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Context: Estrogen levels and their metabolites are higher in obese vs lean postmenopausal women, and obesity increases breast cancer risk. Quinone derivatives of 4-hydroxylated estrogen metabolites, independently of the estrogen receptor, cause depurination and impaired DNA repair (genotoxic). 16α-Hydroxy (16α-OH)-estrone (E1), eg, promotes tumor proliferation and 2-methoxy-estradiol (E2) may be chemoprotective. Childhood obesity increases breast cancer death risk in women, but levels of estrogen derivatives had not been previously studied in young children., Objective: The objective of the study was to investigate whether total and genotoxic estrogens are increased in prepubertal obese girls compared with lean controls., Design: Stored sera from 12 lean and 23 obese prepubertal girls (Tanner stage I breast and pubic hair) studied previously were assayed for E1, E2, and their multiple metabolites (12 steroids total) using highly sensitive liquid chromatography and tandem mass spectrometry., Results: E2 concentrations were significantly higher in obese [3.45 (0.5, 4.65) pg/ml (median [quartile 1, quartile 3])] vs lean girls [0.5 (0.5, 2.37), P = .04], 57% of values upper quartile or greater (quartile 3) of controls. Concentrations of 16α-OH-E1 were higher in obese [7.17 (0.5, 9.64) pg/mL] vs lean girls [0.5 (0.5, 1.72, P = .007)], 65% of values quartile 3 or greater of controls. 2-Methoxy-E2 concentrations were lower in the obese group (P = .012). 16α-OH-E1 concentrations were positively correlated with body mass index, percentage fat mass, and IL-6 concentrations (P < .001)., Conclusions: E2 and genotoxic metabolites were higher in obese vs lean prepubertal girls. These data suggest that obesity is associated with an increased extraglandular estrogen production and metabolism before the onset of puberty in girls. Long-term epidemiological studies are needed to assess any potential increase in breast cancer risk.

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: The European Quality of Life in Short Stature Youth (QoLISSY) is a novel condition-specific instrument developed to assess health related quality of life (HrQoL) in children/adolescents with short stature from patient and parent perspectives. Study objective was to linguistically validate and psychometrically test the American-English version of the QoLISSY instrument., Methods: Upon conversion of the British-English version to American-English, content validity and acceptance of the questionnaire were examined through focus group discussions with cognitive debriefing in 28 children/adolescents with growth hormone deficiency (GHD) or idiopathic short stature (ISS) and their parents. In the subsequent field test with 51 families and a re-test with 25 families the psychometric performance of the American-English version was examined and compared with the original European dataset., Results: Pilot test results supported the suitability of the American-English version. Good internal consistency with Cronbach's Alpha ranging from 0.84 to 0.97 and high test-re-test reliabilities were observed in the field test. The QoLISSY was able to detect significant differences according to the degree of short stature with higher HrQoL for taller children. Correlations with a generic HrQoL tool support the QoLISSY's concurrent validity. The scale's operating characteristics were comparable to the original European data., Conclusion: Results support that the QoLISSY American-English version is a psychometrically sound short stature-specific instrument to assess the patient- and parent- perceived impact of short stature. The QoLISSY instrument is fit for use in clinical studies and health services research in the American-English speaking population.

Background: Traditional, hypothesis-oriented research approaches have thus far failed to generate sufficient evidence to achieve consensus about the management of children with many endocrine disorders, partly because of the rarity of these disorders and because of regulatory burdens unique to research in children., Objective: The Pediatric Endocrine Society is launching a quality improvement network in spring 2015 for the management of pediatric endocrine disorders that are relatively uncommon in any single practice and/or for which there is no consensus on management., Design: The first of the quality improvement programs to be implemented seeks to improve the care of 11- to 17-year-old girls with Turner syndrome who require initiation of estrogen replacement therapy by providing a standardized clinical assessment and management plan (SCAMP) for transdermal estradiol treatment to induce pubertal development. The SCAMP algorithm represents a starting point within current best practice that is meant to undergo refinement through an iterative process of analysis of deidentified data collected in the course of clinical care by a network of pediatric endocrinologists., Conclusion: It is anticipated that this program will not only improve care, but will also result in actionable data that will generate new research hypotheses and changes in management of pediatric endocrine disorders.

Background: Children with type 1 diabetes (T1D) and elevated LDL-C have an increased risk for cardiovascular disease, a process that can begin in childhood., Objective: To assess the safety and efficacy of atorvastatin improving lipid profiles in children with T1D and elevated LDL-C., Subjects: Sixty children (31M/29F) with T1D, mean age: 15 ± 0.3 yr, mean diabetes duration: 6.8 ± 0.5 yr, HbA(1c) : 8.8 ± 0.2%, with mean LDL-C 124 ± 4.0mg/dl were recruited., Methods: After a 3-month run-in period, subjects were randomized double-blindly to atorvastatin or placebo for 6 months. Lipoprotein subfractions were measured by ion mobility and glucose control by HbA1C; continuous glucose monitors were worn quarterly., Results: After a run-in period, 42 subjects were randomized. There were decreases in total cholesterol (-21%), LDL-C (-32%), non-HDL-C (-31%) and apoB (-26%) in the atorvastatin group versus placebo (p < 0.001). Lipoprotein subparticles (LDL-large 1 and 2A, IDL-large and small, VLDL- medium and small) decreased with statins (p < 0.03 all). Insulin sensitivity scores remained constant in both groups and correlated inversely with apoB (r = -0.312 p = 0.039) and small LDL 3A (r = -0.404 p = 0.007). One subject had asymptomatic elevation of creatinine kinase which normalized after atorvastatin discontinuation., Conclusions: Atorvastatin lowered LDL-C, apoB, and atherogenic lipoprotein subparticles in children with T1D and elevated LDL-C without worsening insulin resistance. The drug was well tolerated and safe. Long-term studies would provide better insight on the impact of these interventions in the development of cardiovascular disease in children with diabetes., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To determine whether children with type 1 diabetes mellitus (T1DM) have evidence of increased aortic stiffness or early atherosclerosis as measured by magnetic resonance imaging (MRI)., Background: T1DM increases risk for cardiovascular disease in adults but whether this process starts in childhood is unknown., Subjects: A total of 54 T1DM patients (15.4 ± 2.6 yr) and 30 age-matched controls (14.8 ± 2.7 yr) participated., Methods: MRI was performed to assess aortic arch pulse wave velocity (PWV), strain, and distensibility of the ascending and descending thoracic aorta and measures of atherosclerosis., Results: Groups were well-matched for age, pulse pressure, and gender. Low-density lipoprotein-cholesterol (LDL-C) was higher in T1DM (119.3 ± 50 vs. 76.1 ± 13.5 mg/dL, p < 0.0001). There was a trend toward decreased strain and distensibility in T1DM vs. controls in the ascending (distensibility: T1DM 62.2 ± 19.9 kPa⁻¹ × 10⁻³, control 71.6 ± 26.4 kPa⁻¹ × 10⁻³, p = 0.08) and descending aorta (strain: T1DM 25.8 ± 6.2% vs. control 28.3 ± 6.8%, p = 0.09). There was no difference in arch PWV. Advancing age and male gender was negatively associated with aortic stiffness. Hemoglobin A1c (HbA1c) was inversely related to descending aorta strain and distensibility (p < 0.05). Children with diabetes in the lowest two tertiles of insulin sensitivity demonstrated thoracic descending aortas with significantly lower strain (p = 0.027) and distensibility (p = 0.039) and increased measures of wall irregularity (p = 0.005). There were no differences in measurements of atherosclerosis between the two groups., Conclusions: Adolescents with T1DM, especially those with lower insulin sensitivity, demonstrated a trend toward stiffer, less compliant thoracic aortas, which was inversely associated with diabetes control. These data suggest large vessel aortopathy starts early in T1DM., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Context: We have recently demonstrated short-term (6-month) efficacy and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with central precocious puberty (CPP)., Objective: To assess long-term (36-month) hypothalamic-pituitary-gonadal axis suppression and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with CPP., Design: Open-label, 36-month extension., Setting: Twenty pediatric endocrine centers., Patients: Seventy-two children (mean age, 8.5 ± 1.6 y; 65 females) with CPP completed and showed maintenance of LH suppression after a 6-month lead-in study., Intervention: Leuprolide acetate depot (11.25 or 30 mg) administered im every 3 months., Main Outcome Measures: Peak-stimulated LH, estradiol, T, growth rate, pubertal progression, and adverse events (AEs)., Results: Twenty-nine of 34 subjects in the 11.25-mg group and 36 of 38 subjects in the 30-mg group had LH values < 4 mIU/mL after day 1 at all time points. All seven subjects who escaped LH suppression at any time still maintained sex steroid concentrations at prepubertal levels and showed no signs of pubertal progression. AEs were comparable between groups, with injection site pain being the most common (26.4% overall). No AE led to discontinuation of study drug. The safety profile over 36 months was comparable to that observed during the 6-month pivotal study., Conclusions: The two doses of leuprolide acetate 3-month depot were associated with an acceptable safety profile and provided maintenance of LH suppression in the majority of children with CPP during the 36 months of the study or until readiness for puberty.

