during a one-year period were reviewed. Maternal mean age was 27.7 +/- 9.37 years, mean pregestational weight 64.0 +/- 9.50 kg, mean gestational weight gain 15.4 +/- 4.33 kg, mean height 169.7 +/- 5.81 cm, and mean gestational age 40.1 +/- 0.95 weeks. Paternal mean age was 31.4 +/- 6.22 years, mean weight 84.6 +/- 10.35 kg, and mean height 182.8 +/- 6.84 cm. Mean birth weight was 3,709.8 +/- 500.48 g and 3,562.5 +/- 443.02 g, and mean birth length 51.5 +/- 1.91 cm and 50.7 +/- 1.62 cm in male and female newborns, respectively, yielding a birth weight greater by 147.3 g and birth length by 0.8 cm in the former. Study variables showed statistically significant correlations: maternal age contributed to the significant correlation between maternal weight and parity, maternal pregestational weight, weight at delivery, gestational weight gain and body height correlated significantly with neonatal birth weight and birth length, gestational age correlated significantly with neonatal weight and length (p = 0.01 all), parity had no major impact (p > 0.05). Paternal height and weight correlated significantly with neonatal birth weight and birth length (p = 0.01). Study results pointed to a significant correlation of maternal pregestational weight, gestational weight gain and body height, and of paternal weight and height with the neonate birth weight and birth length.     

Final height data, body composition and glucose metabolism in growth hormone-treated short children born small for gestational age

Low birth weight has been associated with impaired insulin sensitivity, type 2 diabetes mellitus, hypertension and cardiovascular disease in later life. GH therapy is known to increase fasting and postprandial insulin levels. For this reason concern has been expressed regarding the possible detrimental effects of GH therapy in children born small for gestational age (SGA). To assess the effects of GH therapy on body composition, carbohydrate metabolism and final height in short SGA children, 165 prepubertal short children born SGA were enrolled in either a multicentre, double-blind, randomized, dose-response GH trial (n = 75) or in a GH controlled trial (n = 90). The inclusion criteria were: (1) birth length standard deviation score (SDS) below -2; (2) age 3-8 years; (3) height SDS below -2. The children's mean (SD) age was 7.3 (2.1) years (GH dose-response trial) and 6.0 (1.5) years (GH controlled trial), birth length SDS was -3.6 and height SDS was -3.0 (0.7). In the GH dose-response trial, children were randomly assigned to either 1 mg GH/m(2) per day (group A, n = 41) or 2 mg GH/m(2) per day (group B, n = 38) ( approximately 0.033 or 0.067 mg/kg per day, respectively). In the GH controlled trial, children were randomly assigned to 1 mg GH/m(2) per day (n = 60) or served as controls (n = 30). Subjects underwent standard oral glucose tolerance tests and measurement of body mass index, systolic and diastolic blood pressure and serum lipids at baseline and after 1 and 6 years of GH therapy and again 6 months after discontinuation of GH. Body composition was measured by dual energy x-ray absorptiometry at baseline and again after 3 years in the GH controlled trial. Mean (SD) final height SDS was not significantly different between the two GH dosage groups: -1.2 (0.7) in group A and -0.8 (0.7) in group B. At the start of GH therapy, 8% of children had impaired glucose tolerance (IGT). Systolic blood pressure was significantly higher in comparison with healthy peers. GH therapy induced considerably higher fasting and glucose-stimulated insulin levels after 1 and 6 years, regardless of GH dosage. After 6 years, 4% of children had IGT. Six months after discontinuation of GH, glucose levels remained normal, whereas fasting and glucose-stimulated insulin returned to levels comparable to those of healthy peers. None of the children developed diabetes. During 6 years of GH therapy both systolic and diastolic blood pressure decreased significantly and remained so after discontinuation of GH therapy. At baseline all children had reduced bone mineral content and lean body mass. Fat mass was not significantly lower than normal. Treatment with 1 mg GH/m(2) per day resulted in a significant increase in (and normalization of) bone mineral content and lean body mass in comparison with untreated short SGA controls. Fat mass decreased during the first year of GH but returned to values comparable to those at baseline in the following 2 years of GH therapy. We found that long-term, continuous GH therapy in short children born SGA leads to a normalization of height during childhood and to a normal final height in most children, regardless of GH dosage. Only very short or relatively older children may need a dosage of 2 mg GH/m(2) per day. Long-term GH therapy had no adverse effects on glucose levels and serum lipids and had a positive effect on blood pressure, even with GH dosages of up to 2 mg/m(2) per day. However, as has been reported in other patient groups, GH induced higher fasting and glucose-stimulated insulin levels, indicating insulin resistance. After discontinuation of GH serum insulin levels returned to normal age-reference levels. Short SGA children have a reduction in bone mineral content and lean body mass when compared with healthy controls, which significantly improved (normalized) with GH therapy at a dose of 1 mg/m(2) per day.     

Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome

OBJECTIVE: Classical growth hormone insensitivity syndrome (GHIS) comprises a dysmorphic phenotype, extreme short stature (height SDS < 3), normal GH and low IGF-I and IGFBP-3. Wide clinical variation is recognised with classical and atypical forms. We aimed to delineate features of the milder "atypical" GHIS phenotype, and to determine whether this correlates with milder auxological and biochemical features. METHODS: Fifty-nine patients from a European series of 82 patients with GHIS, with strict diagnostic criteria of GHIS, were studied and assigned to classical or atypical GHIS groups according to facial phenotype, i.e. "classical" required 2 of 3 recognized GHIS features (frontal bossing, mid-facial hypoplasia and depressed nasal bridge), "atypical" required 0 or 1 of these facial features. Classical and atypical GHIS groups were compared in terms of (1) phenotypic features, including high-pitched voice, sparse hair, blue sclera, hypoglycaemia, microphallus, (2) birth length, height SDS, and (3) basal IGF-I, IGF-II, IGFBP-1, IGFBP-3, GHBP and increase in IGF-I on IGF-I generation testing. RESULTS: Fifty patients [24 males, 26 females, aged 8.6 +/- 4.6 years (mean +/- SD)] had "classical GHIS", 9 patients (7 males, 2 females, aged 7.8 +/- 4.1 years) had "atypical GHIS", 7 with normal facies. Atypical GHIS patients had lesser height deficit (Ht SDS -4.0 +/- 1.4) compared to classical GHIS (-6.7 +/- 1.4), less reduction in IGFBP-3 SDS (atypical -5.5 +/- 3.3; classical -8.6 +/- 2.4), and more had normal GHBP (>10% binding). Other variables were also less frequent in atypical GHIS patients: high-pitched voice 11% (70% classical), sparse hair 11% (42% classical), blue sclera 0% (38% classical), hypoglycaemia 11% (42% classical), and microphallus 14% (1 of 7 males), compared to 79% of classical (19 of 24 males). CONCLUSIONS: Atypical GHIS patients, with relatively normal facial appearance, demonstrate less height defect and biochemical abnormalities compared to classical patients. GH insensitivity may be present in children with short stature and an otherwise normal appearance.     

Effect of low birth weight on adrenal steroids and carbohydrate metabolism in early adulthood

AIM: Data are inconsistent whether hyperinsulinemia might be associated with adrenal hyperandrogenism in young adults born with low birth weight (LBW). METHOD: We investigated the insulin and adrenal steroid production of 70 young LBW adults [33 women (birth weight: 1,795 +/- 435 g) and 37 men (birth weight: 1,832 +/- 337 g)]. Their results were compared to those of 30 controls (14 men, 16 women), born with normal weight. RESULTS: In LBW women, we measured higher basal DHEA (33.5 +/- 13.1 vs. 23.6 +/- 8.7 nmol/l, p < 0.05), DHEAS (8.0 +/- 2.3 vs. 6.3 +/- 2.1 micromol/l, p < 0.05), androstenedione (8.3 +/- 2.8 vs. 6.0 +/- 2.2 nmol/l, p < 0.05) and cortisol (0.25 +/- 0.07 vs. 0.20 +/- 0.07 micromol/l, p < 0.05) levels and higher insulin response during oral glucose tolerance test (log.AUCins: 2.62 +/- 0.06 vs. 2.57 +/- 0.03, p < 0.05). DHEA levels correlated with fasting insulin levels (r = 0.45, p < 0.01) and insulin response (r = 0.33, p < 0.05). In LBW men, higher cortisol (0.27 +/- 0.06 vs. 0.22 +/- 0.06 micromol/l, p < 0.01) and SHBG (18.4 +/- 10.4 vs. 12.7 +/- 5.9 nmol/l, p < 0.05) levels were found. CONCLUSIONS: Our results suggest that modest hypercortisolism is present in young LBW adults. While the endocrine sequel of hypercortisolism raised insulin response and hyperandrogenism is detectable in apparently healthy young LBW women, it is absent in young LBW men. This suggests that gender-dependent mechanisms might play a role in the development of insulin resistance in LBW adults.     

