Near Adult Height in Girls with Turner Syndrome Treated with Growth Hormone Following Either Induced or Spontaneous Puberty.

OBJECTIVE: To understand whether spontaneous vs induced puberty and the type and route of estrogen influence the height of girls with Turner syndrome on growth hormone (GH). STUDY DESIGN: Search of an international database of children treated with GH revealed 772 girls with Turner syndrome followed from GH initiation to near adult height. Data from girls with sustained spontaneous puberty (n = 145) were compared with those requiring estrogens for induction or maintenance of puberty (n = 627). RESULTS: At GH start, mean age (7.5 vs 7.9 years), weight (-1.7 vs -1.7 SDS), and body mass index (0.2 SDS vs 0.1 SDS) were similar for girls with spontaneous puberty and with induced puberty. Although those girls with spontaneous puberty were shorter than those with induced puberty, when midparental height was taken into consideration, starting heights in both groups averaged -2.8 SDS. Both groups received approximately 0.3 mg/kg/week of GH. Girls with spontaneous puberty initiated puberty and reached near adult height earlier than girls with induced puberty (12.6 ± 1.8 years vs 13.4 ± 1.4 years and 16.0 ± 1.3 years vs 16.9 ± 1.4 years, respectively). Although girls with spontaneous puberty grew more in the first year of GH therapy and between the onset of puberty and near adult height (11.0 cm vs 9.3 cm), height SDS at near adult height and the length of time in puberty before reaching near adult height were comparable. A 45,X karyotype was detected in 22.1% of girls with spontaneous puberty and in 58.4% of girls with induced puberty. Patients receiving transdermal estrogens did not grow better than those on oral estrogens. Adverse event reporting was comparable between groups. CONCLUSIONS: Girls with Turner syndrome with spontaneous puberty tended to grow better in response to GH than girls with induced puberty, but not enough to produce a difference in height SDS at near adult height.

GH/IGF-1 Signaling and Current Knowledge of Epigenetics; a Review and Considerations on Possible Therapeutic Options.

Epigenetic mechanisms play an important role in the regulation of the Growth Hormone- Insulin-like Growth Factor 1 (GH-IGF1) axis and in processes for controlling long bone growth, and carbohydrate and lipid metabolism. Improvement of methodologies that allow for the assessment of epigenetic regulation have contributed enormously to the understanding of GH action, but many questions still remain to be clarified. The reversible nature of epigenetic factors and, particularly, their role as mediators between the genome and the environment, make them viable therapeutic target candidates. Rather than reviewing the molecular and epigenetic pathways regulated by GH action, in this review we have focused on the use of epigenetic modulators as potential drugs to improve the GH response. We first discuss recent progress in the understanding of intracellular molecular mechanisms controlling GH and IGF-I action. We then emphasize current advances in genetic and epigenetic mechanisms that control gene expression, and which support a key role for epigenetic regulation in the cascade of intracellular events that trigger GH action when coupled to its receptor. Thirdly, we focus on fetal programming and epigenetic regulation at the IGF1 locus. We then discuss epigenetic alterations in intrauterine growth retardation, and the possibility for a potential epigenetic pharmaceutical approach in short stature associated with this fetal condition. Lastly, we review an example of epigenetic therapeutics in the context of growth-related epigenetic deregulation disorders. The advance of our understanding of epigenetic changes and the impact they are having on new forms of therapy creates exciting prospects for the future.

Elevated second-trimester maternal serum ß-human chorionic gonadotropin and amniotic fluid alpha-fetoprotein as indicators of adverse obstetric outcomes in fetal Turner syndrome.

