Ethinylestradiol and testosterone have divergent effects on circulating IGF system components in adolescents with constitutional tall stature.

OBJECTIVE: Pharmacological doses of estrogens or testosterone are used to limit the final height of girls or boys with constitutional tall stature but the mechanism behind this growth inhibition is still debated. We therefore studied the changes in the circulating components of the insulin-like growth factor (IGF) system during high dose sex steroid therapy. DESIGN AND METHODS: Twenty three girls and twenty boys with constitutional tall stature were treated with 100 microg ethinylestradiol per day or 250 mg testosterone ester every 14 days respectively. In 19 girls and 18 boys, the levels of IGF-I, free IGF-I, IGF-II, acid-labile subunit (ALS) and IGF binding proteins (IGFBP)-2 to -6 were measured before and 3-6 months after the start of therapy (group 1). In 18 girls and 11 boys, samples were collected at the end of therapy and 3 to 6 months afterwards (group 2). Fourteen girls and nine boys belonged to both groups. All parameters were measured by radioimmunoassay or ELISA. RESULTS: Levels of IGF-I were decreased significantly by estrogen treatment but remained unchanged during testosterone treatment. Free IGF-I decreased during estrogen treatment but increased during testosterone therapy. Estrogens increased IGF-II and testosterone reduced it. The important reduction of IGFBP-2 during estrogen therapy is not reproduced by androgen therapy, neither is the stimulation by estrogens of IGFBP-4. IGFBP-3 is not modulated by either sex steroid. We found that IGFBP-6 is up-regulated by testosterone but not by estrogens; the reverse is true for ALS, which increased during estrogen treatment but remained unchanged during testosterone treatment. CONCLUSIONS: Our findings demonstrate that androgens and estrogens exert differential effects on the circulating levels of several IGF components.

A nonmosaic 45,X karyotype in a mother with Turner's syndrome and in her daughter.

OBJECTIVE: To describe a woman with a nonmosaic (45,X) form of Turner's syndrome who gave birth to a girl with 45,X Turner syndrome. DESIGN: Patient report. SETTING: Outpatient clinic of a university hospital. PATIENT(S): A woman with typical phenotypic features of Turner syndrome and a 45,X karyotype and her daughter with the same karyotype. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Routine karyotype analysis on 200 white blood cells on two different occasions, on skin fibroblasts (1,000 mitoses) and on ovarian fibroblasts. Translocation of X-chromosome material was investigated by a complete X paint and fluorescent in situ hybridization analysis. RESULT(S): The patient had a spontaneous puberty and became pregnant on three occasions. Her first daughter has a normal karyotype, the second pregnancy ended in spontaneous abortion, and after the third pregnancy, a girl was born with a 45,X karyotype. Karyotype analysis of a large number of mitoses in three different cell types failed to demonstrate any mosaicism. Translocation of X-chromosome material was ruled out by fluorescent in situ hybridization analysis with an X paint. CONCLUSION(S): This is a rare case of pregnancy in a nonmosaic Turner syndrome patient and, to our knowledge, is the only one that resulted in a live-born baby with the same karyotype. Cryptic mosaicism could not be found despite thorough investigations. Some hypotheses are presented that may explain this unique event.

Female children and adolescents with type 1 diabetes have more pronounced early echocardiographic signs of diabetic cardiomyopathy.

OBJECTIVE: This study was designed to assess whether children and adolescents with type 1 diabetes have early echocardiographic signs of subclinical cardiac dysfunction and whether sex, state of metabolic control, and diabetes duration are of influence. RESEARCH DESIGN AND METHODS: Systolic and diastolic blood pressure in supine and upright positions and echocardiographic parameters, including tissue Doppler measurements of the septal mitral annulus, were evaluated in 80 children and adolescents with stable type 1 diabetes and 52 age- and sex-matched control subjects. A possible correlation was examined for age, sex, HbA(1c), and diabetes duration with univariate and multivariate regression analysis. RESULTS: Female diabetic patients showed significantly larger left ventricular wall dimensions (left ventricular posterior wall in diastole 0.54 +/- 0.08 vs. 0.48 +/- 0.11 cm) and signs of significant diastolic filling abnormalities on conventional and tissue Doppler echocardiography (mitral valve-atrial contraction velocity 0.47 +/- 0.12 vs. 0.40 +/- 0.09 m/s; tricuspid valve-atrial contraction velocity 0.35 +/- 0.09 vs. 0.30 +/- 0.07 m/s; early filling velocity/myocardial velocity during early filling 7.15 +/- 1.47 vs. 6.17 +/- 1.07; isovolumetric relaxation time [IVRT] 66 +/- 8 vs. 58 +/- 8 ms) compared with female control subjects, suggesting delayed myocardial relaxation. Male diabetic patients only differed significantly from their control subjects for IVRT (66 +/- 9 vs. 59 +/- 8 ms). The measured parameters showed an expected correlation with age and BMI standard deviation scores in the control group. This correlation was significantly weaker in the diabetic population; only a weak influence was found for diabetes duration and glycosylated hemoglobin levels. CONCLUSIONS: Young diabetic patients already have significant changes in left ventricular dimensions and myocardial relaxation, with the girls clearly being more affected. Tissue Doppler proved to have additional value in the evaluation of ventricular filling in this population. Almost no correlation was found for diabetes duration and HbA(1c) with the cardiovascular changes.