Differential effects of hGH and IGF-I on body proportions

The differential growth effects of hGH and IGF-I on the upper/lower (U/L) body segment in relation to height (Ht) were analyzed in 15 patients with isolated Growth hormone deficiency (IGHD,:7M, 8F) mean age 5.0 +/- 3.2 (SD) years treated with hGH; 21 patients with multiple pituitary hormone deficiency including growth hormone (MPHD: 14M, 7F) aged 10.0 +/- 3.8, treated with hGH; 9 patients with Laron Syndrome (LS) (4M,5F) aged 6.9 +/- 5.6 years treated with IGF-I; 9 boys with intrauterine growth retardation (IUGR) aged 6.3 +/- 1.25 years treated by hGH; and 22 boys with idiopathic short stature (ISS) aged 8.0 +/- 1.55 years treated by hGH. The dose of hGH was 33 microg/kg/day, that of IGF-I 180-200 microg/kg/day. RESULTS: the U/L body segment ratio in IGHD patients decreased from 2.3 +/- 0.7 to 1.1 +/- 0.7 (p <0.001), and the Ht SDS increased from -4.9 +/- 1.3 to 2.3 +/- 1 (p < 0.001) following treatment. In MPHD patients the U/L body segment decreased from 1.1 +/- 1.1 to -0.6 +/- 1.0 (p < 0.001), and the Ht SDS increased from -3.3 +/- 1.4 to -2.5 +/- 1.0 (p < 0.009). In the LS group the U/L body segment ratio did not change with IGF-I treatment but Ht improved from -6.1 +/- 1.3 to -4.6 +/- 1.2 (p < 0.001), The differential growth response of the children with IUGR and with ISS resembled that of the children with LS. CONCLUSIONS: hGH and IGF-I act differentially on the spine and limbs.     

Long-term treatment of growth hormone insensitivity syndrome with IGF-I. Results of the European Multicentre Study. The Working Group on Growth Hormone Insensitivity Syndromes.

A total of 33 patients (17 female, 16 male) with Laron syndrome (n = 31) or hGH-1 gene (n = 2, type IA deletion) from 22 centres in 12 countries were enrolled in a study conducted by Pharmacia & Upjohn, Stockholm, which was designed to test the efficacy, in terms of growth promotion and safety, of IGF-I (Igef(TM)). The patients were treated with 40-120 microg/kg IGF-I s.c. twice daily after meals. After the study ended, the patients continued to be treated on an individual basis. The results of 17 patients, who were treated for 48 months or longer were available for the present analysis. Six patients were treated for up to 72 months. When treatment started, the mean age of these patients (8 female, 9 male) was 9.1 (3.7-13.5) years and mean height was -6.5 +/- 1.3 SDS. At the end of the observation period, the mean age of the 17 patients was 14.2 (9.1-17. 7) years and mean height was -4.9 +/- 1.9 SDS. All patients showed a significant increase in growth during the final year on IGF-I, with two of them reaching the age-corresponding 3rd centile. The total gain in height (DeltaHT) was 1.7 +/- 1.2 SDS. DeltaHT SDS correlated negatively with age at onset of treatment (R(2) = -0.78, p < 0.02). BMI was 0.6 +/- 1.8 SDS at start of treatment and 1.8 +/- 1.5 SDS at the end of observation. Total DeltaHT SDS correlated positively with total DeltaBMI SDS (R(2) = 0.59, p < 0.01). Long-term treatment of patients with GHIS thus proved to be effective in promoting growth. If treatment is started at an early age, there is considerable potential for achieving height normalisation. The treatment modalities need to be optimized with respect to the growth-promoting and metabolic effects of IFG-I.     