Context: Glycemic control is limited by the barrier of hypoglycemia. Recurrent hypoglycemia impairs counterregulatory (CR) hormone responses to subsequent hypoglycemia., Objective: To determine the glucagon and epinephrine responses to insulin-induced hypoglycemia in adolescents with recent-onset type 1 diabetes mellitus (T1DM)., Methods: We assessed the CR responses to hypoglycemia by performing a hyperinsulinemic (2.0 mU/kg/min), euglycemic (BG 90 mg/dL; 5.0 mmol/L)-hypoglycemic (BG 55 mg/dL; 3.0 mmol/L) clamp in 25 recent-onset (<1 yr duration) patients 9-18 yr old (mean ± SD: 13.4 ± 2.7) with T1DM and 16 non-diabetic controls 19-25 yr old (mean ± SD 23.3 ± 1.8). Twenty of the T1DM subjects were retested 1-yr (53 ± 3 wk) later., Results: At the initial and 1-yr studies, peak glucagon (pGON) and incremental glucagon (ΔGON) during hypoglycemia were lower in the T1DM subjects [median pGON = 47 pg/mL (quartiles: 34, 72), ΔGON = 16 (4, 27) initially and pGON = 50 pg/mL (42, 70), ΔGON = 12 (9, 19) at 1-yr] than in controls [pGON = 93 pg/mL (60, 111); ΔGON = 38 pg/mL (19, 66), p = 0.01 and p = 0.004 for ΔGON at initial and 1-yr study, respectively]. In contrast, peak epinephrine (pEPI) and incremental epinephrine (ΔEPI) levels were similar in the T1DM (pEPI = 356 pg/mL (174, 797) and ΔEPI = 322 pg/mL (143, 781) initially and pEPI = 469 pg/mL (305, 595) and ΔEPI = 440 pg/mL (285, 574) at 1 yr) and in controls (pEPI = 383 pg/mL (329, 493) and ΔEPI = 336 pg/mL (298, 471) p = 0.97 and 0.21 for ΔEPI at initial and 1-yr study, respectively)., Conclusions: Even within the first year of T1DM, glucagon responses to hypoglycemia are blunted but epinephrine responses are not, suggesting that the mechanisms involved in the loss of these hormonal responses, which are key components in pathophysiology of hypoglycemia-associated autonomic failure, are different., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children., Research Design and Methods: Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition., Results: Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects., Conclusions: These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

Background: The ability to lie still in an MRI scanner is essential for obtaining usable image data. To reduce motion, young children are often sedated, adding significant cost and risk., Objective: We assessed the feasibility of using a simple and affordable behavioral desensitization program to yield high-quality brain MRI scans in sedation-free children., Materials and Methods: 222 children (4-9.9 years), 147 with type 1 diabetes and 75 age-matched non-diabetic controls, participated in a multi-site study focused on effects of type 1 diabetes on the developing brain. T1-weighted and diffusion-weighted imaging (DWI) MRI scans were performed. All children underwent behavioral training and practice MRI sessions using either a commercial MRI simulator or an inexpensive mock scanner consisting of a toy tunnel, vibrating mat, and video player to simulate the sounds and feel of the MRI scanner., Results: 205 children (92.3%), mean age 7 ± 1.7 years had high-quality T1-W scans and 174 (78.4%) had high-quality diffusion-weighted scans after the first scan session. With a second scan session, success rates were 100% and 92.5% for T1-and diffusion-weighted scans, respectively. Success rates did not differ between children with type 1 diabetes and children without diabetes, or between centers using a commercial MRI scan simulator and those using the inexpensive mock scanner., Conclusion: Behavioral training can lead to a high success rate for obtaining high-quality T1-and diffusion-weighted brain images from a young population without sedation.

The aim of this study was to assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function. Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10 years across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data, and T1D glycemic history since diagnosis were collected. The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5 years and average onset age was 4 years. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < .001). Learning and memory (p = .46) and processing speed (p = .25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory. Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time.

Studies of brain structure in type 1 diabetes (T1D) describe widespread neuroanatomical differences related to exposure to glycemic dysregulation in adults and adolescents. In this study, we investigate the neuroanatomical correlates of dysglycemia in very young children with early-onset T1D. Structural magnetic resonance images of the brain were acquired in 142 children with T1D and 68 age-matched control subjects (mean age 7.0 ± 1.7 years) on six identical scanners. Whole-brain volumetric analyses were conducted using voxel-based morphometry to detect regional differences between groups and to investigate correlations between regional brain volumes and measures of glycemic exposure (including data from continuous glucose monitoring). Relative to control subjects, the T1D group displayed decreased gray matter volume (GMV) in bilateral occipital and cerebellar regions (P < 0.001) and increased GMV in the left inferior prefrontal, insula, and temporal pole regions (P = 0.002). Within the T1D group, hyperglycemic exposure was associated with decreased GMV in medial frontal and temporal-occipital regions and increased GMV in lateral prefrontal regions. Cognitive correlations of intelligence quotient to GMV were found in cerebellar-occipital regions and medial prefrontal cortex for control subjects, as expected, but not for the T1D group. Thus, early-onset T1D affects regions of the brain that are associated with typical cognitive development.

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.