AIM: The objective of this study was to determine the ability of biochemical analytes to identify adverse outcomes in pregnancies with Turner syndrome. METHODS: Maternal serum and amniotic fluid (AF) marker concentrations were measured in 73 singleton pregnancies with Turner syndrome (10-22 weeks of gestation). Fetal Turner syndrome was definitively established by cytogenetic analysis. Two subgroups, fetuses with hydrops fetalis versus fetuses with cystic hygroma, were compared. Receiver operating characteristic curves and relative risk were established for a cut-off multiples of the median ≥3.5 for ß-subunit of human chorionic gonadotropin (hCG) or AF alpha-fetoprotein (AFP). RESULTS: Forty-nine (67%) of 73 pregnant women had an abnormal maternal serum. While levels of pregnancy-associated plasma protein-A and free ß-subunit (fß)-hCG were not different to those of the control group, AFP, unconjugated estriol and ß-hCG concentrations were significantly different in the study group (P < 0.05), when compared to those of unaffected pregnancies. Levels of ß-hCG in pregnancies with hydrops fetalis were significantly higher than in those with cystic hygroma (P <0.0001), as were AF-AFP concentrations (P <0.0015). In addition, abnormalities in both maternal serum ß-hCG and AF-AFP predicted fetal death. The relative risk of adverse obstetric outcome was 10.667 (P = 0.0004; 95% confidence interval [CI]: 1.554-73.203) for ß-hCG and 2.19 (P = 0.0256; 95% CI: 1.001 to 4.779), for AF-AFP. CONCLUSION: Maternal serum ß-hCG and AF-AFP levels may preferentially identify those Turner syndrome pregnancies with the highest risk of fetal death.

Is the growth outcome of children with idiopathic short stature and isolated growth hormone deficiency following treatment with growth hormone and a luteinizing hormone-releasing hormone agonist superior to that obtained by GH alone?

AIM: The aim of this study was to evaluate the effect of combined therapy with growth hormone (GH) and luteinizing hormone-releasing hormone agonist (LHRHa) on the near-final height (NFH) of children with idiopathic short stature (ISS) and growth hormone deficiency (GHD) in early puberty. METHODS: A retrospective analysis of 20 patients with ISS and 9 patients with GHD treated with combined therapy was undertaken. Twelve children with ISS and ten with GHD, treated with GH alone, served as controls. Patients were matched at baseline for chronological age, bone age, height standard deviation score (SDS), and pubertal development. RESULTS: Patients with ISS or GHD treated with combined therapy improved both their predicted adult height (PAH) at 2 years of therapy (ISS, p < 0.001; GHD, p = 0.03) and their NFH (ISS, p < 0.05; GHD, p = 0.05). Treatment with combined therapy did not generate additional benefits on the PAH after 2 years of therapy (ISS children, an increase of 7.9 +/- 4.9 cm with combined therapy vs. 7.3 +/- 6.0 cm with GH; GHD children, an increase of 6.8 +/- 7.8 cm with combined therapy vs. 5 +/- 5.9 cm with GH). The total height gain SDS was higher in patients treated with GH alone compared with those with combined therapy, but the difference was not significant (ISS children, a gain of 2.4 SDS with GH vs. 0.8 SDS with combined therapy; GHD children, a gain of 1.8 SDS with GH vs. 0.6 SDS with combined therapy). CONCLUSIONS: Although 2 years of combined treatment with GH and LHRHa improved the PAH and the NFH of ISS and GHD patients in early puberty, this improvement was not significant compared with that observed in similar subjects treated with GH alone.

Latin American consensus: children born small for gestational age.

BACKGROUND: Children born small for gestational age (SGA) experience higher rates of morbidity and mortality than those born appropriate for gestational age. In Latin America, identification and optimal management of children born SGA is a critical issue. Leading experts in pediatric endocrinology throughout Latin America established working groups in order to discuss key challenges regarding the evaluation and management of children born SGA and ultimately develop a consensus statement. DISCUSSION: SGA is defined as a birth weight and/or birth length greater than 2 standard deviations (SD) below the population reference mean for gestational age. SGA refers to body size and implies length-weight reference data in a geographical population whose ethnicity is known and specific to this group. Ideally, each country/region within Latin America should establish its own standards and make relevant updates. SGA children should be evaluated with standardized measures by trained personnel every 3 months during year 1 and every 6 months during year 2. Those without catch-up growth within the first 6 months of life need further evaluation, as do children whose weight is ≤ -2 SD at age 2 years. Growth hormone treatment can begin in SGA children > 2 years with short stature (< -2.0 SD) and a growth velocity < 25th percentile for their age, and should continue until final height (a growth velocity below 2 cm/year or a bone age of > 14 years for girls and > 16 years for boys) is reached. Blood glucose, thyroid function, HbA1c, and insulin-like growth factor-1 (IGF-1) should be monitored once a year. Monitoring insulin changes from baseline and surrogates of insulin sensitivity is essential. Reduced fetal growth followed by excessive postnatal catch-up in height, and particularly in weight, should be closely monitored. In both sexes, gonadal function should be monitored especially during puberty. SUMMARY: Children born SGA should be carefully followed by a multidisciplinary group that includes perinatologists, pediatricians, nutritionists, and pediatric endocrinologists since 10% to 15% will continue to have weight and height deficiency through development and may benefit from growth hormone treatment. Standards/guidelines should be developed on a country/region basis throughout Latin America.