Auxological and endocrine evolution of 28 children with Prader-Willi syndrome: effect of GH therapy in 14 children

We report on the auxological and endocrine evolution of 28 patients presenting with Prader-Willi syndrome. Half of them received growth hormone (GH) therapy (group 2). The spontaneous auxological evolution was analyzed in the two groups from 2 to 8 years; the mean SDS for height remained stable (-0.6 +/- 0.6) in group 1 and decreased (from -2.0 +/- 0.9 to -2.7 +/- 0.6) in group 2. Magnetic resonance imaging showed marked pituitary hypoplasia in the two groups. In group 2, the mean GH peak after two provocative tests was 3.8 +/- 2.4 microg/l, the mean SDS values for insulin-like growth factor I levels were -2.0 +/- 1.5 (range from -0.5 to -5.0). The mean duration of GH treatment was 3.6 +/- 2.9 (range 1-9.3) years. 14 children completed 1 year of treatment. The two groups had opposite evolutions in Delta SDS for height (-0.8 +/- 0.8 vs. +1.1 +/- 0.8), for growth velocity (-1.9 +/- 2.2 vs. +2.9 +/- 2.7), and for Z score of the body mass index (+0.37 +/- 1.3 vs. -0.14 +/- 0.76; group 1 vs. group 2). This retrospective study shows that, in children with Prader-Willi syndrome and true GH deficiency, long-term GH therapy is effective in increasing growth velocity and in maintaining body mass index.     

Chronicled report on the period from May 1 to September 27, 1989. Discussion of risk factors]

The Institute of Mother and Child was invited in 1988 by professor J. Nauman to his Chernobyl program, so as to inspect children born after Chernobyl accident, particularly these born in first days following the accident dated 26 april 1986. The central part of Poland is covered with screening for congenital PKU and hypothyroidism therefore all children had estimated TSH-spot levels between 3rd and 5th day of life. So as to control the present state of general health and thyroid state in the study group a questionnaire with a letter to parents explaining the aim of the inquiry was sent to the parents (see addenda). About 14000 letters were send from which around 12000 responses were returned to the Institute. From informations received this way we draw the preliminary conclusion that no significant damage in health of these children or their siblings can be found. About 20% of the mothers admitted taking the Lugol solution in a last day of pregnancy. However it should be taken into account that these data were collected 2 years after the accident and are not fully reliable. In the period 1989-1990 a group of 1912 children (938 boys and 974 girls) was called to the Department of Endocrinology of the Institute and inspected. The age was from 2.9 to 4.2 years. All children had screening TSH-spot test result negative (below 30 microIU/ml). General health state The general health state of the children inspected was good. Only 33 of them (1.7%) had various congenital malformations what is not different from general population of polish children. Mental development was in 1897 cases normal, in 15 cases IQ was decreased and the score varied from 75 to 80 according the Brunet-Lezine scale. Average physical development was normal. Body height evaluated in standard deviation score (SDS) was as follows: SDS = 0.0 in 359; SDS = +0.9 +/- 0.6 in 906 and SDS = -0.5 +/- 0.3 in 647 cases. Thyroid state At 1904 inspected and analytically estimated children the thyroid function was normal. Only in 8 cases (0.8%) a goiter was found with euthyroid state. Analytical data were as follows: total T4 serum level = 111.8 + 43.1 nmol/l (50.4-171.9), ref. value: 50.1-170.0 nmol/l; total T3 serum level = 2.5 +/- 0.4 nmol/l (ref. value 1.9-3.6); TSH serum level 4.4 +/- 2.6 uIU/ml. Trace amounts of antithyroid membrane antibodies were found at 12 children (0.63%) of the group in serum diluted 1:250.(ABSTRACT TRUNCATED AT 400 WORDS)     