Continuous glucose monitors (CGM), devices that can measure interstitial glucose in "real time," have become widely available particularly for use in patients with diabetes, and their accuracy and ease of use have greatly improved over the last decade. A number of large and well-controlled clinical trials have firmly established their usefulness in improving metabolic control (as measured by HbA1C) and decreasing time spent in hypoglycemia in adults; however, data have been less robust proving benefit in children and adolescents. Benefits are clearly linked to near-continuous wear. Insulin dosing algorithms based on CGM glucose trends have proven useful in dissecting the large volume of data generated daily by these devices, although these are imperfect tools, particularly in children. The technology is likely to be most useful when integrated with insulin pump delivery systems (sensor augmented). In this review, we concentrate on the analysis of published results of the largest trials in adults and children, including the very young, with diabetes.

Objective: To establish normative data for lipoprotein subfractions using a novel ion mobility assay in healthy lean children and to compare their data with those of obese children preselected with normal glucose, blood pressure, and relatively normal lipids., Study Design: Fasting blood samples in 162 children aged 7.0-18.9 years (75 lean [body mass index: 18.6 ± 6.6 kg/m(2)] and 87 obese [body mass index: 31.7 ± 5.4 kg/m(2)]) were analyzed. Correlation of lipoprotein subfractions with anthropometric and laboratory markers was performed. Principal component analysis was used to avoid using correlated variables., Results: Normative data for lipid subfractions were obtained in healthy children. Lean children had higher high-density lipoprotein (HDL)-large (76%), HDL-small (13%), and HDL-total (27%) compared with obese (P < .01), and lower low-density lipoprotein (LDL)-medium (-30%, P < .01) and medium + small (-21%, P = .02) as well as LDL-total (-13%, P = .035). In both groups, the LDL component was higher in males and pubertal children (P < .01). Prepubertal children had a higher HDL component than pubertal ones (P < .004). Adjusting for sex and pubertal status LDL component was positively, and HDL component negatively, correlated with obesity (P < .004)., Conclusions: Despite relatively normal triglycerides and cholesterol measured with standard assays at screening, ion mobility analysis showed significant differences in lipid and apolipoprotein subfractions between lean and obese children, even those prepubertal. Long-term, prospective follow-up may better characterize the predictability of lipid subfractions for future cardiovascular disease risk in children., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Context: GnRH agonist (GnRHa) monthly injections are frequently used in the treatment of central precocious puberty (CPP). The 3-month leuprolide depot 11.25- and 30-mg formulations are newly approved treatment options., Objective: The aim of the study was to investigate the safety and efficacy of leuprolide acetate 3-month depot formulations for the treatment of CPP in children., Design: This was a phase III, randomized, open-label, dose-ranging 6-month study., Setting: Twenty-two U.S. medical centers (including Puerto Rico) participated., Patients: Children diagnosed with CPP (n = 84), who were either treatment naive or previously treated with GnRHa, were recruited. Chronological age at onset of pubertal signs was less than 8 yr in girls and less than 9 yr in boys, and bone age was advanced over chronological age at least 1 yr., Intervention: Leuprolide acetate depot (11.25 or 30 mg) was administered im every 3 months., Main Outcome Measures: Biochemical [peak-stimulated LH, estradiol (girls), and testosterone (boys)] and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed., Results: Peak-stimulated LH was suppressed in the 11.25- and 30-mg dose groups in 78.4 and 95.2%, respectively, of children from months 2 through 6. There were nine treatment failures (peak-stimulated LH >4 IU/liter) in the 11.25-mg group and two in the 30-mg group. Basal sex steroid suppression, growth rates, pubertal progression, bone age advancement, and adverse events were similar with either dose., Conclusions: Treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis, was well tolerated, and may positively impact patient convenience and compliance.

Purpose: Obesity in adolescence increases the risk for early adult cardiovascular disease. We recently showed that 6 months of diet, exercise, and metformin resulted in reductions in adiposity and that diet/exercise alone reduced proinflammatory factors and intrahepatic fat in pubertal children with uncomplicated obesity. The purpose of the present study was to determine whether changes in cardiorespiratory fitness (CRF) after 6 months of structured diet and exercise (DE) or DE plus metformin are related to the previously observed changes in adiposity, markers of inflammation, and intrahepatic fat., Methods: Sixteen obese pubertal adolescents between the ages of 10 and 17 were randomized into a structured lifestyle program consisting of DE or DE plus metformin. Subjects performed aerobic and resistance exercise 3 d·wk⁻¹, 30 min per session. Cycle ergometer maximal oxygen consumption (V˙O2max), body composition, blood markers (glucose, insulin, homeostatic model assessment-insulin resistance, interleukin-6, hsCRP), and intrahepatic fat were measured at baseline and 6 months., Results: In the cohort, as whole-body weight decreased by 4.0% (P = 0.009), body mass index decreased by 4.9% (P = 0.003), percent body fat decreased by 8.8% (P < 0.001), and V˙O2max improved in 10 of 16 subjects. The addition of metformin provided no further effect on body composition, CRF, or inflammatory factors. More favorable changes in adiposity, adiponectin, and a trend toward blood glucose and interleukin-6 concentrations (P = 0.07) were observed in subjects who increased V˙O2max at 6 months (n = 10) compared with no change in these variables in those who did not improve V˙O2max., Conclusions: Metformin did not provide benefits above lifestyle modification for improving CRF in obese adolescents. Improvements in V˙O2max seem to be associated with more favorable metabolic outcomes.

The best type, dose and route of estrogen replacement in hypogonadal females has not been fully elucidated and is the subject of this brief review. When feminizing girls with different forms of hypogonadism micronized 17betaE2 should be considered the first choice as it is the most physiological and can be accurately measured in plasma. Most studies of the metabolic effects of the different routes have also used different types of estrogen making comparisons difficult. However, when using the same estradiol compound, 17betaE2 transdermal results in E2, E1 and bioestrogen concentrations closer to normal as compared to oral and achieves greater suppression of LH/FSH but similar IGF-I and lipid concentrations. Whether this translates into better body composition and metabolic outcomes in girls with hypogonadism is being actively investigated and data will soon be available.

