S. Loche

Growth hormone response to oral clonidine test in normal and short children

We evaluated the growth hormone (GH) response to an acute Clonidine test (0.15 mg/m2 po) in 30 normal prepubertal children (stature between the 3rd and 97th centile), in 29 short children (stature <3rd centile for age) with height velocity (HV) >10th centile and in 20 short children with HV <10th centile. The three groups had comparable chronological ages. After clonidine administration mean peak GH levels were similar in the three groups (19.4±9.8, 17.7±8.8 and 14.6±8.9 μg/l, mean±SD, respectively). By chosing 10 μg/l as the limit for a normal response we found that stimulated GH levels had a sensitivity of 50% and a specificity of 83% in identifying children with suspected GHD (short children with subnormal HV). The diagnostic accuracy was almost superimposable, for cutoff values of 10 and 12 μg/l. Eight of the 10 children with subnormal HV and a GH peak <10 μg/l had a GH peak <10 μg/l also after a second stimulation test. Six of the 29 short children with normal HV had a GH peak <10 μg/l. Only one of them had a GH peak <10 μg/l after a second stimulation test. Five of the normal children had peak GH levels <10 μg/l. These results indicate that HV is a useful variable to predict the GH response to an acute GH stimulus, since the great majority of children with a normal growth rate had a normal GH response to at least one stimulation test.

rs9939609 in the FTO Gene is Associated with Obesity but not with Several Biochemical Parameters in Sardinian Obese Children

Several studies have reported an association of the intronic single nucleotide polymorphism (SNP) rs9939609 of the fat mass and obesity‐associated (FTO) gene with obesity and with a number of obesity‐related features. We studied the association of rs9939609 with obesity in 912 obese children and adolescents (426 males and 486 females, mean ± SD age 10.5 ± 3.3 years) and in 543 normal weight subjects. A number of biochemical and clinical parameters was also evaluated in 700 of these patients. In the obese group, mean body mass index standard deviation score (BMI‐SDS) was similar between the three genotypes. The A allele was present in 55% of the patients’ and in 43% of controls’ chromosomes. The distribution of heterozygotes was similar between patients and controls (47%), while the distribution of AA homozygotes was significantly higher in patients (31% vs. 20%). Logistic regression analysis on the genotypes yielded a χ2 of 35.5 with an odds ratio of 1.6 (CI = 1.3–1.8), P < 1 × 10−5. None of the clinical and metabolic parameters tested was associated with the genotype. In conclusion, we have confirmed the strong association between FTO and obesity, and shown that only AA homozygotes are predisposed to develop obesity while TT homozygotes might be protected. Finally, we found no association between rs9939609 and a number of obesity‐related abnormalities.

The growth hormone response to hexarelin in patients with Prader-Willi syndrome

Hexarelin (Hex) is a synthetic hexapeptide with potent GH-releasing activity in both animals and men. Aim of this study was to evaluate the GH response to a maximal dose of Hex and GH-releasing hormone (GHRH) in a group of patients with Prader-Willi syndrome (PWS). Seven patients (4 boys and 3 girls, age 2.4–14.2 yr) with PWS, 10 prepubertal obese children (7 boys and 3 girls, age 7.5–12.0 yr), and 24 prepubertal short normal children (11 boys and 13 girls, age 5.9–13 yr) with body weight within ± 10% of their ideal weight were studied. All subjects were tested on two occasions with GHRH 1–29 at the dose of 1 µg/Kg iv, and with Hex at the dose of 2 µg/Kg iv. In the PWS patients the GH response to GHRH (peak=6.4±2.0 µg/l, p<0.0001; AUC=248±70 µg min/l, p<0.0001) was significantly lower than that observed in the short normal children and similar to that observed in the obese children. In the PWS children the GH response to Hex (peak=7.5±1.6 µg/l; AUC=309±53) was similar to that observed after GHRH and significantly lower than that observed in the obese children (p<0.05). The results of this study show that PWS patients have a blunted GH response to the administration of a maximal dose of Hex. Whether these findings reflect a more severe pituitary GH deficiency in PWS than in obese children or a deranged hypothalamic regulation of GH secretion need further investigation.

Growth hormone treatment in non-growth hormone-deficient short children

The unlimited availability of GH obtained by recombinant DNA technology has allowed optimization of treatment in GH-deficient (GHD) children. At the same time it has prompted a number of studiesin conditions not characterized by GHD such as Turner syndrome, intrauterine growth retardation, chronic renal failure and other chromosomal and genetic abnormalities associated with short stature. Several controlled and uncontrolled studies have now reported the adult height of patients with short stature and normal GH secretion. Critical reviewing of the data shows that some short non-GHD children may benefit from a prolonged treatment with GH. However, further studies are needed in order to be able to identify the subjects for whom treatment is really beneficial.