Efficacy and safety of long-term continuous growth hormone treatment of children born small for gestational age

Twelve years of growth hormone (GH) therapy of short children born small for gestational age (SGA) have demonstrated that GH is an effective and well-tolerated therapy. Most children will reach a normal adult height (AH). AH of 55 SGA adolescents was comparable for those treated with a GH dose of 1 or 2 mg/m2 (approximately 0.033 or 0.066 mg/kg) per day, mean (SD) AH SDS being -1.2 (0.7) and -0.8 (0.7), respectively. GH therapy had no influence on the age at onset, the progression of puberty, duration of puberty and pubertal height gain. GH therapy induced higher fasting and glucose-stimulated insulin levels after 1 and 6 years, but 6 months after GH stop, all levels returned to normal. At baseline mean systolic blood pressure was significantly increased, but both systolic and diastolic blood pressure decreased significantly during 6 years of GH and remained so after GH stop. GH therapy demonstrated a beneficial effect on serum lipid profiles, body composition, bone mineral density and head growth. Treatment with 2 mg GH/m2 per day induced mean serum IGF-I levels of +2 SDS, whereas IGF-I levels remained within the normal range with 1 mg GH/m2 per day. In conclusion, long-term GH therapy of short SGA children with 1 mg/m2 per day appears to be effective and safe. Since the future consequences of high serum IGF-I levels during long-term GH therapy with 2 mg/m2 per day are as yet unknown, it seems safer to treat short prepubertal SGA children with a GH dose of 1 mg/m2 per day when children are to be treated continuously for many years.     

Dynamic changes of orexin A and leptin in obese children during body weight reduction

In this study, we describe changes of plasma levels of the hypothalamic neuropeptide orexin A in obese children during the reduction of body weight and its relationship to other biochemical and anthropometrical parameters. We measured orexin A fasting plasma levels by the RIA method in 58 obese children--33 girls and 25 boys; mean age 13.1+/-0.38 years (range 7-18.5) before and after 5 weeks of weight-reduction therapy. Leptin, IGF-1, and IGFBP-3 levels were measured in all the subjects and were compared to orexin A levels and anthropometrical data. Average weight in subjects before weight-reduction was 74.2+/-2.79 kg and after weight-loss 67.4+/-2.60 kg (p<0.0001). Orexin A levels before the therapy were 33.3+/-1.97 pg/ml and after the therapy 51.7+/-3.07 pg/ml (p<0.0001). Levels of orexin A were not significantly different between girls and boys (p=0.7842). We found negative correlation between orexin A and age (r = -0.5395; p<0.0001), body height (r = -0.4751; p=0.0002), body weight (r = -0.4030; p=0.0017) and BMI (r = -0.2607; p=0.0481). No correlation was found between orexin A and IGF-1, IGFBP-3 or leptin. Orexin A plasma levels increased during body weight loss, whereas the reverse was true for leptin levels. These findings support the hypothesis that orexin A may be involved in regulation of nutritional status in children.     

Insulin-like growth factor-1, leptin, body composition, and clinical status interactions in children with cystic fibrosis

BACKGROUND/AIMS: Children with cystic fibrosis (CF) are of increased risk of reduced fat body mass (FBM) and lean body mass (LBM). Serum concentrations of insulin-like growth factor-1 (IGF-1)and leptin could be markers of LBM and/or FBM depletion. To evaluate the relationships between disease activity, body composition, IGF-1 and leptin concentrations in CF children. METHODS: A cross-sectional study with 26 CF children aged 5.0-15.5 years and 33 healthy controls, mean age 9.4 years. Body composition was evaluated by dual-energy X-ray absorptiometry. Fasting blood samples were analyzed for leptin, IGF-1 and IGFBP-3. RESULTS: FBM standard deviation score (SDS; CF boys -0.02 +/- 0.88 vs. 0.78 +/- 0.65, p < 0.01; CF girls -0.37 +/- 1.15 vs. 0.70 +/- 0.97, p < 0.05), leptin concentration (CF boys 2.07 +/- 0.79 vs. 3.07 +/- 1.28 ng/ml, p < 0.05; CF girls 2.71 +/- 0.86 vs. 5.00 +/- 2.95 ng/ml, p < 0.05) and IGF-1SDS (CF boys -1.43 +/- 1.50 vs. -0.32 +/- 0.88, p < 0.05; CF girls -0.66 +/- 1.66 vs. 0.64 +/- 0.57, p < 0.01) were lower in CF children compared to controls. Shwachman score was the strongest predictor of lean body mass (R = 0.63). Leptin levels explain 60% of the variability in FBM. CONCLUSION: Serum concentrations of IGF-1 and leptin are decreased in children with CF and are associated with clinical conditions and body composition.     

