Gian Luigi Spadoni

Height velocity and IGF‐I assessment in the diagnosis of childhood onset GH insufficiency: do we still need a second GH stimulation test?

objective The diagnosis of GH insufficiency (GHI) in childhood is not straightforward. Our aim was to test the sensitivity and specificity of height velocity (HV), IGF‐I, IGFBP‐3 and GH stimulation tests alone or in combination in the diagnosis of GHI.

Hormone-modulated rRNA gene activity is visualized by selective staining of the NOs

The role of Growth Hormone and Dexamethasone in the regulation of rRNA gene activity was evaluated on cultured human fibroblasts by the cyto-chemical method of selective silver staining. By this method the transcriptionally active r-gene clusters can be specifically visualized in individual cells. Statistically significant increases in the rate of rRNA transcriptional activity were demonstrated after hormone administration.

Prediction of the outcome of growth hormone therapy in children with idiopathic short stature: A multivariate discriminant analyis

OBJECTIVE To identify, with the use of pretreatment clinical data, the children with idiopathic short stature responsive to treatment with growth hormone (GH). DESIGN Open, prospective study in a university hospital. SUBJECTS Patients admitted to the study met the following criteria: birth weight at least 2.5 kg, no sign of dysmorphic disease, stature less than the 3rd percentile for chronologic age (CA), linear growth velocity (GV) less than the 25th percentile for bone age (BA), no sign of puberty, maximal GH response to pharmacologic stimulation greater than 10 micrograms/L, no evidence of organic disease, treatment with daily subcutaneous administration of GH at a dose of 12 to 16 IU/m2 per week. MAIN OUTCOME MEASURES Eight pretreatment growth variables and the increase of GV after 6 months of therapy were measured. Children with a change in GV that was greater than 2.5 cm/yr after 6 months of GH therapy were considered responders to GH. RESULTS We studied 67 patients (44 boys). Forty patients (60%) were responders. With univariate analysis the variables found to have predictive value were GV (z score for gender and CA), bone age (z score for gender and CA), and percentage of ideal body weight. These variables were employed in a multivariate discriminant analysis. Growth velocity and BA showed the best independent discriminant analysis. Growth velocity and BA showed the best independent discriminant significance in predicting responsiveness to the initial 6 months of GH therapy. The obtained equation was as follows: Score = -0.40 + 0.92X1 - 0.87X2, where X1 is the GV z value for CA and X2 is the BA z value for CA). Using this scoring system, we obtained a specificity of 96.3% and a sensitivity of 92.5% in predicting responsiveness to GH (chi-square with Yates correction, 48.2; p < 0.001). CONCLUSIONS Discriminant analysis may permit the pretreatment prediction of responsiveness to the initial 6 months of GH therapy in short children without GH deficiency.

Reduced growth hormone secretion in Turner syndrome: is body weight a key factor?

The age-related decline in spontaneous growth hormone (GH) secretion has been suggested to cause growth failure in girls with Turner syndrome (TS). We studied 23 girls (mean age +/- SD: 11.1 +/- 2.7 years) diagnosed to have TS by karyotype analysis. The control group consisted of 18 prepubertal age-matched subjects (10.7 +/- 2.5 years) with growth retardation due to familial short stature and/or constitutional growth delay. In addition, 18 children (10.9 +/- 3.3 years) diagnosed to have GH deficiency by two different provocative tests were chosen as a further comparison group. Spontaneous 12-hour nocturnal GH secretion was assessed by RIA at 30-min intervals. Plasma insulin-like growth factor 1 (IGF-1) levels were determined by RIA after acid-ethanol extraction. Girls with TS had a percentage of ideal body weight significantly higher than controls (p < 0.0001) and showed spontaneous GH secretion significantly lower than controls (mean +/- SD: 3.2 +/- 1.6 in TS vs. 5.5 +/- 1.3 microgram/l in controls; p < 0.0001) but higher than GH-deficient patients (1.3 +/- 0.8 microgram/l; p < 0.0001). No significant difference was found in IGF-1 levels between TS patients and controls, whereas GH-deficient children showed IGF-1 levels significantly lower than those of TS patients (p < 0.0005). As expected, GH concentrations correlated with bone age in controls (r = 0.51, p < 0.05), whereas no relationship was seen in TS. interestingly, in TS, GH levels were negatively related to the percentage of ideal body weight (r = -0.43, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The Response to Gonadotropin Releasing Hormone (GnRH) Stimulation Test Does Not Predict the Progression to True Precocious Puberty in Girls With Onset of Premature Thelarche in the First Three Years of Life

