Endocrine consequences of childhood malignancies.

Advances in cancer therapy over the last years have resulted in improved survival rates for pediatric cancer patients. However, new treatments are associated with short and long-term morbidity. The endocrine system is particularly sensitive to cancer therapies. Long-term survivors of childhood cancer are at risk for hypothalamic pituitary dysfunction, gonadal failure or disorders relating to pubertal progress, thyroid disease, obesity, disorders of lipid metabolism and disorders of bone and mineral metabolism. Long-term follow-up is indicated, as these disorders may not become apparent until adulthood.

Leptin levels in patients with thalassemia major.

AIM: Patients with thalassemia major often present endocrine abnormalities due to dysfunction in their hypothalamic-pituitary axis. Leptin, an adipocyte derived hormone, primarily acts in hypothalamus and its deficiency in the ob/ob mouse results in persistent immaturity of its hypothalamic-pituitary function. The aim of the study was to evaluate leptin levels in thalassemic patients. METHODS: The study involved 33 adult patients (11 males), mean age (SD) 19.3 years (4.4) and a group of 12 prepubertal boys, mean age (SD): 7 years (1.7) with homozygous beta-thalassemia. RESULTS: Mean (SD) leptin concentration was 3.2 (3.3) ng/mL in thalassemic males and 8.6 (3.3) ng/mL in thalassemic females; values significantly lower than matched normal subjects. In the group of prepubertal thalassemic children, leptin levels were also lower compared with matched healthy children, although the difference was not statistically significant. CONCLUSIONS: In conclusion, low leptin levels were observed in thalassemic patients, which may be due to a toxic effect of iron to adipocytes.

Gonadal function of young patients with beta-thalassemia following bone marrow transplantation.

Bone marrow transplantation (BMT) can induce short- and long-term impairment of gonadal function. Patients with beta-thalassemia represent a special group, as their primary diagnosis and its treatment modalities are responsible for gonadal dysfunction. To address the effect of BMT on puberty and gonadal function, we investigated 25 patients (12 males) with thalassemia who received allogenic BMT during childhood or adolescence and at the post-transplant evaluation were at an age that the pubertal process should have started. Pubertal stage by Tanner of breast and pubic hair, as well as testicular volume were assessed pre-BMT once and post-BMT at least twice. Menstrual history was recorded. FSH, LH, testosterone and estradiol levels were also determined. The impact of BMT appears to be different in the two sexes. Males seem to have higher tolerance, as all males who were pubertal at the time of BMT had normal testosterone, and all but one normal gonadotropin levels. From those who were prepubertal at BMT, 62% proceeded to normal pubertal development. Post-menarcheal females seem to be an extremely sensitive group to the deleterious effect of the transplantation process, as 100% of the post-menarcheal females exhibited amenorrhea and elevated gonadotropin levels. These findings are important for pre- and post-BMT counseling.

Tumor necrosis factor-alpha levels in short children.

Growth hormone has been suggested to modulate the release of cytokines, such as tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1). Moreover, TNFalpha synthesis has been shown to be decreased in hypophysectomized rodents. The aim of this study was to evaluate the influence of GH status on TNFalpha levels in a group of 44 short prepubertal children. Among them, 13 children aged 9.8 +/- 3.5 years were growth hormone (GH) deficient and the other 31 short children had normal growth velocity, normal GH response to provocative testing, and did not suffer from any chronic disease, thus this group was diagnosed as having idiopathic short stature (ISS). A group of 40 age- and sex-matched healthy children was used as controls. No significant differences in basal TNFalpha levels (pg/ml) were found between the GH deficient, ISS children and healthy controls. Furthermore, there was no correlation between TNFalpha and basal serum concentrations of GH or peak GH levels after stimulation. Similarly, TNFalpha values did not correlate with either IGF-I or IGFBP-3 serum concentrations.

Consistency of pupillary abnormality in children and adolescents with diabetes.

Repeat measurements on pupillary adaptation to darkness were performed in a cohort of 66 children and adolescents with insulin-dependent diabetes mellitus (IDDM) (initial age 6.9-17.0 years) after a mean interval of 3.5 years, using a portable pupillometer. While there was a close correlation between the results of the two studies (r = 0.94, p < 0.001), the pupillary dilatation, the ratio of the pupil diameter to the iris diameter % (PD%), had decreased significantly (61.5% vs 62.9%, p < 0.001) over these 3.5 years in children with diabetes. The same measurements were performed on 89 healthy control children in the first study and 66 in the reassessment period and PD% was not significantly different in the two control groups. Five children with diabetes identified as having abnormal pupillary dilatation in the first study were outside the normal range 3.5 years later. In addition 4 children in whom initial testing had been normal, showed abnormality at the time of the second study. None of these children had symptoms of autonomic neuropathy. These findings suggest that abnormality in pupillary adaptation in diabetic children is consistent and increases with time and may serve as an early marker of tissue damage associated with diabetes.

Growth and growth hormone therapy in children with achondroplasia: a two-year experience.