Depletion of blood glutathione (GSH), a key antioxidant, is associated with type 1 diabetes mellitus (T1D) and contributes to the pathophysiology of diabetes complications. The aim of the current study was to determine whether acute normalization of blood glucose would restore GSH kinetics in adolescents with poorly controlled T1D. Ten 16.9 ± 1.5-year-old (SE) adolescents who had had T1D for 8.5 ± 1.9 years and were free of complications but were in poor control (hemoglobin A(1c), 9.2% ± 0.5%) received two 5-hour intravenous infusions of L-[3,3-(2)H(2)]cysteine in the postabsorptive state on 2 separate days after blood glucose had been maintained overnight at 246 ± 24 mg/dL (hyperglycemia) or 118 ± 23 mg/dL (euglycemia) using intravenous insulin infusion. Blood GSH fractional synthesis rates were determined by mass spectrometry from (2)H(2)-cysteine incorporation into GSH. Neither blood GSH (551 ± 169 vs 541 ± 232 μmol/L, P = .629) nor GSH fractional synthesis rate (84% ± 30% vs 82% ± 33% d(-1), P = .965) was altered by the short-term change in glycemic control. This finding suggests that, in adolescents with poorly controlled T1D, either (a) blood glucose per se does not regulate GSH metabolism or (b) GSH may only respond to sustained, more chronic changes in blood glucose level., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Continuous glucose monitoring (CGM) has been demonstrated to improve glycemic control in adults with type 1 diabetes but less so in children. We designed a study to assess CGM benefit in young children aged 4 to 9 years with type 1 diabetes., Research Design and Methods: After a run-in phase, 146 children with type 1 diabetes (mean age 7.5 ± 1.7 years, 64% on pumps, median diabetes duration 3.5 years) were randomly assigned to CGM or to usual care. The primary outcome was reduction in HbA(1c) at 26 weeks by ≥0.5% without the occurrence of severe hypoglycemia., Results: The primary outcome was achieved by 19% in the CGM group and 28% in the control group (P = 0.17). Mean change in HbA(1c) was -0.1% in each group (P = 0.79). Severe hypoglycemia rates were similarly low in both groups. CGM wear decreased over time, with only 41% averaging at least 6 days/week at 26 weeks. There was no correlation between CGM use and change in HbA(1c) (r(s) = -0.09, P = 0.44). CGM wear was well tolerated, and parental satisfaction with CGM was high. However, parental fear of hypoglycemia was not reduced., Conclusions: CGM in 4- to 9-year-olds did not improve glycemic control despite a high degree of parental satisfaction with CGM. We postulate that this finding may be related in part to limited use of the CGM glucose data in day-to-day management and to an unremitting fear of hypoglycemia. Overcoming the barriers that prevent integration of these critical glucose data into day-to-day management remains a challenge.

Objective: To determine if metformin improves markers of inflammation, thrombosis, and intrahepatic fat contents in children with uncomplicated obesity., Methods: Obese children with normal glucose tolerance but elevated highly sensitive C-reactive protein (hsCRP) and/or fibrinogen concentrations (>2 standard deviations) were randomized to structured diet/exercise or diet/exercise and metformin for 6 months. Blood samples, dual energy X-ray absorptiometry data, and liver magnetic resonance images were obtained., Results: Forty-two of 66 recruited children (7-18 years) completed 6 months. Weight loss was modest but more pronounced in the metformin group (-4.9 +/- 1.0 kg) than in the diet/exercise group (-1.7 +/- 1.1 kg, p<0.03), whereas hsCRP and fibrinogen decreased more in the diet/exercise pubertal group. Baseline intrahepatic fat was high but decreased only in the diet/exercise (not metformin) pubertal group., Conclusions: Six months of metformin therapy improved weight loss and reduced abdominal adiposity, but did not enhance the beneficial effect of diet and exercise on markers related to inflammation, thrombosis, or hepatic fat in obese children with normal glucose tolerance.

Objectives: To describe the interrelationships of glycemic control measures: hemoglobin A1c (HbA1c), glycated albumin, fructosamine, 1,5-anhydroglucitrol (1,5-AG), and continuous glucose monitoring (CGM) in children and adolescents with type 1 diabetes., Methods: In total, 26 subjects of age 4-17 had HbA1c measurement followed within 14 d by three laboratory measures of glycemia and the collection of CGM glucose data (N = 21)., Results: Glycated albumin and fructosamine levels had a higher correlation with each other than with HbA1c. The correlation of 1,5-AG with HbA1c was lower (absolute r value = 0.25). All four measures had a similar degree of correlation with CGM-measured mean glucose (absolute r value = 0.50-0.56) and with hyperglycemic area under the curve (AUC) at 180 mg/dL (0.50-0.60)., Conclusion: Each of the four measures (i.e., HbA1c, glycated albumin, fructosamine, and 1,5-AG) had a similar correlation with mean glucose and hyperglycemic AUC-180. 1,5-AG did not correlate with hyperglycemic AUC-180 better than did HbA1c., (© 2011 John Wiley & Sons A/S.)

Context: The type, dose, and route of 17β-estradiol (E(2)) used to feminize girls with Turner syndrome (TS) is not well established., Objective: The objective of the study was to characterize pharmacokinetics and pharmacodynamics of oral vs. transdermal E(2)., Setting: The study was conducted at a clinical research center., Subjects: Ten girls with TS, mean age 17.7 ± 0.4 (se) yr and 20 normally menstruating controls (aged 16.8 ± 0.4 yr) participated in the study., Interventions: TS subjects were randomized 2 wk each to: low-dose daily oral (0.5 mg) and biweekly transdermal E(2) (0.0375 mg) with 2 wk washout in between or high-dose oral (2.0 mg) and transdermal (0.075 mg), studied for 24 h each. Tandem mass spectrometry E(2) and estrone (E(1)) assays and a recombinant cell bioassay were used., Results: Controls consisted of the following: E(2), 96 ± 11 pg/ml (se), E(1), 70 ± 7 (mean follicular/luteal). TS consisted of the following: E(2), average concentration on low-dose oral, 18 ± 2.1 pg/ml, low-dose transdermal, 38 ± 13, high-dose oral, 46 ± 15, high-dose transdermal, 114 ± 31 pg/ml. E(1) concentrations were much higher on oral E(2) (low or high dose) than transdermal in TS and higher than controls. Bioestrogen was closest to normal in the high-dose transdermal group. LH and FSH decreased more in transdermal than oral low-dose routes and similarly in the high-dose oral and transdermal groups. IGF-I concentrations were variable (P = NS) among groups, and low-density lipoprotein/high-density lipoprotein cholesterol responses were variable., Conclusions: Transdermal E(2) results in E(2), E(1), and bioestrogen concentrations closer to normal and achieves greater suppression of LH/FSH in lower doses compared with normal. Whether the long-term metabolic effects of estrogen differ using the same form of E(2), depending on route, awaits further study in TS.

The approach to the child with growth retardation who is in puberty remains an important clinical challenge. The use of high-dose growth hormone (GH), suppression of puberty with GnRH analogs in combination with GH, and the use of selective inhibitors of the aromatase enzyme with aromatase inhibitors (also in combination with GH) are all therapeutic choices that have been studied. Aromatase blockade effectively blocks estrogen production in males with a reciprocal increase in testosterone, and a new generation of aromatase inhibitors, including anastrozole, letrozole and exemestane, is under investigation in adolescent subjects with severe growth retardation. This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Identify factors predictive of severe hypoglycemia (SH) and assess the clinical utility of continuous glucose monitoring (CGM) to warn of impending SH., Research Design and Methods: In a multicenter randomized clinical trial, 436 children and adults with type 1 diabetes were randomized to a treatment group that used CGM (N = 224), or a control group that used standard home blood glucose monitoring (N = 212) and completed 12 months of follow-up. After 6 months, the original control group initiated CGM while the treatment group continued use of CGM for 6 months. Baseline risk factors for SH were evaluated over 12 months of follow-up using proportional hazards regression. CGM-derived indices of hypoglycemia were used to predict episodes of SH over a 24-h time horizon., Results: The SH rate was 17.9 per 100 person-years, and a higher rate was associated with the occurrence of SH in the prior 6 months and female sex. SH frequency increased eightfold when 30% of CGM values were ≤ 70 mg/dL on the prior day (4.5 vs. 0.5%; P < 0.001), but the positive predictive value (PPV) was low (<5%). Results were similar for hypoglycemic area under the curve and the low blood glucose index calculated by CGM., Conclusions: SH in the 6 months prior to the study was the strongest predictor of SH during the study. CGM-measured hypoglycemia over a 24-h span is highly associated with SH the following day (P < 0.001), but the PPV is low.