GHR and VDR genes do not contribute to the growth hormone (GH) response in GH deficient and Turner syndrome patients.

We have prospectively assessed the influence of GHR and VDR gene polymorphisms on the response to rhGH therapy in Venezuelan children with growth hormone deficiency (GHD, n=28) and Turner syndrome (TS, n=25). Clinical data during rhGH treatment were compared in GH and TS patients with different genotypes. PCR amplifications were performed to obtain the genotype frequencies of the polymorphisms. Clinical data at the start of treatment and rhGH doses were indistinguishable among patients with GHD or TS with different GHR or VDR genotypes. After the first two years of rhGH treatment, clinical data in both GHD and TS patients were not different according GHR or VDR genotypes. In addition, there was no significant difference among the subjects when both these genotypes were combined. Gene polymorphisms in low penetrance genes do not contribute to the rhGH therapy response in patients with GHD and TS.

Metabolic Syndrome as a Risk Factor for Sensorineural Hearing Loss in Adult Patients with Turner Syndrome.

BACKGROUND AND PURPOSE: Metabolic syndrome (MetS) is a disorder associated with an increased risk of cardiovascular disease. The frequency of each component of MetS in Turner syndrome (TS) subjects is high. An elevated incidence of hearing loss has also been reported in TS. Sensorineural hearing loss (SNHL) affects at least half of young women with TS. The association between MetS and SNHL has not been previously considered in TS. The aim of this study is to evaluate the association between these two conditions. PATIENTS AND METHODS: Cross-sectional anthropometric, cardio-metabolic and audiological data were obtained from a cohort consisting of unrelated TS subjects (>20 years of age; n = 93). Metabolic syndrome was defined according to the International Diabetes Federation criteria. Types and severity of hearing loss were based on the American Speech Hearing Association guidelines. RESULTS: Hearing loss was detected in 74% of ears from adult TS subjects and SNHL was observed in half of our TS subjects. The prevalence of MetS in TS subjects with or without SNHL was 64% and 11%, respectively (P < 0.05). After adjusting for age, MetS was related to a ninefold increase in the odds of SNHL. This odds increased in a stepwise manner as the number of MetS components increased. CONCLUSION: MetS and its individual components were associated factors for SNHL in TS subjects. A reduction in the number and severity of the components of MetS might potentially contribute to decreasing the progression of SNHL at younger ages, but further studies will be needed to explain the underlying pathological mechanism connecting MetS and SNHL.

Anthropometric variables as cardiovascular risk predictors in a cohort of adult subjects with Turner syndrome.

BACKGROUND AND PURPOSE: Excessive adiposity is associated with cardiometabolic complications in Turner syndrome (TS) subjects. Reference data for predictive anthropometric indices of overweight/obesity and metabolic syndrome (MetS) are lacking for subjects with TS. The purpose of this study was to identify the best anthropometric predictor of cardiometabolic risk in a Latin-American cohort of TS subjects. PATIENTS AND METHODS: This was a cross-sectional correlational study conducted in adult TS subjects (n=88) over the past seven years. Anthropometric parameters, body composition and biochemical variables were evaluated in a study and in a reference (n=57) group. Overweight/obesity and MetS were diagnosed using international consensus. The area under the ROC curve (AUC-ROC) was then used to determine the value of each anthropometric variable in predicting MetS or overweight/obesity. RESULTS: The prevalence of MetS and overweight/obesity in TS subjects was 40% and 48%, respectively. All anthropometric and cardiometabolic variables were significantly increased in TS subjects when compared to the reference group, except for body mass index (BMI) and HDL-c. To detect MetS and overweight/obesity, waist to height ratio (WHtR) was found to have a higher correlation with cardiometabolic variables (TC, LDL-c, HDL-c levels and the LDL-c/HDL-c ratio), and to have a higher AUC-ROC and odds ratio than BMI, waist circumference (WC) and the waist to hip ratio (WHR). CONCLUSION: The prevalence of MetS and overweight/obesity is elevated in TS subjects. WHtR was the most useful variable in predicting the presence of MetS and overweight and obesity in this TS cohort. A combination of WHtR with BMI or with WC could have the best clinical utility in identifying adult TS subjects with overweight/obesity and MetS, respectively.