The efficacy and safety of recombinant human growth hormone (hGH) administration was studied in children with achondroplasia. Fifteen children with achondroplasia, seven boys (4.8-12.2 years of age) and 12 girls (5.7-2.2 years of age), were treated daily with hGH at a dosage of 1 IU/kg/week. Auxological assessments were performed 6 months before, at initiation of, and at 6, 12, and 24 months following initiation of growth hormone (GH) therapy. Before initiating GH therapy, hypothalamic-pituitary and thyroid functions were evaluated. Levels of serum insulin-like growth factor (IGF)-I and IGF binding protein (BP)-3 (IGFBP-3) were assessed, as was GH response to provocative stimuli. GH responses in two stimulation tests were normal for all but three children. During the first semester of GH treatment, a significant increase in height velocity (HV), from 3.2 to 8.3 cm/year, was observed in all children. However, during the second semester, a relative decrease in growth rate was observed. By the end of the first year, HV had increased from 3.2 to 6.9 cm/year (mean, 3.7 cm/year; range, 1.1-8 cm/year) in 13 children and remained unchanged in two children. HV declined progressively during the next 12 months and, by the end of the second year of treatment, had increased in seven of the nine children who had completed 2 years of therapy (mean increase, 3.1 cm/year); two children did not respond to GH therapy, as shown by the lack of increase in HV. Sitting-height (SH) to standing-height ratio % (SH%) remained unchanged throughout GH therapy, and no significant change in skeletal maturation was observed. In conclusion, hGH treatment resulted in an increased growth rate in some children with achondroplasia; however, this increase waned during the second year of treatment. Children with the lowest pretreatment HVs seemed to benefit most from GH therapy. Nonetheless, the usefulness of GH treatment in achondroplasia will be known only when a study of final height is completed.

Effect of growth hormone therapy on bone metabolism of growth hormone deficient children.

UNLABELLED: The effects of human growth hormone (hGH) therapy on biochemical markers of bone metabolism were studied in 17 children (10 boys and 7 girls, aged 3.7-13.1 years old) with idiopathic GH deficiency, before and 1 and 6 months after GH therapy (0.5 0.7 IU/kg weekly SC). Serum levels of calcium, phosphate, alkaline phosphatase osteocalcin, parathyroid hormone, 1,25 dihydroxyvitamin D, insulin-like growth factor I (IGF-I) and renal phosphate per 100 ml glomerular filtrate (TPO4/GFR) were assessed. During therapy with hGH a significant decrease of serum calcium levels and increases of phosphate, osteocalcin, parathyroid hormone 1,25 dihydroxyvitamin D and IGF-I were observed. TPO4/GFR was also significantly increased. Growth response (increment in HV) was positively related with changes in alkaline phosphatase and IGF-I levels after 6 months of hGH therapy. There was also a significant positive correlation between increment in HV and increment in TPO4/GFR after 1 month of GH therapy, whereas no correlation between HV and changes in osteocalcin levels was found. CONCLUSION: GH treatment significantly influences mineral metabolism and the measurement of TPO4/ GFR after 1 month of GH therapy may serve as a useful predictor of growth response to hGH therapy in GH-deficient children.

Consistency of microvascular and autonomic abnormalities in diabetes.

The progression of early measures of microvascular disease and autonomic neuropathy were studied in a group of 81 children with insulin dependent diabetes mellitus over a mean interval of 4.2 years. Repeated measurements were made of blood pressure, albumin excretion, joint mobility, and pupillary dilatation in darkness. Over the years between the first and the second study, systolic and diastolic blood pressure showed positive tracking correlations (r = 0.38 and r = 0.32) with a small but significant deviation from normality; albumin/creatinine ratio was significantly increased (0.79 v 0.55); a greater number of children were identified in the second study as having limitation of mobility of the fifth metacarpophalangeal joint; and pupillary dilatation in darkness significantly decreased (61.5% v 62.9%); 62% of the children with one or more abnormal measurements in the first study were found to have measurements outside the normal ranges in the second study, indicating a consistency in observations over time. It remains to be seen with what accuracy these measurements predict adult onset clinical disease.

Endothelin 1-21 plasma concentrations in children and adolescents with insulin-dependent diabetes mellitus.

This study is based on the hypothesis that endothelins (ETs), which are 21-amino acid peptides with vasoactive and proliferative properties, could be implicated in the development of complications of insulin dependent diabetes mellitus (IDDM) in children and adolescents. We determined plasma ET 1-21 concentrations by radioimmunoassay in 59 patients with IDDM (32 male, 27 female) and in 41 healthy siblings (20 male, 21 female) and investigated the association of ET 1-21 concentrations with age, sex, control of diabetes (expressed as % of glycosylated hemoglobin), duration of disease and presence of complications. Plasma ET 1-21 concentrations (mean +/- SEM) were 14.12 +/- 0.30 pg/ml in IDDM and 15.34 +/- 0.47 pg/ml in healthy siblings. The difference was statistically significant (p = 0.01) after controlling for age and sex by multiple logistic regression. In the group with IDDM, analysis of covariance showed duration of disease to be the only variable associated with ET 1-21 values (b = 0.2179 pg/ml/yr, p = 0.04). It is concluded that in youngsters with IDDM ET plasma concentrations are lower than in healthy controls, negatively associated with duration of the disease and not directly implicated in diabetic angiopathy.