Objective: To examine whether supplemental nutrition augments the anabolic actions of growth hormone (GH) in boys with constitutional delay of growth and maturation (CDGM)., Study Design: We conducted a randomized, controlled trial at an outpatient clinical research center. Subjects were 20 prepubertal boys (age, 9.3 ± 1.3 years) with CDGM (height standard deviation score, -2.0 ± 0.5; bone age delay, 1.8 ± 0.8 years; body mass index standard deviation score, -1.2 ± 1.0; peak stimulated GH, 15.7 ± 7.7 ng/mL), who were randomized (n = 10/group) to 6 months observation or daily nutritional supplementation, followed by additional daily GH therapy in all for another 12 months. t tests and repeated measures analyses of variance compared energy intake, total energy expenditure (TEE), growth, hormones, and nutrition markers., Results: Energy intake was increased at 6 months within the nutrition group (P = .04), but not the observation group, and TEE was not statistically different within either group at 6 months. Addition of 6 months GH resulted in higher energy intake and TEE in the GH/nutrition group at 12 months (P < .01), but not in the GH group versus baseline. Height, weight, lean body mass, hormones, and nutrition markers increased comparably in both groups throughout 18 months., Conclusion: Boys with CDGM use energy at an accelerated rate, an imbalance not overcome with added nutrition. GH therapy increases growth comparably with or without added nutrition in these patients., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: To evaluate the efficacy, tolerability, and pharmacokinetics of bicalutamide plus anastrozole in young males with testotoxicosis., Methods: This was a multicenter, open-label, single-arm, 12-month, Phase II pilot trial in 14 males (2-9 years) with testotoxicosis treated with bicalutamide (12.5, 25, 50, or 100 mg) and anastrozole (0.5 or 1 mg) daily. The primary outcome was change in growth rate., Results: At 1 year, the mean (standard deviation) change from baseline in growth rate was -1.6 (+/- 5.1) cm/year and -0.1 (+/- 1.8) SD units, and in bone maturation was -2.3 (+/- 0.5) years. The bone age/chronological age ratio was reduced from 2.1 (+/- 0.6) at baseline to 1.0 (+/- 0.4) (p = 0.00013). Steady-state trough R-bicalutamide and anastrozole concentrations were attained by Day 21 and 8, respectively. Gynecomastia (42.9%) and breast tenderness (12.5%) were the most common treatment-related adverse events., Conclusions: Treatment of testotoxicosis with bicalutamide plus anastrozole resulted in slower growth rate.

Background: Metabolic syndrome (MS)-related comorbidities in obesity, such as hypertension, dyslipidemia, and glucose intolerance, are increasingly recognized in children, predisposing them to early cardiovascular disease., Objective: The objective of the study was to investigate whether markers of inflammation and prothrombosis are abnormal in obese children without established MS comorbidities across puberty, as compared with lean, age-matched controls., Subjects and Methods: Obese children (body mass index >95%) with normal fasting glucose, blood pressure, cholesterol and triglycerides were recruited; lean controls (body mass index 10-75%) had no first-degree relatives with MS. High-sensitivity C-reactive protein (hsCRP), IL-6, plasminogen activator inhibitor 1, and fibrinogen concentrations were measured. Body composition was assessed by waist circumference and dual-energy x-ray absorptiometry., Results: Of 623 children screened, 203 enrolled (106 males, 97 females), aged 7-18 yr, 115 obese, 88 lean (balanced for age and gender), 99 prepubertal, and 104 pubertal. Many screen failures were due to silent comorbidities. Obese subjects with insulin resistance but without MS comorbidities had about 10 times higher hsCRP concentrations than controls and higher fibrinogen, IL-6, and plasminogen activator inhibitor-1 (P < 0.01 all). Differences were significant, even in the prepubertal cohort. hsCRP and fibrinogen correlated with waist circumference (r = 0.73 and 0.40, respectively) and percent fat mass (r = 0.76 and 0.47) (P < 0.0001)., Conclusion: Childhood obesity per se is associated with a proinflammatory and prothrombotic state before other comorbidities of the MS are present and even before the onset of puberty. Whether biomarkers like hsCRP and fibrinogen are useful in assessing cardiovascular risk and whether these abnormalities are reversible with earlier therapeutic interventions in very young obese children requires further study.

The achievement of final adult height occurs much earlier than the acquisition of peak bone mass and muscle strength in both genders, males achieving these milestones later than females. This transition period is particularly challenging in adolescents that were treated with GH during childhood. A high percentage of these adolescents in transition are no longer considered GH-deficient at the completion of their linear growth, making it necessary to retest GH reserves using potent secretagogues (such as insulin tolerance tests (ITT) or arginine/GHRH) and more stringent cutoff peaks (<6 ng/ml in this age group for ITT for example) to establish the correct diagnosis of GH deficiency. This is especially important in those with idiopathic isolated GH deficiency. Who, how and when to test are critical so that patients who are truly GH-deficient can be selected for lifelong therapy while others are spared. Data on the efficacy of GH in these patients have shown mixed results (some positive changes, others minimal or no improvement) on body composition and bone mineral density (BMD) accrual, e.g., most likely due to the differences in the length of time that patients have been off GH in the published studies. In those persistently deficient with abnormally low BMD (i.e. <-2 SD), low IGF-1 and abnormal body composition (high % body fat), GH should be continued starting at doses of 12.5 microg/kg x day and IGF-1 measured periodically and kept in the mid to upper limits of normal (within +1 SD). A repeat DEXA scan for BMD and body composition assessment a year after initiation of treatment is useful to guide therapy. GH is no substitute for healthy eating, weight control and regular exercise in diminishing cardiovascular risk, but these subjects should likely be treated at least through their mid-20s when peak BMD and muscle strength are achieved, at which time reassessment of the lifelong need for GH can be made in the idiopathic GH-deficient group. Those with multiple pituitary hormone deficiencies on the other hand should be replaced indefinitely with GH. The treatment of the GH-deficient adolescent in transition should be individualized., (Copyright 2010 S. Karger AG, Basel.)

Background: Chronic administration of glucocorticosteroids (GCs) can have significant catabolic effects in vivo in a host of metabolic systems, including amino acid metabolism, skeletal muscle, bone and linear growth. GCs inhibit protein synthesis and increase protein breakdown at the skeletal muscle and whole-body level and impair growth hormone (GH) secretion and action. Conversely, GH and insulin-like growth factor I (IGF-I) are potent protein-anabolic and growth-promoting agents in vitro and in vivo. This review summarizes both the catabolic effects of GCs and the anabolic and metabolic effects of GH and IGF-I., Conclusions: Both GH and IGF-I may decrease the catabolic effects of chronic steroid use in humans, particularly by enhancing lean body mass accrual and, in children, by increasing linear growth., (Copyright 2009 S. Karger AG, Basel.)