Dexamethasone differentially inhibits thyroxine- or growth hormone-induced body and organ growth of Snell dwarf mice.

Supraphysiological doses of glucocorticoids cause growth retardation in both animals and humans. Many studies have addressed the interaction of glucocorticoids with the GH/IGF system, but little is known about the effect of glucocorticoids on T(4)-stimulated growth. The Snell dwarf mouse is deficient in GH, thyroid-stimulating hormone, and prolactin and therefore allows the study of the effect of glucocorticoids on the growth induced by GH and T(4) without their mutual interaction. Four weeks of treatment with T(4) (1 micro g/d) or human GH (50 mU/d) equally increased nose-tail length (3.1 +/- 0.1 cm and 3.0 +/- 0.2 cm, respectively). Dexamethasone (DXM) had much less impact on T(4)-stimulated growth than on GH-induced growth (T(4) + DXM: 2.4 +/- 0.1 cm vs. GH+ DXM: 1.4 +/- 0.1 cm). Similar data were obtained for body weight gain. T4 and GH had a different effect on the weight of various organs: GH caused a higher increase in liver and lumbar vertebrae weight, and T(4) was a better stimulator for kidney (P < 0.05), thymus, and spleen growth. Remarkably, T(4)-stimulated growth of the organs was less affected by DXM than GH-induced organ growth. GH even potentiated the growth inhibition by DXM in the thymus and tibia. In conclusion, T(4)-stimulated growth in Snell dwarf mice is less affected by DXM than growth stimulated by GH

Growth and ovarian function in girls with 48,XXXX karyotype--patient report and review of the literature.

The loss of an X chromosome results in short stature and often in primary ovarian failure, but the effect of extra X chromosomes is less clear, especially in 48,XXXX women. We report a girl with a 48,XXXX karyotype with tall stature (181.8 cm), primary ovarian failure and low DHEAS levels. A review of the literature shows that, apart from an intellectual deficit, the phenotype is very heterogeneous. The few data that are available in the literature indicate that tall stature and primary ovarian failure are not essential characteristics of the 48,XXXX phenotype.

QTc interval prolongation and QTc dispersion in children and adolescents with type 1 diabetes.

OBJECTIVES: To evaluate whether QT interval, QT interval corrected for heart rate (QTc), and QTc dispersion changes are already present in children and adolescents with diabetes. STUDY DESIGN: QT interval, QTc, and QTc dispersion were measured on a 12-lead surface electrocardiogram in 60 children and adolescents with stable type 1 diabetes and in 63 sex- and age-matched control subjects. Differences were evaluated by using the Kolmogorov-Smirnov Z test. The number of patients with QTc > 440 ms was compared in the two groups. The possible influence of age, sex, diabetes duration, and glycosylated hemoglobin (HbA(1c)) was examined by using Spearman correlation analysis. RESULTS: Diabetic children had significantly longer QTc intervals and a significantly larger QTc dispersion. The number of individuals with a QTc >440 ms was significantly higher in the diabetic group (14/60) than in the control group (2/63). The effect of age on R-R interval and QTc dispersion in healthy children was less pronounced in children with diabetes. HbA(1C) values did not significantly correlate with any of the parameters. CONCLUSIONS: QTc prolongation and a larger QTc dispersion are already present in a significant proportion of children and adolescents with diabetes.

IGF-I, IGF-II, 'free' IGF-I and IGF-binding proteins-2 to -6 during high-dose oestrogen treatment in constitutionally tall girls.

OBJECTIVE: To investigate the effect of high-dose oestrogen treatment on IGF-I, IGF-II, free-dissociable IGF-I and the IGF-binding proteins (IGFBP)-2 to -6 in girls with constitutional tall stature. METHODS: In patient cohort 1, blood samples were drawn before and after 3 months of daily oral treatment with 0.1 mg ethinyloestradiol. In cohort 2, samples were collected at the end of the treatment period and 3 to 6 months afterwards. IGFs and IGFBPs were analysed by specific immunoassays and by Western ligand blot. RESULTS: Total IGF-I decreased significantly on oestrogen treatment and increased again after oestrogen withdrawal. Ligand blot analysis showed a clear reduction in a 34 kDa band, corresponding to IGFBP-2, and a strong induction of a 24 kDa band, corresponding to the non-glycosylated form of IGFBP-4. These changes were confirmed by specific immunological methods. The serum levels of IGFBP-3, IGFBP-5 and IGFBP-6 remained unchanged during the first 3 months of treatment. In cohort 2, IGFBP-3 and IGFBP-6 increased after oestrogen withdrawal. Free-dissociable IGF-I fell to 35+/-4% during oestrogen therapy and rose again when the treatment was stopped. CONCLUSIONS: Oestrogens modulate the serum concentrations of several components of the IGF system. The fall in total IGF-I is not explained by a decrease in IGFBPs but probably results from a decreased synthesis.