Correlation between cortisol and components of the metabolic syndrome in obese children and adolescents

BackgroundIn obese subjects it has been shown that cortisol (F) contributes to the reduction in insulin sensitivity, suggesting a role in the development of the metabolic syndrome (MS).AimThe aim of this retrospective study was to evaluate the relationship between F and components of MS in 1,027 obese children and adolescents.Subjects and methodsWaist circumference, systolic and diastolic blood pressure (SP, DP), F, serum glucose (Glyc), cholesterol HDL, triglycerides and homeostatic model assessment (HOMA index) were evaluated in all subjects. MS was defined according to the International Diabetes Federation criteria. Accordingly, patients were subdivided into three age groups: 6–10, 10–16 and >16xa0years.ResultsIn univariate regression analysis, F was correlated with Glyc, SP and HOMA in groups 1 and 2, with DP in Group 2. In multivariate regression analysis including age, sex, puberty, BMI-SDS and F as independent variables and one of the component of the MS as the dependent variable, F was a weak predictor of the variability when DP and Glyc were introduced as dependent variables in Group 2 and when SP was introduced as dependent variable both in groups 1 and 2. When patients were subdivided into subgroups according to the IDF criteria, in Group 2 patients with one or more components of the MS had higher F concentrations.ConclusionsIn this cohort of obese children and adolescents, F was weakly associated with components of the MS. These findings do not support a major role for F in the development of MS.

Exogenous growth hormone administration does not inhibit the growth hormone response to hexarelin in normal men

Administration of exogenus human growth hormone (GH) blunts the GH response to physiological as well as pharmacological stimuli, including GH-releasing hormone (GHRH). Hexarelin (Hex) is a new synthetic GH-releasing peptide (GHRP) similar to GHRP-6 with potent GH-releasing activity in animals and men. To determine whether the short-term administration of GH inhibits the Hex-induced GH release, we measured the GH response to Hex (2 μg/kg iv) in five normal adult males (age 26–32 yr) three h after an iv bolus of rhGH (2 IU) or saline. Mean incremental change of serum GH from value at time 0 was 47.5±5.5 and 41.5±4.1 μg/l after saline+Hex and GH+Hex, respectively. Mean incremental area under the curve over baseline was 3216±586 and 3735±506 μg.min.1 after saline+Hex and GH+Hex, respectively. One of the proposed mechanism of action of GHRPs is to serve as functional somatostatin (SRIH) antagonists, and it is known that GH feeds backs on the hypothalamus to stimulate SRIH release. Therefore, we speculate that antagonisms of SRIH function by Hex prevented the inhibitory effect of exogenous GH, thus lending further support to the hypotheses that SRIH is involved in the feedback regulation of GH secretion, and that GHRPs action involves inhibition of SRIH function.

Turner syndrome mosaicism: an unusual case with a de novo large dicentric marker chromosome: mos 45,X/46,X, ter rea(X;X)(p22.3;p22.3)

X/X translocations are quite rare in humans. The effect of this anomaly on the phenotype is variable and depends on the amount of deleted material and whether the chromosomes are joined by their long or short arms. We report an unusual case of Turner syndrome mosaicism in a 16-year-old girl, who was referred to our Institute for primary amenorrhoea associated with short stature. Endocrine evaluation revealed hypergonadotropic hypogonadism, which required a study of the karyotype. Cytogenetic analysis, performed on peripheral blood leucocytes, showed a mos 45,X/46,X,ter rea (X;X)(p22.3;p22.3) de novo karyotype. The prevalent cell line was 45,X (90% cells). A second cell line (10% cells) showed a very large marker chromosome, similar to a large metacentric chromosome. FISH (fluorescent in situ hybridisation) and molecular analysis revealed that the marker chromosome was dicentric and totally derived from the paternal X chromosome.

Growth hormone response to physical exercise in growing patients with classic congenital adrenal hyperplasia

Glucocorticoid over-treatment in children with congenital adrenal hyperplasia (CAH) may suppress GH secretion and growth. Aims of our study were: 1) to evaluate post-exercise GH response in patients affected by CAH due to 21 -hydroxylase deficiency, in comparison with a group of healthy subjects; 2) to investigate the relationship between the hormonal markers of adequate steroid therapy and GH secretion. We evaluated GH secretion every 6 months in 20 young CAH patients (8 girls, 12 boys). Mean follow-up was 4.6±0.9 yr (107 tests performed, 5.35±2.05 repeated tests for each patient). Forty-four healthy subjects (25 boys, 19 girls) were selected as a control group. The range of post-exercise GH peak was very wide, but medians were not statistically different in cases and controls (p=0.570). Multivariate analysis showed that post-exercise GH peak was not related to age (p=0.743), gender (p=0.296) or pubertal status (p=0.440) in both groups. GH increase from baseline showed the same behavior (p=0.265, 0.639 and 0.105, respectively). In CAH patients, GH peak and GH increase were both directly related to 17-OH-progesterone levels [GH peak: p=0.032–95% confidence interval (CI): 0.01–0.34 — ²=0.18; GH increase: p=0.008–95% CI: 0.06–0.35 - β=0.20]. The negative effect of glucocorticoid therapy on GH secretion seems to be dominant in CAH. The most effective approach to adjust treatment remains monitoring growth. Relying on hormonal markers to adequate steroid therapy may result in over-treatment, GH suppression. and finally poor linear growth.