The triglyceride/HDL-cholesterol ratio as a marker of cardiovascular risk in obese children; association with traditional and emergent risk factors.

OBJECTIVES: To determine the presence of traditional and emergent cardiovascular risk factors and to evaluate the triglyceride/high-density lipoprotein cholesterol (Tg/HDL-C) ratio as a marker for cardiovascular disease and metabolic syndrome (MS) in obese children. MATERIAL AND METHODS: Sixty-seven prepubertal children of both sexes, between the ages of 6 and 12 yr, 20 normal-weight children, 18 overweight, and 29 obese subjects, were studied. Anthropometric measures, blood pressure, body mass index (BMI), and fat mass (FM), were measured. Plasma glucose, serum insulin, lipid profile, C-reactive protein (CRP), and leptin concentrations were quantified. Glucose and insulin concentrations 2 h post-glucose load were determined. The Tg/HDL-C ratio, homeostasis model assessment index (HOMA), and quantitative insulin sensitivity check index (QUICKI) were calculated. RESULTS: Systolic, diastolic, and mean blood pressures (MBP), low-density lipoprotein cholesterol (LDL-C), Tg/HDL-C, total cholesterol/HDL-C, LDL-C/HDL-C ratios, basal and 2 h postload insulin, CRP, and leptin were significantly higher and the QUICKI index were lower in the obese group. MBP, Tg/HDL-C ratio, HOMA, CRP, and leptin levels showed a positive and significant correlation and QUICKI a negative correlation with abdominal circumference, BMI, and FM. The Tg/HDL-C ratio correlated positively with MBP. The frequency of MS in the obese group was 69%. While Tg/HDL-C ratio, CRP, and leptin were higher and the values of QUICKI were lower in subjects with MS, it was the Tg/HDL-C ratio and the BMI that significantly explained the MS. CONCLUSIONS: Obesity increases the cardiovascular risk in childhood. The Tg/HDL-C ratio could be a useful index in identifying children at risk for dyslipidemia, hypertension, and MS.

Circulating levels of high-sensitivity C-reactive protein and soluble markers of vascular endothelial cell activation in growth hormone-deficient adolescents.

BACKGROUND/AIMS: Significant endothelial dysfunction as determined by lower flow-mediated vasodilation of the brachial artery was recently reported by us in growth hormone-deficient (GHD) adolescents. The circulating concentrations of markers of vascular endothelial cell and platelet activation and their relationship to inflammatory markers have not been previously evaluated in this group of patients. OBJECTIVE: To assess the relationship between circulating levels of high-sensitivity C-reactive protein (CRP) and soluble markers of vascular endothelial cell activation in GHD adolescents. DESIGN/METHODS: Twenty-eight GHD children on GH treatment with a chronological age of 15.7 +/- 2.6 years and 16 untreated GHD adolescents with a chronological age of 16.6 +/- 3.3 years were studied. Concentrations of CRP, as an inflammatory marker, were measured in all patients and the association between CRP and the fasting soluble markers of vascular endothelial cell activation intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin levels was evaluated. Sixteen healthy adolescents with a mean chronological age of 15.1 +/- 2.2 years served as controls. RESULTS: CRP and P-selectin levels were significantly higher in untreated GHD adolescents than in treated GHD subjects or in healthy controls (p < 0.02), while VCAM-1 concentrations were increased in both untreated and treated GHD adolescents when compared to controls (p < 0.007). E-selectin and ICAM-1 levels were similar in all three groups. CRP was found to be associated with BMI (r: 0.62; p < 0.001), P-selectin (r: 0.43; p < 0.01), E-selectin (r: 0.27; p < 0.03), ICAM-1 (r: 0.23; p < 0.05) and VCAM-1 (r: 0.40; p < 0.001) concentrations in untreated GHD adolescents and with P-selectin (r: 0.88; p < 0.001) and E-selectin (r: 0.29; p < 0.01) in treated GHD subjects. A weak inverse association was observed in a subgroup of patients between brachial artery endothelium-dependent dilation and P-selectin (r: -0.56; p < 0.07). CONCLUSIONS: Low-grade inflammation as manifested by increased circulating levels of CRP seems to be associated with the early activation of vascular endothelial cells in GHD adolescents.

