We have evaluated the effect of acute administration of atenolol, a selective β-adrenergic antagonist, on the GH response to GHRH in nine obese children and in eight age-matched controls. The GH response to GHRH (1–29, 1 μg/kg iv), evaluated both as the GH peak and as integrated area under the curve, was significantly lower in the obese children than in the controls. Pretreatment with atenolol (50 or 100mg orally in subjects with body weight <or >40 kg, respectively, administered 120 min before the GHRH injection) significantly increased the GH response to GHRH in the obese subjects, such that their mean peak GH levels and mean integrated area under the curve after atenolol plus GHRH were similar to those of the control children after GHRH. Also in control children, atenolol caused a significant augmentation of the GH response to GHRH. Mean peak GH levels and mean integrated area under the curve after atenolol plus GHRH were significantly higher in the controls than in the obese children given the same treatment. These data show that inhibition of central β-adrenergic receptors counteracts the blunted GH response to GHRH present in the obese children. In view of the alleged mechanism of action of β-adrenergic blockade (inhibition of endogenous SRIH release), our data suggest that the somatostatinergic system is intact in obesity, and that the suppressed GH secretion is due to other causes.
Sandro Loche, Stefano Pintus, Daniela Carta, Anna Carla Muntoni, Gabriella Congiu, Patrizia Civolani and Carlo Pintor
Mohamad Maghnie, Maria Cristina Pennati, Elisa Civardi, Natascia Di Iorgi, Gianluca Aimaretti, Maria Loreta Foschini, Ginevra Corneli, Carmine Tinelli, Ezio Ghigo, Renata Lorini and Sandro Loche
Objectives: Evaluation of GH response to ghrelin in patients with GH deficiency (GHD) may help to elucidate the site and mechanism of action of ghrelin. We aimed to investigate the GH-releasing effect of ghrelin in children and young adults with childhood-onset GHD.
Design: All subjects underwent ghrelin testing and neuro-imaging examination. Magnetic resonance imaging evidenced the presence of a vascular pituitary stalk (VPS) or its complete absence (PSA).
Patients and methods: Seventeen prepubertal children and nine adult patients with childhood-onset GHD were selected for the study. The children were enrolled at a median age of 5.8 years. The adult subjects were included at a median age of 23.3 years. The diagnosis of GHD in the adult patients had been established at a median age of 8.5 years. Ghrelin was administered at a dose of 1 μg/kg body weight, i.v. at time zero, and blood for GH determination was obtained at 0, 15, 30, 45, 60, 75, 90, 105 and 120 min.
Results: Median GH response after ghrelin was similar between children and adults. Median peak GH response to ghrelin (7.45 μg/l, IQR: 3.9–11.3 μg/l) was significantly higher in patients with VPS (10.9 μg/l, IQR: 2.4–15.1 μg/l) than in those with PSA (IQR: 2.3–6.7 μg/l; P = 0.001). It was significantly higher in subjects with isolated GHD (12.5 μg/l, IQR: 10.8–15.5 μg/l) than in those with multiple pituitary hormone deficiencies (5.15 μg/l, IQR: 2.4–9.0 μg/l; P = 0.003). No correlation was found between the GH peak after ghrelin and body mass index.
Conclusion: The GH response to ghrelin in patients with congenital hypopituitarism depends on the degree of the anatomical abnormalities and lends further support to the assumption that the main action of the peptide is exerted at the hypothalamic level and requires the integrity of hypothalamic–pituitary connections.
Chiara Guzzetti, Anastasia Ibba, Sabrina Pilia, Nadia Beltrami, Natascia Di Iorgi, Alessandra Rollo, Nadia Fratangeli, Giorgio Radetti, Stefano Zucchini, Mohamad Maghnie, Marco Cappa and Sandro Loche
The diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents.
Retrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests.
Seventy four patients with organic GHD (GH peak <10μg/L after two provocative tests) and 298 control subjects (GH response >10μg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS.
The optimal GH cut-off for arginine resulted 6.5μg/L, 5.1μg/L for ITT and 6.8μg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC=0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity.
The results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.
Lucia Ghizzoni, Marco Cappa, Alessandra Vottero, Graziamaria Ubertini, Daniela Carta, Natascia Di Iorgi, Valentina Gasco, Maddalena Marchesi, Vera Raggi, Anastasia Ibba, Flavia Napoli, Arianna Massimi, Mohamad Maghnie, Sandro Loche and Ottavia Porzio
Premature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP.
Patients and methods
A total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects.
Baseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values <2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was <18.2 μg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations.
In children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.