Objective: Hypoglycemia in young children with type 1 diabetes is an acute complication of intensive insulin therapy and is commonly observed in the absence of signs or symptoms. The effect of intensive treatment and patient age on sympathoadrenal responses has not been established in youth with type 1 diabetes because of difficulties in testing procedures., Research Design and Methods: We developed a standardized inpatient continuous subcutaneous insulin infusion protocol to produce a progressive fall in plasma glucose concentrations in insulin pump-treated patients. Plasma glucose and counterregulatory hormone concentrations were measured in 14 young children (3 to <8 years, A1C 7.7 +/- 0.6%) vs. 14 adolescents (12 to <18 years, A1C 7.6 +/- 0.8%)., Results: Plasma glucose decreased to similar nadir concentrations in the two groups. Four young children and four adolescents never had an epinephrine response. In the four young children and five adolescents who had a modest epinephrine response, this only occurred when plasma glucose fell to <60 mg/dl. In evaluating symptom scores, 29% of parents of young children felt that their child looked hypoglycemic, even at the lowest plasma glucose concentrations. Adolescents were better able to detect symptoms of hypoglycemia. In comparison with our data, epinephrine response to hypoglycemia in 14 nondiabetic adolescents studied at the Children's Hospital of Pittsburgh was higher., Conclusions: These data suggest that even young children and adolescents with type 1 diabetes are prone to develop hypoglycemia-associated autonomic failure regardless of duration. Whether these abnormalities can be reversed using continuous glucose monitoring and closed-loop insulin delivery systems awaits further study.

The approach to the child with growth retardation who is in puberty remains an important clinical challenge. The use of high-dose growth hormone (GH), suppression of puberty with GnRH analogs in combination with GH, and the use of selective inhibitors of the aromatase enzyme with aromatase inhibitors (also in combination with GH) are all therapeutic choices that have been studied. Aromatase blockade effectively blocks estrogen production in males with a reciprocal increase in testosterone, and a new generation of aromatase inhibitors, including anastrozole, letrozole and exemestane, is under investigation in adolescent subjects with severe growth retardation. This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study.

OBJECTIVE The potential benefits of continuous glucose monitoring (CGM) in the management of adults and children with well-controlled type 1 diabetes have not been examined. RESEARCH DESIGN AND METHODS A total of 129 adults and children with intensively treated type 1 diabetes (age range 8-69 years) and A1C <7.0% were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level < or =70 mg/dl, A1C level, and severe hypoglycemic events. RESULTS At 26 weeks, biochemical hypoglycemia (< or =70 mg/dl) was less frequent in the CGM group than in the control group (median 54 vs. 91 min/day), but the difference was not statistically significant (P = 0.16). Median time with a glucose level < or =60 mg/dl was 18 versus 35 min/day, respectively (P = 0.05). Time out of range (< or =70 or >180 mg/dl) was significantly lower in the CGM group than in the control group (377 vs. 491 min/day, P = 0.003). There was a significant treatment group difference favoring the CGM group in mean A1C at 26 weeks adjusted for baseline (P < 0.001). One or more severe hypoglycemic events occurred in 10 and 11% of the two groups, respectively (P = 1.0). Four outcome measures combining A1C and hypoglycemia data favored the CGM group in comparison with the control group (P < 0.001, 0.007, 0.005, and 0.003). CONCLUSIONS Most outcomes, including those combining A1C and hypoglycemia, favored the CGM group. The weight of evidence suggests that CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%.

Context: Use of aromatase inhibitors to suppress estrogen production is being actively investigated in a variety of experimental conditions in both females and males. Anastrozole (Arimidex) is a potent and selective reversible inhibitor of the aromatase enzyme in females., Objective: Our objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of anastrozole in adolescent males with gynecomastia of less than 1 yr duration. The effect of anastrozole on breast size was also assessed as an exploratory aim., Design: We conducted a PK/PD open-label study., Setting: This clinical research center study was undertaken at pediatric academic centers., Patients: Forty-two boys with gynecomastia (mean age 13 +/- 1.8 yr; duration of gynecomastia 7.0 +/- 2.5 months; body mass index 28.3 +/- 5.9 kg/m(2)) were recruited., Interventions: Anastrozole, 1 mg, was given daily for 6 months., Main Outcomes: We assessed PK/PD of anastrozole after 14 d daily dosing and changes in breast size (exploratory aim) by manual tape measurements (area) and ultrasound (volume) after 6 months., Results: Anastrozole was rapidly absorbed orally (time to reach maximum concentration, 1 h) with a slow apparent clearance of 1.54 liters/h and a terminal half-life of 46.8 h. Testosterone/estradiol ratios increased significantly with concomitant increase in LH/FSH concentrations indicating aromatase blockade. There was a reduction in breast area (approximately 63%) and breast volume (approximately 57%) in the study group as compared with baseline (P = 0.004). The drug was well tolerated., Conclusions: Anastrozole is a potent aromatase inhibitor in adolescent males, with rapid absorption and slow elimination kinetics after oral dosing. Exploratory analysis of changes in breast size showed breast reduction in the cohort; this deserves further study.

Objective: For continuous glucose sensors to improve the treatment of children with type 1 diabetes (T1D), they must be accurate, comfortable to wear, and easy to use. We conducted a pilot study of the FreeStyle Navigator Continuous Glucose Monitoring System (Abbott Diabetes Care) to examine the feasibility of daily use of a continuous glucose monitor (CGM) in an extended ambulatory setting., Methods: Following a 13-wk trial of daily Navigator use, 45 children with T1D [10.7 +/- 3.7 yr, range 4.6-17.6, 24 using insulin pumps; continuous subcutaneous insulin infusion (CSII) and 21 using glargine-based multiple daily injections (MDI)] used the Navigator for an additional 13 wk., Results: Navigator use was initially slightly higher in the CSII users than in the MDI users but declined similarly in both groups by 22-26 wk. After 26 wk, 11 (46%) of 24 CSII users and 7 (33%) of 21 MDI users were using the CGM at least 5 d a week. No baseline demographic or clinical factors were predictive of the amount of sensor use at 26 wk. However, Navigator use during weeks 1-13 and scores on a CGM satisfaction survey at 13 wk were predictive of use in weeks 22-26., Conclusions: CGM was generally well-tolerated in children with T1D for more than 6 months, and early acceptance of CGM was predictive of extended use of the device. Although many subjects and parents found CGM valuable, the declining usage over time underscores the need to develop new technologies and strategies to increase acceptance, effectiveness, and long-term use of these devices in youth with T1D.

Radioimmunoassays (RIA) for the measurement of estradiol are sufficiently sensitive to assess the reproductive status of pre-menopausal women but lack sufficient sensitivity for low concentrations found in post-menopausal women. Bioassays have been used in the past to measure low estrogen levels but are impractical for handling high volumes of tests, particularly routine and non-research specimens. In this study, we compared results for estradiol using several different methods including bioassay, RIA, and two tandem mass spectrometry methods. At the lower tertile of estradiol measurements by RIA, the overall excellent correlation with results obtained by tandem mass spectrometry (i.e. r=0.83) was lost (i.e. r=0.29). In addition, results were much lower with bioassay and mass spectrometry than with RIA suggesting that RIA measures undesired noise or estrogen metabolites. The mass spectrometry methods correlate best with isotopic kinetic methods when assessing aromatase inhibition. On this basis, we conclude that mass spectrometry assays are the best option for measurement of low estradiol concentrations. With such assays, greater discrimination should be achievable when using estradiol levels as a predictor of the risks for breast cancer and for fractures.