Is testosterone and estrogen priming prior to clonidine useful in the evaluation of the growth hormone status of short peripubertal children?

AIM: To determine the usefulness of priming with gonadal steroids prior to growth hormone (GH) stimulation with clonidine in the evaluation of the GH status of short peripubertal children. CHILDREN AND METHODS: Thirty-nine children, eight females and 31 males, were studied, with a mean chronological age of 12.37 +/- 2.24 years (range 8-15 years), mean bone age 9.58 +/- 2.21 years, Tanner stage 1-2, with height 134.12 +/- 11.27 cm (Ht-SDS -2.24 +/- 0.95), growth velocity (GV) 4.2 cm/yr (GV SDS -2.12 +/- 1.32) and an inadequate response to an initial GH stimulation test with clonidine (peak GH <10 microg/l). A second stimulation test with clonidine was performed in the same patients after gonadal steroid priming: 100 mg i.m. testosterone enanthate 5-8 days prior to GH stimulation in the males, and 1 mg estradiol valerate daily for 3 days in the females. GH, IGF-I, and testosterone/estradiol were measured before and after priming. RESULTS: Twenty-one of 39 children (53.8%) increased their GH response to a level of >10 microg/l following priming with gonadal steroids. Mean peak GH after priming was 12.32 +/- 8.7 microg/l compared to a peak GH level of 4.87 +/- 2.72 microg/l prior to gonadal steroid priming (peak GH 17.42 +/- 8.46 microg/l in the responders versus 5.95 +/- 2.76 microg/l in the non-responders). Although a significant increase in GH and IGF-I concentrations was noted following priming, we were unable to find a correlation between IGF-I concentrations and peak GH following priming. IGF-I levels were not different in the responders and non-responders to clonidine following priming. There was no correlation between pubertal staging and testosterone/estradiol concentrations before priming with the peak GH after priming. CONCLUSIONS: Priming with gonadal steroids significantly improves GH secretion following GH stimulation with clonidine and diminishes the possibility of a false diagnosis of GH deficiency. Gonadal steroid priming should therefore be considered in the evaluation of the GH status of short children close to or during the early stages of puberty.

Epigenetics in Turner syndrome.

Background: Monosomy of the X chromosome is the most frequent genetic abnormality in human as it is present in approximately 2% of all conceptions, although 99% of these embryos are spontaneously miscarried. In postnatal life, clinical features of Turner syndrome may include typical dysmorphic stigmata, short stature, sexual infantilism, and renal, cardiac, skeletal, endocrine and metabolic abnormalities. Main text: Turner syndrome is due to a partial or total loss of the second sexual chromosome, resulting in the development of highly variable clinical features. This phenotype may not merely be due to genomic imbalance from deleted genes but may also result from additive influences on associated genes within a given gene network, with an altered regulation of gene expression triggered by the absence of the second sex chromosome. Current studies in human and mouse models have demonstrated that this chromosomal abnormality leads to epigenetic changes, including differential DNA methylation in specific groups of downstream target genes in pathways associated with several clinical and metabolic features, mostly on autosomal chromosomes. In this article, we begin exploring the potential involvement of both genetic and epigenetic factors in the origin of X chromosome monosomy. We review the dispute between the meiotic and post-zygotic origins of 45,X monosomy, by mainly analyzing the findings from several studies that compare gene expression of the 45,X monosomy to their euploid and/or 47,XXX trisomic cell counterparts on peripheral blood mononuclear cells, amniotic fluid, human fibroblast cells, and induced pluripotent human cell lines. From these studies, a profile of epigenetic changes seems to emerge in response to chromosomal imbalance. An interesting finding of all these studies is that methylation-based and expression-based pathway analyses are complementary, rather than overlapping, and are correlated with the clinical picture displayed by TS subjects. Conclusions: The clarification of these possible causal pathways may have future implications in increasing the life expectancy of these patients and may provide informative targets for early pharmaceutical intervention.