IGF-I and IGF binding protein-3 levels during initial GH dosage step-up are indicators of GH sensitivity in GH-deficient children and short children born small for gestational age

BACKGROUND: A stepwise increment of the GH dose is an approach aimed at avoiding adverse events. We investigated GH sensitivity by studying IGF-I and IGFBP-3 concentrations during the initial phase of GH treatment. METHODS: Our investigation was part of the regular follow-up of prepubertal children with GH deficiency (GHD) (n = 31) and small for gestational age (SGA) (n = 23). Dosage was increased in three steps: one-third at the start, two-thirds after 14 days, and the full dose after 28 days (full dose: GHD = 28 microg/kg body weight (BW)/day; SGA = 60 microg/kg BW/day). Blood samples were taken on days 0, 14 and 28, as well as in conjunction with anthropometrical examinations after 3, 6 and 12 months. IGF-I and IGFBP-3 were measured by means of published in-house RIAs and age-related references were used to calculate standard deviation scores (SDS). Height velocity (cm/year) and Delta HT SDS were taken as growth response parameters. RESULTS: Before GH treatment (GHD vs. SGA; median and p values): age (years) (6.6 vs. 6.0; n.s.), HT SDS (-2.6 vs. -3.2; p < 0.05); GH amount after stepping up (mug/kg BW/day) (28 vs. 60; p < 0.01); BW SDS (-0.5 vs. -2.9; p < 0.01); max. GH stimulated (microg/l) (5.6 vs. 10.8; p < 0.01); IGF-I SDS (-3.5 vs. -1.8; p < 0.01); IGFBP-3 SDS (-2.0 vs. 0.8; p < 0.01). After 1 year of GH therapy: HT velocity (cm/year) (9.8 vs. 9.6; n.s.), Delta HT SDS (0.9 vs. 0.9; n.s.); WT velocity (kg/year) (3.3 vs. 3.5; n.s.). Our results show that changes in growth similar to GHD could be induced in SGA by a dosage that was twice as high as the replacement dose given in GHD. GH dose and HT velocity did not correlate in both groups. IGF-I and IGFBP-3 increased as follows in GHD and SGA during stepping up of the dosage (ng/ml, GHD vs. SGA): at start, 54 vs. 89; at day 14, 78 vs. 132; at day 28, 90 vs. 167; at 3 months, 118 vs. 218. There was the same relationship between dose levels and absolute IGF-I concentrations in both groups. In terms of IGF-I SDS, the dose-response curve in SGA showed a shift to the right in comparison to GHD, thus indicating lower sensitivity to GH. The dynamics of IGF-I and IGFBP-3 differed, as IGFBP-3 peaked earlier (on day 28). In GHD, IGF-I SDS at 3 months was -0.7 vs. +0.9 in SGA. Near-identical levels were found for Delta IGF-I SDS and IGFBP-3 SDS above basal levels for each time-point investigated. First year HT velocity in GHD correlated negatively with basal IGF-I SDS (R(2) = 0.33; p <0.001) and basal IGFBP-3 (R(2) = 0.17; p <0.05) but did not correlate with the IGF-I increment during the 0- to 3-month period. Conversely, first year HT velocity correlated (+) in SGA with the IGF SDS increment during the 0- to 3-month period (R(2) = 0.26; p = <0.05). Height velocity in SGA, however, correlated neither with basal IGF-I and IGFBP-3 nor with the 0- to 3-month increments of IGFBP-3 SDS. CONCLUSIONS: IGFs increase during initial GH therapy, thus raising questions about short-term IGF generation tests. (I) In terms of IGF generation, substantially lower sensitivity to GH was observable in SGA. (II) Higher GH sensitivity during first year catch-up growth is associated with GHD, but in SGA it is attributable to increases in IGF. A wider range of GH dosages needs to be explored in order to gain further insight into the relationship between GH dose, IGF levels, and growth. Monitoring IGFs is a practical means for exploring GH sensitivity during dosage stepping up.     

