Birth Weight Is Associated With the IGF-1 Response to GH in Children: Programming of the Anabolic Action of GH?

CONTEXT: Intrauterine programming of the somatotropic axis has been hypothesized in cases of intrauterine growth retardation. OBJECTIVE: The objective of the study was to study the effects of birth weight and body composition on GH sensitivity. DESIGN: This was a cross-sectional study with a single GH administration to assess GH sensitivity. SETTING: The study was conducted at the Department of Pediatric Endocrinology of an academic medical center. PATIENTS: One hundred normal short children aged from 4 to 17 years old (44 girls, 56 boys) separated into four groups: early childhood (aged 4-8 y, n = 14), late childhood (aged 9-12 y, pubertal stage 1, n = 30), early puberty (aged 10-15 y, stage 2, n = 32), and midpuberty (aged 12-17 y, stages 3 and 4, n = 24). INTERVENTION AND MAIN OUTCOME MEASURE: Serum IGF-1 at baseline and 24 hours after a single administration of GH (2 mg/m(2)) were measured. RESULTS: δIGF-1 significantly increased across the groups (P < .0001) with no gender difference, whereas the percentage of change in IGF-1 was similar (47% ± 32%). Independent predictors of δIGF-1 were birth weight SD score, fat percentage, fasting insulin (all positive predictors), and free fatty acids (negative predictor), with age, puberty, and baseline IGF-1 as adjusting variables (multiple R = 0.73, P < .0001). Independent predictors of the percentage of change in IGF-1 were birth weight SD score, fat percentage, and baseline IGF-1 (multiple R = 0.43, P < .001). CONCLUSION: This study suggests that in cases of low birth weight, intrauterine programming of GH sensitivity may be an adaptation to an expected poor postnatal nutritional environment, serving to restrict the anabolic action of GH. Conversely, postnatal excess energy stores may promote the anabolic action of GH.

[Mass spectrometry for steroid assays]. / Dosages des stéroïdes par spectrométrie de masse.

Steroid hormone measurement, first developed with radioimmunoassay, is now becoming easier with the use of automated platforms of immunoassay. However, some hormones remain uneasily detectable because of their low blood concentration, their structural homology or the presence of interferences. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can be considered as an alternative to immunoassays. This approach allows the simultaneous determination of several parameters thanks to its selectivity led by the detector mass spectrometer and the separate dimension of chromatography liquid. In addition, recourse to UHPLC (ultra high performance liquid chromatography) allows improving selectivity and sensitivity while limiting the samples volumes. The "ready-to-use" kits are now available and added to the "homemade" techniques developed by laboratories, thus giving opportunity for measurement of a wide steroid panel with only one sample. Finally, mass spectrometry methods, including a prior extraction step, allow the use of varied biological fluids (blood, urine, saliva…). Also, several clinical indications could gain from mass spectrometry, especially when hormone levels are low, when several steroids have to be identified, when the sample volume is low. However, this technology represents an important financial investment and in-depth staff training. In addition, some steroids are not easily quantifiable by mass spectrometry. It is likely by immunoassay and mass spectrometry, well-matched technologies, that we could answer the best to clinical questions about steroids.

High birth weight and early postnatal weight gain protect obese children and adolescents from truncal adiposity and insulin resistance: metabolically healthy but obese subjects?

OBJECTIVE: Low birth weight (LBW), no early catch-up weight, and subsequent fat accumulation have been associated with increased risks of insulin resistance from childhood onward and later cardiovascular disease. We sought to clarify the effects of high birth weight (HBW) and postnatal weight gain on insulin resistance. RESEARCH DESIGN AND METHODS: A total of 117 obese children aged 10.4 +/- 2.4 years were divided into three groups according to fetal growth after exclusion of maternal diabetes. They were comparable for age, sex, puberty, and percent body fat. Customized French birth weight standards, adjusted for maternal characteristics and gestation number, identified subjects with true altered fetal growth: 32 had increased fetal growth according to customized standards (HBWcust), 52 were eutrophic, and 33 had restricted fetal growth according to customized standards (LBWcust). Fat distribution by dual-energy X-ray absorptiometry, insulin sensitivity indexes from an oral glucose tolerance test (OGTT), and leptin, adiponectin, and visfatin levels were compared between groups. RESULTS: The HBWcust subjects had a higher adiponectin level, higher whole-body insulin sensitivity index (WBISI), and lower hepatic insulin resistance index, lower insulin and free fatty acid concentrations during OGTT, and lower trunk fat percent than eutrophic (P < 0.05) and LBWcust subjects (P < 0.05). Besides birth weight, weight gain between 0 and 2 years was a positive predictor (P < 0.05) of WBISI, whereas weight gain after 4 years was a negative predictor (P < 0.05). CONCLUSIONS: HBW and early weight gain may program insulin sensitivity and adipose tissue metabolism and contribute to so-called metabolically healthy obesity.