Evaluación del desempeño cognitivo en escolares y adolescentes con diabetes mellitus tipo 1 / Evaluation of cognitive performance in children and adolescents with type 1 diabetes mellitus

Resumen El objetivo del trabajo fue evaluar el funcionamiento cognitivo de niños y adolescentes con diabetes mellitus tipo 1 (DM1) de la consulta de Endocrinología del IAHULA, y compararlo al de niños no diabéticos, así como investigar la posible influencia de factores relacionados con la enfermedad sobre la cognición. Se realizó un estudio observacional analítico, transversal, que incluyó un grupo de 30 pacientes con DM1 de 8 a 16 años de edad (16 varones) y un grupo control de 30 individuos pareados por edad, género, escolaridad y condición socioeconómica. Se realizó interrogatorio y revisión de historias clínicas para obtener datos sobre las características clínicas y el tratamiento de la DM1. Se les aplicó el test WISC IV para evaluar cognición y cociente intelectual (CI). La edad promedio de los pacientes fue de 13,27 ± 2,31 años, la mitad de ellos masculinos. Se encontraron puntajes menores en los distintos dominios del WISC IV en el grupo con DM1 al compararlos con los del grupo control (p<0,01). El CI fue menor en los niños con DM1 que en los controles (75,47 ± 13,87 frente a 88,57±11,06; p=0,0001); así mismo, se observó con mayor frecuencia un puntaje del CI inferior al percentil 10 en los pacientes con DM1 en comparación con los controles (63,3% frente a 33,3%; p=0,02; Odds ratio: 3,45; IC95%: 1,19-9,99). Se concluyó que la DM1 impacta negativamente el desempeño cognitivo de niños y adolescentes. Se recomienda la evaluación cognitiva de estos pacientes, ya que podría repercutir en su vida diaria.

Abstract The study aimed to evaluate the cognitive functioning of children and adolescents with type 1 diabetes mellitus (T1DM) recruited from the IAHULA Endocrinology Outpatient Unit and to compare it to that of non-diabetics as to investigate the influence on cognition of factors related to the disease. An analytical, cross-sectional observational study was carried out on a group of 30 patients with T1DM between 8 and 16 years of age and on a control group of 30 individuals matched by age, gender, education, and socioeconomic status. Interrogation and review of medical records to obtain data on the clinical characteristics and treatment of T1DM were conducted. The WISC IV test was then applied to evaluate cognition and intellectual coefficient (IQ). The average age of the diabetic patients was 13.27±2.31 years, and half of them were male. Lower scores were found in the different domains of the WISC IV in the group with T1DM (p<0.01). The IQ was found to be lower in children with T1DM than in controls (75.47±13.87 vs. 88.57±11.06; p=0.0001). Likewise, a higher frequency of IQ scores below the 10th percentile was observed in the diabetic children (63.3% vs. 33.3%; p=0.02; Odds ratio: 3.45; 95%CI: 1.19-9.99). It was concluded that T1DM negatively impacts the cognitive performance of children and adolescents. Cognitive evaluation of these patients is recommended, as it could affect their daily life.

Relationship between different fasting-based insulin sensitivity indices in obese children and adolescents.