Long bone fracture healing: IGF-I concentrations and specific binding to erythrocytes.

Animal experiments suggested a possible interaction between GH or GH-dependent growth factors and bone healing. The aim of this study was to determine whether there were any significant changes in serum levels of IGF-I and/ or the activity of its receptors while a fractured bone was healing. Serum concentrations of IGF-I and its specific binding to erythrocyte receptors (IGF-I SB) were determined in a group of 12 prepubertal children treated for long bone fractures. Results were compared to those obtained from a group of age- and sex-matched controls. Blood samples were taken from all patients two weeks following the fractures, when bone formation rate should have been maximal. We found no difference in IGF-I SB between the two groups. However, serum IGF-I levels were increased in the group of children with fractures compared to controls. Results are suggestive of a possible interaction between IGF-I and bone repair processes as other investigators have suggested on the basis of animal experiments.

Serum levels of IGFBP-3: usefulness in diagnosis of GH deficiency and relationship to measurements of GH secretion in children.

Aims of the study were to assess the relationship between serum levels of IGFBP-3 with IGF-I serum levels, peak GH levels in response to two stimulation tests (PKGH) and GH urinary excretion in children, and to examine the usefulness of IGFBP-3 for diagnosis of GH deficiency. Our study group consisted of 86 children with normal stature, 12 children with normal short stature and 12 children with GHD. In all children, serum levels of IGF-I and IGFBP-3 were measured and GH urinary excretion was assessed in overnight urine collections. Children with short stature had two stimulation tests and the peak GH level was used in the analysis. IGFBP-3 SDS was strongly correlated with IGF-I SDS (r = 0.63, p < 0.001), significantly correlated with peak GH (r = 0.42, p < 0.05) and weakly, but not significantly, correlated with urinary GH excretion. Among the 12 children with GHD, only two had normal IGFBP-3 values (sensitivity 83%). In contrast, all normal short children except one had IGFBP-3 levels within the normal range, defined by the 5th and 95th percentile (specificity 92%). Sensitivity and specificity of IGF-I were respectively 67% and 50%. In conclusion, IGFBP-3 levels are strongly correlated with IGF-I levels, weakly correlated with peak GH response to provocative tests and may serve as a valuable parameter, in combination with others, in the evaluation of the GH-IGF axis.

Is microalbuminuria progressive?

In 1990, 81 children and adolescents with insulin dependent diabetes were studied for early signs of diabetic nephropathy. Nine patients were identified as having microalbuminuria (incipient nephropathy). These subjects were re-examined three years later. In five of these cases, the second examination revealed normal albumin excretion; in three of the four cases in whom microalbuminuria persisted, the rate of albumin excretion had decreased. The general improvement in albumin excretion rates in the initially microalbuminuric group could not be explained by improved glycaemic control nor interventional drug treatment. The lack of progression in this microalbuminuric group from the original prevalence study suggests that this method of identifying early nephropathy in childhood may not be valid or that the progression of incipient nephropathy in childhood is more irregular or slower than in later life.

Month of birth, atopic disease, and sensitization to common aeroallergens in Greece.

The aim of the study was to evaluate the influence of the month of birth on the development of atopic disease and the rate of sensitization to common environmental allergens in Greece. Analysis of the month of birth of 1755 individuals with atopic disease (asthma, rhinitis, atopic dermatitis), out of whom 771 had positive skin tests/RAST to Dermatophagoides pteronyssinus and mixed grasses, in comparison to total live births (2,877,733) in Greece during 1968-88, was performed and showed significant correlation (p < 0.001) between month of birth and development of atopic disease in general. Months of birth May to August correlated best with bronchial asthma (p < 0.05) and rhinitis (p < 0.05), and July to August with atopic dermatitis (p < 0.05). Significantly greater than the expected frequency was found for D. pteronyssinus sensitivity for months of birth May to August (p < 0.01), for mixed grass pollen March to August (p < 0.01), and for Olea europaea pollen mainly March (p < 0.05). Our results indicate that in Greece high-risk birth months for development of atopy are May to August, whereas for sensitization to common aeroallergens they are March for O. europaea, March to August for mixed grasses, and May to August for D. pteronyssinus.

Expression of the c-myc oncoprotein in human metaplastic epithelial cells of fibrocystic disease.

Sections derived from fibrocystic disease in human breast tissue were examined for the presence of the c-myc oncoprotein by using the c-myc specific monoclonal antibody 9E10 (1). The results obtained revealed that the c-myc gene was not expressed in normal epithelial cells either of ducts or lobules. It was expressed mainly in mucous metaplastic cells and very rarely in apocrine cells. The c-myc protein was observed at a higher level in mucous metaplastic cells of epitheliosis and multiple papillomas. The number and intensity of positive mucous metaplastic cells was significantly increased after pretreating the sections with neuraminidase. We suggest that elevated expression of the c-myc nuclear oncoprotein in human breast metaplastic epithelial cells play a role in the early stages of malignant cell transformation.