Alejandra Avila

Ponderal gain, waist‐to‐hip ratio, and pubertal development in girls with type‐1 diabetes mellitus

Abstract:  Objectives:  We assessed pubertal development, height, weight, and waist‐to‐hip ratio (WHR), an index of central adiposity during puberty, in girls with type‐1 diabetes mellitus (T1DM), compared to a contemporary control group.

Frequency of Familial Hyperaldosteronism Type 1 in a Hypertensive Pediatric Population: Clinical and Biochemical Presentation

Familial hyperaldosteronism type 1 is an autosomal dominant disorder attributed to a chimeric CYP11B1/CYP11B2 gene (CG). Its prevalence and manifestation in the pediatric population has not been established. We aimed to investigate the prevalence of familial hyperaldosteronism type 1 in Chilean hypertensive children and to describe their clinical and biochemical characteristics. We studied 130 untreated hypertensive children (4 to 16 years old). Blood samples for measuring plasma potassium, serum aldosterone, plasma renin activity, aldosterone/renin ratio, and DNA were collected. The detection of CG was performed using long-extension PCR. We found 4 (3.08%) of 130 children with CG who belonged to 4 unrelated families. The 4 patients with CG had very high aldosterone/renin ratio (49 to 242). In addition, we found 4 children and 5 adults who were affected among 21 first-degree relatives. Of the 8 affected children, 6 presented severe hypertension, 1 presented prehypertension, and 1 presented normotension. High serum aldosterone levels (>17.7 ng/dL) were detected in 6 of 8 subjects (range: 18.6 to 48.4 ng/dL) and suppressed plasma renin activity (⩽0.5 ng/mL per hour) and high aldosterone/renin ratio (>10) in 8 of 8 children (range: 49 to 242). Hypokalemia was observed in only 1 of 8 children. We demonstrated that the prevalence of familial hyperaldosteronism type 1 in a pediatric hypertensive pediatric population was surprisingly high. We found a high variability in the clinical and biochemical characteristics of the affected patients, which suggests that familial hyperaldosteronism type 1 is a heterogeneous disease with a wide spectrum of presentations even within the same family group.

Insulin gene VNTR genotype is associated with insulin sensitivity and secretion in infancy.

aims  We have previously demonstrated that insulin sensitivity and secretion at age 1 year was in part related to variation in weight and height gain during infancy. In order to determine whether genetic variation at the insulin gene could also influence these associations, we have studied the relationship between insulin gene variable number of tandem repeat (INS VNTR) genotypes, insulin secretion and early postnatal growth.

Effects of Prenatal Ethanol Exposure on Postnatal Growth and the Insulin-Like Growth Factor Axis

Aims: To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation. Methods: We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≧48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age. Results: IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects. Conclusion: Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.

Aldosterone, Plasma Renin Activity, and Aldosterone/Renin Ratio in a Normotensive Healthy Pediatric Population

Primary aldosteronism is an important cause of secondary hypertension and is suspected in adults with an aldosterone/renin ratio ≥25. The normal aldosterone/renin ratio is unknown in children. The aim was to establish serum aldosterone, plasma renin activity, and aldosterone/renin ratio values in a healthy pediatric population. A cross-sectional study was performed in 211 healthy normotensive children (4 to 16 years old). Two subgroups of normotensive children were obtained: with hypertensive parents (NH) (n=113) and normotensive parents (n=98). Blood samples for measuring serum aldosterone, plasma renin activity, aldosterone/renin ratio, and DNA were collected. In subjects with aldosterone/renin ratio ≥25, the chimeric CYP11B1/CYP11B2 gene was investigated by long-extension PCR. Results are expressed as median [Q1–Q3]. NH and normotensive parents groups were similar in serum aldosterone (6.5 [3.6 to 9.0] ng/dL versus 6.5 [2.9 to 9.7] ng/dL; P=0.968) and plasma renin activity (2.3 [1.6 to 3.1] versus 2.4 [1.7 to 3.7] ng/mL per hour; P=0.129). The aldosterone/renin ratio was higher in the NH group, but this difference did not reach statistical significance (2.8 [1.9 to 4.1] versus 2.5 [1.4 to 4.0], P=0.104). In one subject of the NH group, the chimeric CYP11B1/CYP11B2 gene was detected. We demonstrated that normal aldosterone/renin ratio values in a healthy pediatric population without NH were lower than those reported for an adult normotensive population.

Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone–insulin‐like growth factor I axis in growth hormone–deficient children

Ibutamoren mesylate (MK‐0677), an orally active nonpeptide growth hormone (GH) secretagogue, stimulates GH release through a pituitary and hypothalamic receptor that is different from the GH–releasing hormone receptor. We evaluated the safety and tolerability and the GH–insulin‐like growth factor (IGF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children (15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 ± 0.8 years (mean ± SD), bone age of 7.4 ± 0.7 years, growth velocity <10th percentile for age, height <10th percentile for age, and a maximum GH response of ≤10 μg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1–7 or 8–14) and matching placebo for the alternate 7 days (groups I and II, respectively) or 0.8 mg/kg per day for 7 days (days 8–14, group III). On day 15 all patients received an 0.8‐mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose before advancement to the high dose. Hormonal profiles were evaluated on day −1 (baseline) and day 15, and the results were expressed as the change from baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 μg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 μg · h/L (range, 1.3 to 35.6) for the GH area under the concentration‐time curve from time zero to 8 hours (AUC0–8) (P < .001), 12 μg/L (range, −4 to 116) for serum IGF‐I (P = .01), and 0.4 μg/L (range, −0.9 to 1.5) for serum IGF‐binding protein 3 (IGFBP‐3) (P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24‐hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short‐term administration of ibutamoren mesylate can increase GH, IGF‐I, and IGFBP‐3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.