OBJECTIVES: To evaluate insulin sensitivity from data obtained from baseline values and from an oral glucose tolerance test (OGTT) in normal and obese children and adolescents. STUDY DESIGN: We recruited 89 children 4-10 years old and 82 adolescents 11-18 years old divided into moderately obese (Mod OB), severely obese (Severe OB), and non-obese (Non-OB) controls. We evaluated the relationship between four simple measures of insulin sensitivity: homeostatic model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), fasting glucose to insulin ratio (FGIR), and fasting insulin resistance index (FIRI), with an insulin sensitivity measure derived from the standard 2-hour OGTT, the composite whole body insulin sensitivity index (ISI Comp). RESULTS: The strongest correlation was between QUICKI and ISI Comp and between FGIR and ISI Comp, (correlations [r] 0.81-0.85 in the Mod OB and 0.63-0.67 in the Severe OB). The relationship between HOMA-IR and ISI Comp and between FIRI and ISI Comp did not appear to be as strong (correlations [r] -0.36 and -0.53 in Mod OB and Severe OB, respectively). Moderately obese and severely obese children had fasting and 2-hour insulin levels 2-3 fold higher than the control group. CONCLUSIONS: QUICKI and FGIR, are strongly correlated with OGTT measures of insulin sensitivity in children and adolescents with different degrees of obesity. These simple fasting-based indices may help the pediatrician identify patients at risk of developing insulin resistance.

Cardiovascular Risk in Growth Hormone Deficiency: Beneficial Effects of Growth Hormone Replacement Therapy.

Growth hormone deficiency (GHD) in adulthood is associated with an increased risk of developing adverse cardiovascular events and with reduced life expectancy. Cardiovascular and metabolic abnormalities have so far been evaluated only in a small number of children with GHD and adolescents. In this article we review these abnormalities and their underlying mechanisms and discuss the beneficial effect of growth hormone treatment in subjects with GHD.

Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: apparent effects of growth hormone treatment on these parameters.

OBJECTIVE: The purpose of this study was to determine whether GH-deficient (GHD) adolescents have abnormalities of cardiac and vascular function detectable during the teenage years. DESIGN/METHODS: Ten GHD children on GH treatment with a chronological age (CA) of 14.6 +/- 1.7 yr and 12 untreated GHD adolescents with a CA of 15.0 +/- 3.0 yr were studied. Cardiac mass and function, carotid artery intima-media thickness, flow-mediated endothelium-dependent vasodilation (percent change from baseline diameter during hyperemia), and hyperemia-induced blood flow increase of the brachial artery (percent change from baseline) and epicardial adipose tissue were evaluated by echocardiography. Fourteen healthy adolescents served as controls. RESULTS: Untreated GHD adolescents present with a reduced left ventricular mass when compared with controls (P < 0.05) and a lower flow-mediated endothelium-dependent increase in the diameter of the brachial artery during hyperemia than both controls and treated GHD subjects (P < 0.02), whereas their epicardial adipose tissue is significantly higher than that of healthy controls (P < 0.02). Interventricular septum thickness, posterior wall thickness, left ventricular ejection fraction, and carotid artery intima-media thickness were similar in all three groups. Hyperemia-induced blood flow increase was greater in treated GHD adolescents than both untreated subjects and controls (P < 0.001). Body mass index correlated positively with epicardial adipose tissue in all three groups and with carotid intima-media thickness in treated and untreated GHD adolescents. CONCLUSIONS: GHD adolescents have a reduced left ventricular mass and vascular abnormalities manifested by lower flow-mediated endothelium-dependent vasodilation. These findings together with an increase in epicardial adipose tissue, a good indicator of abdominal/visceral fat, may contribute to an increased cardiovascular risk in the long term. An improvement in endothelial function and a reduction in arterial stiffness appear to occur after GH replacement.

Long-term outcome of growth hormone therapy in children and adolescents.

