G. L. Spadoni

Immune function in growth hormone-deficient children treated with biosynthetic growth hormone

Several studies have shown conflicting data regarding the immune function in children suffering from growth hormone (GH) deficiency (1). Recently Rappaport et al. (2) reported changes in several immunological parameters during human G H (hGH) therapy in GH deficiency. On the other hand, Abbassi & Bellanti (3) did not find any immunological changes during the first year of treatment with hGH. The recent disturbing reports of deaths from Creutzfeldt-Jakob disease in patients treated with hGH have halted treatment with pituitary-derived h G H in many countries. Therefore, treatment with biosynthetically obtained GH preparation is currently the only treatment in GH-deficient children. Up to now no data are available regarding the effect of recombinant G H on the immune system. We have looked at the immune function of six patients with GH deficiency 6-11 years of age. Five of the patients had isolated G H deficiency, and one had multiple pituitary hormone deficiency. None of the patients had been on h G H therapy previously. Four of the patients were on treatment with biosynthetic GH for 6 months and two for 2 months. Recombinant hGH (Biotechnology General, Israel) was given at a dose of 0.1 U/kg subcutaneously three times weekly. We found that levels of B-lymphocytes, serum immunoglobulins, total TandT-lymphocyte subsets, and the proliferative response of lymphocytes to polyclonal mitogens (phytohemagglutinin, concanavalin A, pokeweed mitogen) were all in the normal range (Table 1).

Twelve-hour Spontaneous Nocturnal Growth Hormone Secretion in Growth Retarded Patients

Twelve-hour nocturnal GH secretion was studied in 30 children with familial short stature (FSS), constitutional growth delay (CGD), total growth hormone deficiency (TGHD), partial growth hormone deficiency (PGHD), or idiopathic short stature (ISS). No difference was observed between subjects with FSS and children wtih CGD. The mean 12-hour serum GH concentration was significantly lower in patients with TGHD (p < 0.001), children with PGHD (p < 0.01), and subjects with ISS (p < 0.01) than in subjects with FSS and CGD. No overlap was observed between the range of mean concentration values of children with TGHD and that of subjects with FSS. A significant correlation was found between growth velocity expressed as SD from the mean for bone age and GH concentration (p < 0.001). All patients with a growth velocity <3rd percentile for bone age showed a mean nocturnal concentration <4 ng/ml. These data suggest that evaluation of 12-hour spontaneous nocturnal GH secretion with GH sampling every 30 minutes can be usefully employed in the diagnosis of GH deficiency.

Transient pseudo-precocious puberty by probable oestrogen intake in 3 girls

We report the clinical and laboratory findings in 3 prepubertal girls with transient signs of sexual precocity. Accidental oestrogen intake from contaminated food was the most likely cause, the luteinsing hormone—releasing hormone test showing suppressed secretion of follicle-stimulating hormone and luteinsing hormone at the time of maximal oestrogenisation.

Catch-up growth in body mass index is associated neither with reduced insulin sensitivity nor with altered lipid profile in children born small for gestational age

Objective: Low birth weight is a risk factor for coronary heart disease. Persons who have coronary events as adults tend to have been small at birth and thin at 2 yr of age, after which they tended to increase their body mass index (BMI). Our aim was to determine whether BMI gain is associated to alterations in insulin sensitivity and/or lipid profile in children born small for gestational age (SGA). Design: Retrospective case-control study. Methods: We studied 78 children (mean age 7.8±2.5 yr): 26 SGA children with catch-up growth in BMI (CGB-SGA) (BMI= 10th to 75th centile), 26 SGA without catch-up growth (NCGB-SGA) (BMI<10th centile), and 26 appropriate for gestational age (AGA) control children (BMI: 10th to 75th centile). For each CGB-SGA child, we selected an NCGB-SGA and an AGA child of the same gender, age (with-in 1 yr), and pubertal status. SGA children were also subdivided into 2 groups according to post-natal catch-up growth in height (CGH). Results: Glucose was significantly lower in NCGBSGA than AGA group (p=0.02). No significant differences in fasting insulin, fasting glucose/insulin ratio, homeostasis model assessment, quantitative insulin-sensitivity check index, and lipid profile were found among the 3 groups. HDL-cholesterol proved significantly reduced in SGA children with post-natal CGH (p=0.02). Conclusions: Our findings do not support the hypothesis of early alterations in insulin sensitivity and lipid metabolism in CGB-SGA subjects during childhood provided that BMI remains within the normal range. Finally, the finding of reduced HDL-cholesterol levels in CGH-SGA children suggests detrimental metabolic effects of the height gain.

GH Assessment and Three Years’ hGH Therapy in Girls with Turner Syndrome

Fifteen girls with Turner syndrome (TS) were submitted to GH secretion assessment before undergoing hGH therapy. In the first 9 months, hGH was given at a dose of 0.5 IU/kg/week s.c. daily; afterward, the dose was increased to 1 IU/kg/week s.c. daily. The girls were prepubertal, with a mean (SD) chronological age (CA) of 12.5 (2.6) years, and a mean (SD) bone age of 10.5 (1.8) years. A clonidine stimulation test, 1-29 GHRH test and GH spontaneous nocturnal secretion assessment were performed in all patients. Results showed a variable pattern of GH secretion in 10 patients, in only 2 did we find all values definitely normal, and in 3 we found a total GH deficiency. Height velocity, expressed as standard deviation scores (SDS) for CA according to Turner references, during the first year of treatment increased significantly: 0.36 (1.15) -3.30 (2.87) (p < 0.001), and the increment remained quite unchanged during both the second and third years: 3.16 (2.96) and 2.55 (3.87), respectively (n.s.). Height, expressed in SDS for CA for Turner references, increased significantly throughout the whole period of treatment and reached the highest value at the end of the third year of therapy. GH secretion parameters poorly correlated with pretreatment auxological data or response to treatment. Our long-term study confirms that in TS GH measurement is not useful in indicating hGH therapy or in predicting the response.