CONTEXT Premature thelarche in early childhood may evolve into true precocious puberty. The individuation of cases progressing to precocious puberty is challenging. OBJECTIVE We analyzed the parameters predictive for progression in girls younger than 3 years. DESIGN AND SETTING We conducted a retrospective longitudinal study. PATIENTS AND METHODS A total of 450 girls referred for premature thelarche were initially evaluated, 353 were clinically monitored at 3-month intervals, and 97 underwent endocrine and imaging assessment. Central precocious puberty (CPP) was diagnosed in girls showing LH peak response to GnRH testing >5 mU/mL with tuber cinereum hamartoma at magnetic resonance imaging, or with normal magnetic resonance imaging but progression of puberty during follow-up. MAIN OUTCOME MEASURE We measured the progression to precocious puberty. RESULTS Idiopathic premature thelarche (IPT) was diagnosed in 85 of the 97 girls who underwent extensive evaluation, CPP in nine girls, and peripheral precocious puberty in three girls. The uterus was >34 mm in six (7%) IPT girls and six (66.6%) CPP girls. Basal LH was >0.2 mU/mL in one (1.17%) IPT girl and eight (88.8%) CPP girls. LH peak was >5 mU/mL in 31 (36.4%) IPT girls and nine (100%) CPP girls. LH peak/FSH peak ratio was >1 in six (66.6%) CPP girls. CONCLUSIONS None of the available tests alone allows identification of girls who will progress to precocious puberty. Elevated LH responses to GnRH are common but are not related to progression toward puberty. The combined measurement of basal LH and longitudinal diameter of the uterus represents a reliable screening approach to identify subjects who should undergo GnRH testing.

Increased chromosome fragility in lymphocytes of short normal children treated with recombinant human growth hormone

A few years ago it was reported that some growth-hormone-deficient children had developed leukemia following therapy with human growth hormone. This raised concern that this therapy may stimulate tumor development. Since it is known that the tendency to develop cancer is closely related to chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy can increase chromosome fragility. Ten short normal children were studied during their first year of treatment. Lymphocytes were collected at 0, 6 and 12 months of rhGH therapy, and we assessed the rate of spontaneous chromosome aberrations, the frequency of sister chromatid exchanges, the proliferative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomycin. At 6 months of therapy, there was a significant increase in bleomycin-induced chromosome aberrations, which remained unchanged after 1 year of treatment. An increase in spontaneous chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are further supported by data obtained from the analysis of 16 short normal children already on rhGH therapy.

Bone Age Assessment in the Workup of Children with Endocrine Disorders

Bone age is a measure of developmental age, or physiological maturity, which represents more truthfully than chronological age, how far an individual has progressed towards full maturity. It is particularly helpful in the clinical workup of children with growth and/or puberty disorders as well as in treating decisions, such as whether to start replacement therapy in a patient with hypogonadism. Skeletal maturity assessment plays a pivotal role in confirming the diagnosis of normal variants of growth such as familial short stature and constitutional delay of growth, in interpreting hormone tests during puberty, and in the diagnosis of precocious puberty and hyperandrogenism. On the other hand, it is important to recognize that overemphasizing bone age evaluation can be misleading if not used in the proper settings. Adult height prediction is based on skeletal maturity assessment and can be used to predict with acceptable accuracy which adult height will be achieved by a ‘normal’ child. However, the predictions do not apply to children with endocrine or bone pathologies affecting growth.