Reproducibility of blood tests of liver fibrosis in clinical practice.

OBJECTIVES: To evaluate the inter-laboratory reproducibility of blood test for liver fibrosis: FibroMeter, Fibrotest, APRI and their composites variables. DESIGN AND METHODS: Four studies, including 147 patients, were performed: study #1 included 2 metachronous blood samples and 2 laboratories; studies #2, #3 and #4 included synchronous samples with assays delayed at day 1 in 12 laboratories, at day 0 in 10 laboratories and at day 0 or 1 in 2 laboratories, respectively. Agreement was evaluated by the intraclass correlation coefficient (r(ic)). RESULTS: In studies #1, #2 and #4, r(ic) for FibroMeter was 0.893, 0.942 and 0.991, respectively. In study #3, the r(ic) were: FibroMeter: 0.963, Fibrotest: 0.984, APRI: 0.949. Large simulated variations in composite variables had a weak impact on FibroMeter. CONCLUSIONS: When blood marker limits are controlled, inter-laboratory agreement of blood tests is excellent in clinical practice conditions. Blood tests are robust against the variability of composite blood variables.

Low serum testosterone assayed by liquid chromatography-tandem mass spectrometry. Comparison with five immunoassay techniques.

BACKGROUND: Low levels of serum testosterone, as typically found in women and children, cannot be measured reliably by immunoassays. Our aim was to develop a sensitive assay to quantitate low serum testosterone concentrations using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results were compared to those obtained with various immunoassay techniques. METHODS: Serum testosterone levels in 70 women and children were measured using LC-MS/MS and compared with two automated, non-isotopic immunoassays, and three manual, isotopic immunoassays. Serum extraction was required only for LC-MS/MS and one of the isotopic methods. RESULTS: Deming regression analysis was used for comparison: the correlation coefficients were between 0.772 and 0.870, and the slopes between 0.972 and 1.365. Using Bland and Altman analysis, all the 5 immunoassays showed a positive mean difference compared with LC-MS/MS: all overestimated the testosterone levels in women and children. CONCLUSION: None of the immunoassays tested proved sufficiently reliable when low testosterone concentrations (< or =3.47 nmol/L) were measured. In contrast to conventional isotopic and non-isotopic immunoassay techniques, LC-MS/MS allows the precise determination of low testosterone levels. It has adequate sensitivity and is not subject to interference from other steroids that were tested.

Maternal and cord blood ghrelin in the pregnancies of smoking mothers: possible markers of nutrient availability for the fetus.

AIMS: To investigate the role of ghrelin in maternal and fetal metabolism, we determined its value in maternal smoking, a specific cause of reduced placenta function and fetal growth. METHODS: In 85 normal term pregnancies, 42 in smoking and 43 in non-smoking mothers, we measured ghrelin in the maternal blood at the onset of labor and in the cord blood of their 85 singletons immediately after birth. We determined the relationships between ghrelin and placental GH (PGH), pituitary GH (pitGH), and IGF-I. RESULTS: The newborns of smoking mothers weighed 0.24 kg less (p < 0.05) than those of non-smoking mothers. Cord blood ghrelin was 71% higher and PGH and cord blood IGF-I were 34% and 32% lower, respectively, in the pregnancies of smoking compared with non-smoking mothers (p < 0.05). Cord blood ghrelin was unrelated to pitGH and cord blood IGF-I. Maternal ghrelin was unchanged in smoking mothers, increased with maternal fasting duration (r = 0.26, p < 0.05), showed no correlation with PGH and negative correlation with cord blood IGF-I (r = -0.42, p < 0.01). CONCLUSION: The decrease in placental function and fetal growth in smoking mothers is associated with an increase in cord blood ghrelin, and no change in maternal ghrelin. Maternal ghrelin concentration increases with fasting, and is negatively correlated with cord blood IGF-I: it may signal a reduction in the level of nutrients available for placental transfer. No correlation supports a role for ghrelin in PGH or pitGH secretion.

Divergent effect of endogenous and exogenous sex steroids on the insulin-like growth factor I response to growth hormone in short normal adolescents.