Blood glutathione concentrations represent a measure of protection against oxidative damage. In earlier studies, we observed that, in adolescents with poorly controlled type 1 diabetes mellitus (T1DM), blood glutathione is significantly depleted because of increased rates of glutathione utilization. To determine whether increased availability of cysteine - one of the three constitutive amino acids of glutathione - would attenuate the alterations in glutathione metabolism, ten 16 +/- 1 yr-old adolescents with poorly controlled T1DM [hemoglobin A1c (HbA1c): 9.9 +/- 1.3%] received 5-h infusions of l-[3,3-(2)H(2)] cysteine and d-[6,6-(2)H(2)]glucose on two occasions, 3 wk apart, after a 10-d oral supplementation with (i) N-acetylcysteine (NAC, 30-45 mg/kg/d) or (ii) L-alanine, in randomized order, and with a 3-wk 'washout' interim period. Blood glucose was maintained in the same hyperglycemic range on both infusion study days, using intravenous insulin. Glutathione fractional synthesis rate (FSR) was determined from (2)H(2)-cysteine incorporation into blood glutathione. NAC supplementation failed to raise erythrocyte cysteine concentrations (23 +/- 6 vs. 17 +/- 1 micromol/L, p = 0.853) and did not alter erythrocyte glutathione concentrations (838 +/- 106 vs. 793 +/- 111 micromol/L, p = 0.220) or glutathione FSR (96 +/- 20 vs. 89 +/- 19%/d, p = 0.974). We conclude that in adolescents with poorly controlled T1DM, dietary cysteine supplementation alone cannot correct glutathione status. In the presence of relative insulinopenia, either higher amino acid doses or aggressive insulin therapy may be needed to achieve this goal. This would require further study.

Background: The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined., Methods: In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks., Results: The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference., Conclusions: Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.), (2008 Massachusetts Medical Society)

Context: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males., Objective: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency., Methods: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months., Results: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8+/-0.1 vs. +2.7+/-0.1 yr, P<0.0001) and after 3 yr (+2.5+/-0.2 vs. +4.1+/-0.1 yr, P<0.0001). This resulted in a net increase in predicted adult height of +4.5+/-1.2 cm in the anastrozole group at 24 months and +6.7+/-1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups., Conclusions: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 2-3 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach.

Glutamine is the most abundant amino acid in the body and is extensively taken up in gut and liver in healthy humans. To determine whether glucocorticosteroids alter splanchnic glutamine metabolism, the effect of prednisone was assessed in healthy volunteers using isotope tracer methods. Two groups of healthy adults received 5-h intravenous infusions of l-[1-(14)C]leucine and l-[(2)H(5)]glutamine, along with q. 20 min oral sips of tracer doses of l-[1-(13)C]glutamine in the fasting state, either 1) at baseline (control group; n = 6) or 2) after a 6-day course of 0.8 mg.kg(-1).day(-1) prednisone (prednisone group; n = 8). Leucine and glutamine appearance rates (Ra) were determined from plasma [1-(14)C]ketoisocaproate and [(2)H(5)]glutamine, respectively, and leucine and glutamine oxidation from breath (14)CO(2) and (13)CO(2), respectively. Splanchnic glutamine extraction was estimated by the fraction of orally administered [(13)C]glutamine that failed to appear into systemic blood. Prednisone treatment 1) did not affect leucine Ra or leucine oxidation; 2) increased plasma glutamine Ra, mostly owing to enhanced glutamine de novo synthesis (medians +/- interquartiles, 412 +/- 61 vs. 280 +/- 190 mumol.kg(-1).h(-1), P = 0.003); and 3) increased the fraction of orally administered glutamine undergoing extraction in the splanchnic territory (means +/- SE 64 +/- 6 vs. 42 +/- 12%, P < 0.05), without any change in the fraction of glutamine oxidized (means +/- SE, 75 +/- 4 vs. 77 +/- 4%, not significant). We conclude that high-dose glucocorticosteroids increase in splanchnic bed the glutamine requirements. The role of such changes in patients receiving chronic corticoid treatment for inflammatory diseases or suffering from severe illness remains to be determined.

Objective: Adult females receiving GH may be less sensitive to the metabolic effects of GH than males, however these differences are less well studied in adolescence. We aimed to investigate if metabolic effects of GH vary by gender during puberty., Design: Sixteen adolescents (8 M/8 F, mean age (SE): 13.1+/-0.2 yr) with significant short stature due to either GH insufficiency or idiopathic short stature were studied before and after 8 w of daily GH therapy. Differences in rates of protein and glycerol turnover ((13)C leucine and d5-glycerol infusions), substrate oxidation rates (indirect calorimetry), hormones, growth factors, lipid concentrations, body composition (DEXA) and 1 yr growth velocity were measured., Results: Protein synthesis rates per kg FFM were similar in boys and girls before and after GH and increased similarly on treatment in both genders. Rates of whole body lipolysis were similar at baseline and increased after GH in both genders comparably. Plasma lipids were similar between boys and girls before and after GH, and triglycerides increased post-GH in both. Insulin increased after GH comparably in both genders, yet no significant difference in glucose or adiponectin concentrations during treatment or between genders was observed. IGF-I concentrations were similar between boys and girls at baseline, but with a more robust increase in males after 8 w of GH (boys: +629+/-65 ng/ml, girls: +331+/-67, p=0.007). Body composition changes and bone mineral density were similar between genders after GH. HT SDS increased comparably after 1 yr (boys -2.2+/-0.09 to -1.77+/-0.11, p=0.0002; girls -2.49+/-0.24 to -2.02+/-0.25, p=0.04). There were no gender differences on the linear growth responses after 12 mo., Conclusions: As compared to girls, boys had: (1) similar sensitivity to GH for protein synthesis, lipolysis, lipid concentrations and body composition changes as well as comparable glucose and adiponectin concentrations; (2) higher IGF-I responses to 8 w of GH. Differences in IGF-I during GH treatment may account in part for the gender differences in physique and strength that develop during human puberty; however, using conventional doses of GH, these differences do not translate into differences in linear growth after 12 mo. Contrary to adults, these data do not support the need for different GH dosing depending on gender during puberty.