Endocrine markers of semistarvation in healthy lean men in a multistressor environment.

We tested the hypothesis that key endocrine responses to semistarvation would be attenuated by changing only the food intake in a multistressor environment that also included sustained workload, inadequate sleep, and thermal strain. Serum hormones were compared within and between two groups of healthy young male volunteers participating in the 8-wk US Army Ranger course, with four repeated cycles of restricted energy intakes and refeeding: group 1 (n = 49) and group 2 (n = 48); energy deficits averaged 1,200 and 1,000 kcal/day, respectively. After 8 wk, most of group 1 achieved a minimum body fat, serum 3,5,3'-triiodothyronine (T(3)) was below normal (78 +/- 20 ng/dl), testosterone (T) approached castrate levels (4.5 +/- 3.9 nmol/l), insulin-like growth factor I (IGF-I) declined by one-half (75 +/- 25 microg/l), and cholesterol rose from 158 +/- 31 to 217 +/- 39 mg/dl. Bioavailable T(3) and T were further reduced by increases in their specific binding proteins in response to declining insulin. Refeeding, even with continuation of the other stressors, produced prompt recovery of T(3), T, and IGF-I. Higher energy intakes in group 2 attenuated the subclinical hypothyroidism and hypercholesterolemia, whereas consistent luteinizing hormone suppression indicated centrally mediated threshold effects on gonadal hormone suppression. We conclude that low T, T(3), and IGF-I remained reliable markers of acute energy deficits in the presence of other stressors; elevated cholesterol and cortisol provided information about chronic status, corresponding to diminishing body fat stores.     

Physiological growth hormone secretion in children with short stature and intra-uterine growth retardation

31 prepubertal children with short stature [mean height standard deviation score (SDS) -2.84] and low birth weight (mean -2.82 SDS) were studied. Mean age was 6.0 years and mean height velocity SDS was -0.76. Patients were classified as having either the clinical characteristics of Russell-Silver syndrome (RSS) (4 F, 13 M) or not (4 F, 10 M). All children had an overnight profile of spontaneous growth hormone (GH) secretion. 4 children achieved a maximum GH concentration of less than 20 mU/l. 9 children with RSS secreted only one large GH peak during the night. Most of the non-RSS group had normal GH pulse frequency but 3 boys had a fast-frequency pattern. Abnormal GH secretion may contribute towards growth failure in children with low birth weight/RSS.     

Plasma levels of insulin-like binding protein-2 in prepubertal short children and its diagnostic value in the evaluation of growth hormone deficiency

AIM: This study was designed to investigate whether determination of plasma insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) levels could be of benefit in the evaluation of childhood growth hormone (GH) deficiency (GHD). METHOD: A retrospective analysis was performed on 91 prepubertal children referred for investigation of short stature. Maximal GH levels in plasma after provocative stimuli were between 1.0 and 93.0 mU/l, 6 subjects exhibiting peak values of <5 mU/l. Initially a GH peak of 20 mU/l was used as a cutoff limit to define GHD and idiopathic short stature (ISS) patients. The results of GH provocative tests were compared to age- and gender-based standard deviation scores (SDS) of plasma IGFBP-2, IGF-I, IGFBP-3 and the molar ratios of the latter two to IGFBP-2. The respective normative range values for these parameters were determined in plasma samples from 353 healthy children (i.e. 171 girls, 182 boys). RESULTS: Circulating IGFBP-2 levels did not correlate with height SDS, height velocity SDS or the peak GH levels after provocative stimuli. A weak negative relationship was found between IGFBP-2 and IGF-I. Plasma levels of IGFBP-2 in GHD patients were higher than those of ISS children, who had normal levels. Although at the optimal cutoff point of -0.71 SDS 91.5% of the GHD patients were identified correctly, a substantial proportion (71.9%) of the ISS subjects also had IGFBP-2 levels above this limit. The use of various combinations of IGFBP-2, IGF-I, IGFBP-3 and the derived ratios only slightly improved the diagnostic efficiency as compared to the results of the individual tests. Neither IGFBP-2 nor the IGFBP-3/IGFBP-2 and IGF-I/IGFBP-2 ratios were found to be related to the short- (1 year) or long-term (3 years) growth response to GH therapy. CONCLUSION: It is concluded that none of the tests investigated, either alone or in various combinations, are reliable in either predicting the peak GH level after provocative stimuli in prepubertal short children or in predicting their growth response to GH.     