Growth hormone (GH) has been available for more than 4 decades for the treatment of GH deficiency. Initially, GH was extracted from the pituitary glands of human cadavers, but its use was discontinued following the transmission of the Creutzfeldt-Jakob virus. After the development of recombinant GH (somatropin) in 1985, an 'unlimited' commercial source of GH has been available, allowing for the treatment of a large number of short GH-deficient and -sufficient children. Refinements in both the dosage and the frequency of administration of GH have allowed GH-deficient children to reach nearly normal final heights, although mostly they are still below their target heights. Decreased bone mineral densities and increased concentrations of fasting and postprandial lipids, coagulation factors, and several independent cardiovascular risk factors have been reported in GH-deficient children and adolescents and appear to improve with GH administration. The short-term administration of GH to mostly non-GH-deficient short children with Turner syndrome, chronic renal insufficiency (CRI), intrauterine growth retardation (IUGR), and idiopathic short stature (ISS) has resulted in increased growth velocities. In addition, the final height of patients with Turner syndrome and CRI appears to improve with the long-term administration of GH. Final height data are still lacking in adolescents with IUGR, but height standard deviation score and final height predictions appear to improve with therapy. Based on the incomplete and inconclusive available data, one must conclude that GH treatment of children with ISS cannot be advised. The use of GH at replacement doses in children with GH deficiency has resulted in rare and generally reversible adverse effects. The long-term administration of pharmacologic GH doses to short, mostly non-GH-deficient children must, however, still be viewed with caution, as long-term complications cannot as yet be fully evaluated. GH therapy must be individualized and should be limited only to children with severe short stature or a significantly decreased growth velocity, to children under considerable stress due to their short stature, and to patients in whom low GH or low insulin-like growth factor-1 secretion might be the rate-limiting factors for growth. The cost of the medication and the inconvenience of daily GH injections to otherwise mostly healthy short children must also be taken into account.

Accelerated versus slowly progressive forms of puberty in girls with precocious and early puberty. Gonadotropin suppressive effect and final height obtained with two different analogs.

OBJECTIVES: To distinguish which children with precocious puberty (PP) and early puberty (EP) should be treated and which followed without therapy. To determine the effect of GnRH analog treatment on the final height of treated patients and compare the effect of two different analogs on gonadotropin suppression and final height. STUDY DESIGN: Sixteen females with PP or EP with a mean chronological age (CA) of 8.8 +/- 1.4 years and a mean bone age (BA) of 10.8 +/- 1.3 years were treated for a mean of 2.7 +/- 1.0 years with a GnRH analog (triptorelin or leuprolide acetate; group A), while 21 girls with a mean CA of 8.5 +/- 1.0 years, a mean BA of 9.7 +/- 1.4 years and a predicted adult height of >155 cm were followed without therapy (group B). Criteria for treatment were one of: a. predicted adult height (PAH) of <155 cm initially or at any time during follow up; b. PAH over 155 cm with a dramatic decrease in PAH over a 6-month follow-up period; c. advanced and rapidly progressing breast development for age (Tanner 3 before the age of 9 years). RESULTS: GnRHa therapy suppressed gonadotropins in group A, while gonadotropins increased gradually in group B. Height velocity (HV) decreased in group A, while it remained accelerated in group B; BA increased a mean of 1.7 +/- 0.5 years in group A and 3.2 +/- 0.3 years in group B. This resulted in a height increase in group A from a baseline PAH of 153.7 +/- 1.2 cm to a final height (FH) of 160.9 +/- 4.0 cm (p <0.001), clearly above their target height (TH) of 157.7 +/- 4.2 cm. The height of group B children did not change over time (164.1 +/- 4.1 cm before therapy and 166.0 +/- 6.0 cm at FH), both above their TH. The mean leuprolide acetate dose utilized in this study decreased during treatment, while both the initial and final triptorelin dose remained unchanged. Adequate gonadotropin suppression (peak level of LH and FSH of <2 IU/l after i.v. GnRH stimulation) was noted with both leuprolide acetate and triptorelin, although LH suppression was slightly more pronounced with triptorelin. BA advanced 1.8 +/- 0.4 years during leuprolide acetate treatment and 1.5 +/- 0.3 years with triptorelin, so that FH increased a mean of 5.5 +/- 1.3 cm with leuprolide acetate and 8.7 +/- 2.2 cm with triptorelin. CONCLUSIONS: PAH of <155 cm before or during therapy, PAH of >155 cm with a dramatic decrease in predicted height over a 6-month follow-up period and/or advanced and rapidly progressing breast development in girls with PP or EP were useful parameters in deciding which patients to treat. GnRHa therapy suppressed gonadotropins, HV and bone maturation in children with an accelerated form of PP or EP, resulting in a significant height increase. Final height remained stable over time in untreated patients. Adequate gonadotropin suppression was noted with both analogs, although with the doses of analog used in our study, LH and BA suppression were more pronounced with triptorelin, resulting in a larger height gain.