Low Birth Weight for Gestational Age Associates with Reduced Glucose Concentrations at Birth, Infancy and Childhood

Background/Aims: Our aim was to investigate glucose homeostasis, insulin sensitivity and insulin-like growth factor (IGF) system status in children born small for gestational age (SGA). Methods: A case-control study was carried out at birth, infancy and childhood, comparing SGA with children appropriate for gestational age strictly matched for age, gender, pubertal status and body mass index. Ninety newborns, 52 infants, and 68 children were studied. Fasting insulin (IF), fasting glucose (GF) to IF ratio (GF/IF), the homeostasis model assessment of insulin sensitivity, the quantitative insulin sensitivity check index, insulinogenic index and the triglyceride/high-density lipoprotein-cholesterol ratio were measured. IGF-I, IGF-binding protein-3 and the IGF-I/IGF-binding protein-3 molar ratio were assessed. Results: Glucose concentrations were lower in SGA newborns (p < 0.0001), infants (p = 0.01), and children (p = 0.001). Birth weight correlated with glucose levels at birth (r = 0.59, p < 0.0001), 12 months (r = 0.29, p = 0.04) and childhood (r = 0.44, p < 0.0001). Conclusion: Our results provide evidence for a developmental adaptation of glucose metabolism in SGA children leading to reduced glucose concentrations.

Responses to GHRH plus arginine test are more concordant with IGF-I circulating levels than responses to arginine and clonidine provocative tests

BACKGROUND/OBJECTIVE Although pharmacological GH stimulation tests are still considered the gold standard for GH deficiency (GHD) diagnosis, they are burdened by poor specificity. The majority of children diagnosed as having GHD show normal GH responses when re-tested at the end of growth, thus questioning the initial diagnosis. We evaluated the concordance between IGF-I levels and GH responses to provocative tests. METHODS We analyzed 105 GHRH plus arginine tests, 79 arginine tests, and 124 clonidine tests performed in 192 short children. IGF-I levels ≤-2SD score (SDS) were considered suggestive for high likelihood of GHD. The percentage of positive and negative results for each test was determined and compared with IGF-I levels, clinical follow-up and response to therapy. RESULTS In children with IGF-I>-2SDS the arginine test showed a concordance rate of 6.9%, the clonidine test of 28.6%, and GHRH plus arginine test of 70%. In children with IGF-I≤-2SDS the concordance was 96.1%, 85.7%, and 46.4%, respectively. The overall concordance was 66.7% for GHRH plus arginine, 42.7% for clonidine, and 27.8% for arginine tests. CONCLUSION Our results suggest that GHRH plus arginine test provides the best concordance with the assessment of IGF-I levels thus suggesting that the combination of the two procedures may significantly reduce the need of a second provocative test.

158 IN VITRO ACURATE RELEASE OF SOMATOSTAIN FROM RAT HYPOTHALAMUS: EFFECT OF IL-1

The cause of growth velocity decrease in children affected by chronic inllammatory diseases is unknown. The response to infection involves production of Interleukin-1β(IL-1), from monocyte cells. The study is aimed at examining the effect of IL-1 on acute release of somatostatin(SS) from rat hypothalamus, and the intracellular mechanism involved. Hypothalami from male Wistar rats were incubated with IL-1 and medium assayed for SS by RIA. IL-1 (1-10 U/ml) increased the release of SS (Tab. 1)SS is expressed as pg/hypothalamus/20 min.; *= p<0.01, **=p<0.001 The production of SS by IL-1 was inhibited by the cyclo-oxygenase inhibitor, naproxen (NAP) (Tab.2) and by the cyclo-lipo-oxygenase inhibitor BW775 (Tab.3), but not by the lipo-oxygenase inhibitor BWA4C (Tab.4). The inhibitors are expressed in μg/ml. IL-1 is a potent stimulator of SS; the intracellular mechanism involved in this action is via cyclo-oxygenase paithway. This action of IL-1 suggest an explanation for the paradoxical GH-responses to TRH in some short children with chronic diseases.