The lower responsiveness to GH in women than in men is probably due to a divergent effect of gonadal steroids. It is unknown, however, how the progressive increase in sex steroid production that occurs during puberty affects this responsiveness. To compare the effects of puberty and sex steroid administration on responsiveness to GH, we used the IGF-I generation test, in which the peak IGF-I level 24 h after a single injection of GH (2 mg/m2) was studied in 117 healthy short subjects (56 females and 61 males). The subjects, aged 8-16 yr, were divided into four groups: prepuberty, early puberty, midpuberty, or pubertal delay. In the latter group, the IGF-I response was determined before and after priming with oral 17beta-estradiol in girls and im testosterone in boys. We also tested for an association between body composition (by dual energy x-ray absorptiometry) and the IGF-I response to GH. The IGF-I increment in response to GH (change in IGF-I from baseline) was correlated with the growth velocity sd score (P < 0.05). Progression throughout puberty was associated with an increase in both baseline IGF-I (P < 0.05) and the IGF-I increment in response to GH (P < 0.05), with no gender difference. Pubertal category (pre-, early, and midpuberty; P < 0.05) and fat percentage (P < 0.05) were the main positive predictors of the IGF-I increment in response to GH, expressed as micrograms per liter as well as sd score, independently of baseline IGF-I. After sex steroid priming, both the GH peak in response to insulin-induced hypoglycemia and baseline IGF-I were increased (P < 0.05, after vs. before sex steroid). However, the IGF-I increment in response to GH decreased after oral 17beta-estradiol (P < 0.05), whereas it was unchanged after testosterone administration. Endogenous gonadal steroid secretion appears to result in increased responsiveness to GH in peripubertal girls and boys. By contrast, exogenous estrogen and testosterone, respectively, produce a relative decrease and no change in responsiveness to GH in similar populations, possibly through the achievement of sex steroid concentrations exceeding physiological ranges for age. Fat percentage was a positive determinant of the responsiveness to GH, suggesting a link between the energy stores and the anabolic action of GH.

Defect in epinephrine production in children with craniopharyngioma: functional or organic origin?

Despite pituitary hormone replacement, patients with craniopharyngioma often complain of fatigue. They may have deficient control of catecholamine secretion caused by hypothalamic lesion. Another hypothesis is a functional defect in catecholamine production through either glucocorticoid deficiency because high intraadrenal glucocorticoid concentration is necessary for epinephrine synthesis or unrecognized hypoglycemia, which can intrinsically alter epinephrine secretion. We measured catecholamine response to insulin-induced hypoglycemia and orthostasis, and 24-h urinary catecholamine excretion, in 16 children with craniopharyngioma (patients) and 27 sex- and age-matched short children. We also studied the influence of a 4-fold increase in the usual daily dose of hydrocortisone on catecholamine excretion (50 vs. 12 mg/m(2) of body surface area) in the glucocorticoid-deficient patients. Last, we compared 24-h continuous sc glucose in patients and 10 sex- and age-matched healthy children. The results are expressed as medians (25th, 75th). For a similar blood glucose nadir after insulin administration, peak plasma epinephrine in response to hypoglycemia was lower in patients vs. controls [420 (120, 715) vs. 730 (460, 1200) ng/liter, P < 0.01], whereas peak plasma norepinephrine was higher [390 (280, 550) vs. 270 (180, 280) ng/liter, P < 0.05]. Catecholamine response to orthostasis did not differ between groups. Urinary epinephrine was significantly lower in patients (P < 0.001), whereas urinary norepinephrine was similar. The extent of epinephrine deficiency correlated with neither tumor size nor hypothalamic involvement. A 4-fold higher hydrocortisone dose did not correct the defective epinephrine excretion in the glucocorticoid-deficient patients. Last, the 24-h sc glucose values were similar between patients and controls. In conclusion, children with craniopharyngioma have a defect in epinephrine but not norepinephrine production. There is no proof of a univocal origin, either organic or functional. Whether abnormal catecholamine secretion alters glucose level during fasting or acute illness, or hampers adaptation to exercise, requires further studies.

Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children.

BACKGROUND: Commercially available testosterone immunoassays give divergent results, especially at the low concentrations seen in women. We compared immunoassays and a nonimmunochemical method that could quantify low testosterone concentrations. METHODS: We measured serum testosterone in 50 men, 55 women, and 11 children with use of eight nonisotopic immunoassays, two isotopic immunoassays, and isotope-dilution gas chromatography-mass spectrometry (ID/GC-MS). RESULTS: Compared with ID/GC-MS, 7 of the 10 immunoassays tested overestimated testosterone concentrations in samples from women; mean immunoassay results were 46% above those obtained by ID/GC-MS. The immunoassays underestimated testosterone concentrations in samples from men, giving mean results 12% below those obtained by ID/GC-MS. In women, at concentrations of 0.6-7.2 nmol/L, 3 of the 10 immunoassays gave positive mean differences >2.0 nmol/L (range, -0.7 to 3.3 nmol/L) compared with ID/GC-MS; in men at concentrations of 8.2-58 nmol/L, 3 of the 10 immunoassays tested gave mean differences >4.0 nmol/L (range, -4.8 to 2.6 nmol/L). CONCLUSION: None of the immunoassays tested was sufficiently reliable for the investigation of sera from children and women, in whom very low (0.17 nmol/L) and low (<1.7 nmol/L) testosterone concentrations are expected.