Relationship between Nocturnal Growth Hormone Concentrations, Serum IGF-I/IGFBP-3 Levels, Insulin Sensitivity and GH Receptor Allelic Variant in Small for Gestational Age Children

Growth hormone may help to increase final height in patients with short stature, but its efficacy is variable. It has been recently reported that the isoform of the GH receptor (GHR) that lacks exon 3 (d3-GHR) is associated with a greater growth response to GH therapy. We hypothesized that nocturnal growth hormone concentrations, basal IGF-I and IGFBP-3 levels, and insulin sensitivity might show variations among individuals depending on their GHR allelic variant. To test this hypothesis, we studied 38 prepubertal LBW children with nocturnal GH concentrations, IGF-I and IGFBP-3 levels and insulin sensitivity during OGTT and Insulin test. The GHR allelic variant was analyzed through multiplex PCR analysis in DNA from peripheral leukocytes. Characteristics of the overnight GH secretion [(mean GH: 6.8 ± 0.6 vs. 6.2 ± 0.5 ng/ml), (AUC: 3,227 ± 280 vs. 2,908 ± 212 ng/ml·min), (peak number: 4.4 ± 0.3 vs. 4.4 ± 0.2), (amplitude: 12 ± 1.1 vs. 10.8 ± 1.1 ng/ml)] did not differ between groups (f1/f1 vs. f1/d3 plus d3/d3). In addition, we did not observe any significant differences in serum IGF-I SDS (–0.49 ± 0.26 vs. –0.40 ± 0.35) or IGFBP-3 SDS (–1.21 ± 0.24 vs. –0.89 ± 0.21) nor in insulin sensitivity (WIBSI: 12 ± 1.2 vs. 10.8 ± 1.1) in LBW children with full length GHR compared to children carrying at least one GHRd3 allele. The distribution of the f1/f1 allelic variant and fi/d3 or d3/d3 was similar in the LBW children with or without catch-up growth. These results suggest that the GHR allelic variant does not play a significant role in the regulation of GH-IGF-I/BP3 axis or in insulin sensitivity in prepubertal LBW children.

Treatment of Central Precocious Puberty with Triptorelin 11.25 mg Depot Formulation

A new triptorelin 11.25 mg long depot formulation is now available for the treatment of central precocious puberty (CPP). The aim of our study was to evaluate the efficacy of triptorelin 11.25 mg administered every 90 days to suppress gonadotropin and sex steroid secretion and pubertal signs in children with CPP during 2 years of treatment. Inclusion criteria were clinical pubertal development before the age of 8 years in girls or 9 years in boys, advanced bone age and a pubertal LH response (peak >5 mIU/ml) to GnRH. We studied 20 patients (19 girls and 1 boy), with a median age at entry into the study of 7.5 +/- 0.2 years for girls, and 9 years for the boy. The basal and GnRH-stimulated serum levels of LH and FSH decreased significantly from baseline to 3 months of therapy (p <0.0001). All patients had a GnRH-stimulated peak below 3 mIU/ml between 6 and 24 months of treatment. The pituitary-gonadal axis recovered adequately after discontinuation of therapy. These results suggest that 3-month depot triptorelin is a satisfactory alternative for the therapy of children with CPP. The longer interval between injections may increase acceptability and compliance with treatment.

Comparison of leptin levels, body composition and insulin sensitivity and secretion by OGTT in healthy, early pubertal girls born at either appropriate‐ or small‐for‐gestational age

Background  Small for gestational age (SGA) has been associated with decreased insulin sensitivity (IS). A possible mechanism is the postnatal development of a metabolically disadvantageous body composition (BC).

Changes in appetite and body weight in response to long-term oral administration of the ghrelin agonist GHRP-2 in growth hormone deficient children.

GHRP-2 (GPA-748, Wyeth-Ayerst) is an orally active peptide growth hormone (GH) secretagogue which acts through a G-protein coupled receptor for which the natural ligand--an acylated 28 amino acid peptide, ghrelin--was recently isolated. Ghrelin and its analogs have potent GH-releasing activities, but in animal studies ghrelin also causes weight gain. As part of a study examining the effect of GHRP-2 on GH secretory dynamics and growth, we evaluated its effects on appetite and body weight. Ten prepubertal children with GH deficiency (growth velocity < or = 4 cm/year in association with a GH response to two provocative stimuli < 10 ng/ml) were included in the study. At the beginning of the study their age was 10.4 +/- 2 years (mean +/- SD), with a height of -3.8 +/- 0.1 SDS. Body mass index (BMI) was 17.9 +/- 3.6 kg/m2, and the BMI Z score 0.21 +/- 1.51 SDS. GHRP-2 was administered orally at a dose of 900 microg/kg b.i.d. for 12 months. Seven out of ten patients reported a significant increase in appetite during the first 6 months of the study. There was a tendency for the BMI SDS to increase during the study, but this increase did not reach statistical significance (0.21 +/- 1.5 vs 0.25 +/- 1.5 SDS). These results suggest that at a dose of 900 microg/kg b.i.d., GHRP-2 appears to have a transient stimulatory effect on appetite, but does not have a chronic clinically significant effect on BMI in children with GH deficiency.