Food intake of children with short stature born small for gestational age before and during a randomized GH trial

Parents of short children born SGA often report that their children have a serious lack of appetite and a low food intake. In this study we investigated food intake, by using a standardized 7-day food questionnaire, in 88 short SGA children before start of GH treatment. The intake was compared with the recommended daily intake (RDI) of age-matched children. We also compared the food intake of GH-treated children (n=62) with randomized controls (n=26) after 1 year of GH treatment. In addition, we evaluated the effect of food intake and GH treatment on body composition and serum levels of IGF-I, IGFBP-3 and leptin. Our study shows that caloric intake, fat and carbohydrate intake of short SGA children aged 5.9 (1.6) years was significantly lower compared to the RDI for age-matched children. One year of GH treatment resulted in a significant increase of caloric, fat, carbohydrate and protein intake compared to baseline. Compared to randomized controls, caloric, carbohydrate and protein intake increased significantly after 1 year of GH treatment. Short SGA children had significantly lower SDS scores for LBM, fat mass, skinfold (SF) and BMI compared to age-matched references. They also had significantly lower serum IGF-I, IGFBP-3 and leptin levels. GH treatment resulted in a significant increase of height, LBM, BMI, IGF-I and IGFBP-3 SDS and a significant decrease of SF SDS and leptin SDS. In conclusion, our study shows that short SGA children have indeed a lower food intake than age-matched controls. During GH treatment the food intake increased significantly compared to baseline in contrast to the randomized control group.     

Leptin concentrations in cord blood in normal newborn infants and offspring of diabetic mothers.

Leptin has been implicated in the regulation of body weight and energy balance; Leptin is produced by adipocytes and placental tissue. Chronic fetal hyperinsulinemia and accelerated fetal growth with increased amounts of body fat are frequent findings in the offspring of diabetic mothers. In this study, we examined whether leptin levels in cord blood of infants of type 1 diabetic mothers (n = 29), gestational diabetic mothers (n = 6 and controls (n = 96) correlated with level of maternal glucose control, maternal leptin level at delivery, gender, fetal and placental size, and C-peptide in cord blood at birth. Leptin was significantly elevated in infants of type 1 diabetic (24.7 ng/ml) and gestational diabetic mothers (29.3 ng/ml) as compared to controls (7.9 ng/ml). C-peptide was also significantly higher in infants of type 1 diabetic (0.91 nmol/l) and gestational diabetic mothers (0.99 nmol/l) vs controls (0.34 nmol/l). Infants of type 1 diabetic mothers with a leptin level in cord blood above the upper normal range, i.e. > 30 ng/ml (n = 13), had an average maternal HbA1c level of 5.4% (normal < 5.5%) that was not different from 5.2% in infants with a leptin level < 30 ng/ml (n = 15). In both neonatal groups of diabetic mothers, leptin in cord blood did not correlate with maternal leptin concentrations, placental weight, birthweight, gender and cord blood C-peptide. In controls, leptin in cord blood was higher in girls than in boys (p = 0.044) and correlated significantly with birthweight (p = 0.41, p < 0.001) and cord blood C-peptide (p = 0.44, p < 0.001) but not with maternal leptin level or placental weight. The 3-4 times higher leptin levels in the offspring of diabetic mothers than normal could reflect increased adipose tissue mass and/or increased contribution from other sources such as placental tissue.