Growth Hormone Secretion in Noonan's Syndrome

Growth hormone (GH) secretion was studied in eight children with Noonans syndrome: while GH response to pharmacologic stimulation was normal in all subjects, low spontaneous nocturnal GH secretion and/or low levels of IGF-1 were found in some patients. Two children received GH therapy for six months: a significative increase in height velocity was observed and no side effects were noted.

Growth hormone therapy does not alter the insulin-like growth factor-I/insulin-like growth factor binding protein-3 molar ratio in growth hormone-deficient children

Background: Recent studies have linked raised levels of IGF-I and/or reduced levels of its main binding protein, IGF binding protein (IGFBP)-3, with the risk of developing cancer. A GH dose-dependent increase in IGF-I/IGFBP-3 molar ratio has been reported in subjects treated with GH, raising concern about the long-term safety. Objective: The aim of this study was to evaluate changes in serum IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio over the first 12 months of replacement GH therapy in GH deficient (GHD) children. Methods: The study included 20 GHD children who had not previously received GH treatment, and 40 untreated non-GHD short children closely matched for age, gender, pubertal stage, and body mass index (BMI), as controls. Serum IGF-I, IGFBP-3 levels were measured before and after 12 months of GH treatment. Based on the molecular weight of IGF-I (7500) and IGFBP-3 (40,000, mean of glycosylated variants), we calculated the molar ratio of IGF-I/IGFBP-3. Results: IGF-I/IGFBP-3 molar ratio significantly increased during GH therapy (p=0.01). No significant difference in IGF-I/IGFBP-3 ratio was found between GHD children and controls at the different time points. In the multiple regression analysis, BMI (β=0.33) and age (β=0.33) proved to be the major predictors of the IGF-I/IGFBP-3 molar ratio (adjusted r2=0.53, p<0.0001). Conclusions: Our results suggest that at a conventional replacement dose GH does not alter the IGF-I/IGFBP-3 molar ratio. Potential fears related to long-term cancer risk are likely to be greatest in patients exposed to high-dose GH therapy and with genetic predisposition to high IGF-I and/or low IGFBP-3 concentrations.

Urinary Excretion of Pyridinium Crosslinks in Short Children Treated with Growth Hormone

The aim of this study was to evaluate the effect of growth hormone (GH) treatment on bone resorption in children with GH deficiency and those with idiopathic short stature. The study population included seven children with subnormal spontaneous GH secretion and 13 children with idiopathic short stature, all of them pre-pubertal. Anthropometric measurements, free, protein-bound and total urinary pyridinoline (Pyd) and deoxypyridinoline (Dpd), serum GH, and serum immunoreactive PTH were measured at baseline and months 1, 3, 6 and 12 of GH treatment. The urinary excretion of total Pyd and Dpd, standardized by the cube of height (m3) in overnight, 24-hour urine collections was not different from age-matched healthy controls at baseline in either group of patients. During treatment with human recombinant GH, both pyridinium crosslinks increased above normal values, reaching a peak after one month in children with GH deficiency and later (after 3-6 months) in children with short stature. Free and total crosslink forms were correlated, and GH treatment did not affect the proportion of free to bound crosslinks. Serum concentrations of iPTH showed a moderate but not statistically significant increase. This study provides no evidence of reduced bone resorption in untreated GH deficiency or in idiopathic short stature. GH treatment induced a marked, but temporary, increase of bone resorption in both groups of patients.

Preliminary validation of a prediction model for the short-term growth response to growth hormone therapy in children with idiopathic short stature

A discriminant scoring system, using multivariate analysis, has been developed for pretreatment prediction of responsiveness to a 6‐month trial of growth hormone (GH) treatment in short children with subnormal growth velocity, but without GH deficiency. Inclusion criteria included a birth weight above 2.5 kg, height below the 3rd centile for chronological age, height velocity below the 25th centile for bone age, no signs of puberty, a maximal GH response to pharmacological stimulation of above 10 μg/l and treatment with GH at a dose of 12–16 IU/m2/week. Children with an increase in height velocity greater than 2.5 cm/year after therapy were considered to be responders. Pretreatment clinical data from 67 patients were employed in a discriminant analysis in order to establish the model. The scoring system developed was as follows: score = ‐0.4 + 0.92X1– 0.87X2, where X1 is the height velocity SD score (SDS) for chronological age, and X2 is the bone age SDS for chronological age. This model had a specificity of 96.3% and a sensitivity of 92.5% in predicting the responsiveness to GH. The model has subsequently been applied to a group of 14 patients in order to establish its validity; in this group its sensitivity was 83.3% and its specificity 100%. These preliminary data suggest that the model can be used as a guideline for selecting short, slowly growing, non‐GH‐deficient children who will respond to short‐term GH therapy.

Differential ribosomal gene responsiveness to human growth hormone is visualized by selective silver staining

Differential activity of rRNA gene clusters following growth-hormone administration has been demonstrated in cultured lymphocytes from subjects with different genetic backgrounds, i.e., with or without in vivo peripheral responsiveness to the hormone. The influence of different culture conditions on ribosomal gene responsiveness was also tested. Ribosomal gene activity was evaluated by selective silver staining of nucleolus organizing regions. The results show that hormone-induced enhancement of transcriptional activity requires both genetically determined cell responsiveness and environmentally determined permissive factors.