Context: C-type natriuretic peptide (CNP), a paracrine factor of the growth plate, plays a key role in stimulating bone growth. The amino-terminal propeptide of CNP (NTproCNP) is produced in equimolar amounts with CNP and is measurable in plasma, providing a potential biomarker for growth plate activity and, hence, linear growth., Objective: We explored the effects of puberty, testosterone, and GH treatment on NTproCNP levels in normal and short-statured children., Design: This was a retrospective analysis of samples obtained during previous studies., Setting: The study was conducted at a pediatric clinical research center., Subjects: Children with short stature due to GH deficiency, idiopathic short stature (ISS), or constitutional delay of growth and maturation (CDGM) were studied (n = 37). A cohort of normal-statured adolescent boys was also studied (n = 23)., Interventions: Children with GH deficiency and ISS were studied before and during testosterone and/or GH treatment. Boys with CDGM and healthy controls were studied once., Main Outcome Measures: The main outcomes were NTproCNP levels before and during growth-promoting therapy and during pubertal growth., Results: Children with short stature due to GH deficiency, ISS, or CDGM had comparable baseline levels of NTproCNP, and levels increased markedly in response to GH or testosterone treatment. In boys with CDGM, levels were comparable with height-matched controls but were less than those from age-matched controls. In healthy boys, NTproCNP appears to peak with the pubertal growth spurt., Conclusions: NTproCNP levels increase during growth-promoting therapy and are increased during puberty in boys. This novel biomarker of growth may have clinical utility in the evaluation of children with short stature and for monitoring growth-promoting therapy.

Background: Transdermal (TD) estrogen is often preferred over the oral route in postmenopausal and GH-deficient women taking estrogen, but this has not been studied in detail in girls., Objective: Our objective was to study the metabolic effects of oral vs. TD estrogen in GH-treated girls with Turner syndrome., Design and Methods: Eleven girls with Turner syndrome, mean age 13.4 +/- 0.5 (se) yr, on GH for at least 6 months were recruited. Studies included [(13)C]leucine and d5-glycerol infusions, indirect calorimetry, dual-emission x-ray absorptiometry, and hormone and substrate measurements. They received, in random order, 17beta-estradiol orally (0.5, 1, and 2 mg for 2 wk each) and TD (0.025, 0.0375, and 0.05 mg for 2 wk each), and studies were repeated after each 6-wk course with 4 wk washout in between., Results: Rates of whole-body protein turnover, oxidation and synthesis, lipolysis, lipid and carbohydrate oxidation, and resting energy expenditure were unaffected by either form of estrogen; nor were lipids, insulin, and fibrinogen concentrations affected. Plasma IGF-I concentrations did not change clinically significantly with either form of estrogen, despite higher estrogen concentrations after oral estrogen. Estradiol concentrations did not correlate with any variables measured., Conclusions: In GH-treated girls with Turner syndrome, neither oral nor TD estrogen adversely affected rates of protein turnover, lipolysis, and lipid oxidation rates or plasma lipids, fibrinogen, or fasting insulin concentrations. There was no clinically significant change in IGF-I concentrations after either form of estrogen. In aggregate, these data suggest that the route of delivery of estrogen does not adversely affect these metabolic effects of GH in young girls with Turner syndrome.

Objective: To examine the feasibility of daily use of a continuous glucose monitor, the FreeStyle Navigator Continuous Glucose Monitoring System ("Navigator"), in children with type 1 diabetes (T1D)., Study Design: After a masked Navigator was used for 4 to 7 days to establish a baseline level of glycemic control, 30 insulin pump users with T1D (average age 11.2 years) were asked to use the Navigator daily for 13 weeks., Results: Subjects averaged 149 h/wk of Navigator use during the first 4 weeks, which decreased slightly to 134 h/wk during weeks 9 to 13 (P = .006). Mean hemoglobin A1c improved from 7.1% at baseline to 6.8% at 13 weeks (P = .02), and the percentage of glucose values between 71 and 180 mg/dL increased from 52% to 60% (P = .01). Subjects and parents reported high satisfaction with the Navigator on the Continuous Glucose Monitor Satisfaction Scale. Two subjects had severe skin reactions related to sensor mount adhesive., Conclusion: This study indicates that incorporating real-time continuous glucose monitoring into the daily treatment of children with T1D is feasible. The results provide a compelling rationale for conducting a randomized trial of daily use of a continuous glucose monitor in children with T1D.

Background, Aims & Methods: To determine whether depletion in plasma glutamine worsens the catabolic response to corticosteroids, seven healthy volunteers received oral prednisone for 6 days on two separate occasions, at least 2 weeks apart, and in random order. On the sixth day of each treatment course, they received 5 h intravenous infusions of L-[1-(14)C]-leucine and L-[1-(13)C]-glutamine in the postabsorptive state (1) under baseline conditions (prednisone only day) and (2) after 24h of treatment with phenylbutyrate (prednisone+phenylbutyrate day), a glutamine chelating agent., Results: Phenylbutyrate treatment was associated with (1) an approximately 15% decline in plasma glutamine concentration (627+/-39 vs. 530+/-31 micromol l(-1); P<0.05), (2) no change in leucine appearance rate, an index of protein breakdown (124+/-9 vs. 128+/-9 micromol kg(-1) h(-1); NS) nor in non-oxidative leucine disposal, an index of whole body protein synthesis (94+/-9 vs. 91+/-7 micromol kg(-1) h(-1); NS), and (3) a approximately 25% rise in leucine oxidation (30+/-1 vs. 38+/-2 micromol kg(-1) h(-1), P<0.05), despite an approximately 25% decline (P<0.05) in leucine concentration., Conclusions: In a model of mild, stress-induced protein catabolism, depletion of plasma glutamine per se may worsen branched chain amino acid and protein wasting.

Objective: This article evaluated whether deviation from developmentally appropriate self-care autonomy moderated the effects of intensive therapy (IT) or usual care (UC) on glycosylated hemoglobin (HbA(1C)) in 142 youths with diabetes., Methods: Youths received an autonomy/maturity ratio (AMR) score at baseline that was a ratio of standardized scores on measures of self-care autonomy to standardized scores on measures of psychological maturity and were categorized by tertile split into low, moderate, and high AMR., Results: Higher baseline AMR was associated with higher baseline HbA(1C) for IT and UC. Baseline AMR scores predicted glycemic outcomes from UC; the high AMR tertile showed deteriorating glycemic control over time, whereas the low AMR tertile maintained better glycemic control. All three AMR groups derived equal glycemic benefit from IT., Conclusion: Children with inordinate diabetes self-care autonomy may fare poorly in UC but these same children may realize less glycemic deterioration during IT.

Background: Behavioral family systems therapy (BFST) for adolescents with diabetes has improved family relationships and communication, but effects on adherence and metabolic control were weak. We evaluated a revised intervention, BFST for diabetes (BFST-D)., Methods: One hundred and four families were randomized to standard care (SC) or to 12 sessions of either an educational support group (ES) or a BFST-D over 6 months. Family relationships, adherence, glycosylated hemoglobin (HbA1c), and health care utilization were measured at baseline and after treatment., Results: BFST-D significantly improved family conflict and adherence compared to SC and ES, especially among those with baseline HbA1c > or = 9.0%. BFST-D and ES significantly improved HbA1c compared to SC among those with baseline HbA1c > or = 9.0%., Conclusions: The revised intervention (BFST-D) improved family conflict and treatment adherence significantly, while both ES and BFST-D reduced HbA1c significantly, particularly among adolescents with poor metabolic control. Clinical translation of BFST-D requires further study.

Context: Children with constitutional delay of growth and maturation (CDGM) tend to be thin and have a growth pattern reminiscent of nutritional insufficiency., Objective: Our objective was to compare differences in nutrition, body composition, bone mineral density, and resting and total energy expenditure (REE/TEE) in boys with CDGM and controls. We hypothesized that an imbalance between energy intake and expenditure may contribute to the pathogenesis of CDGM., Design and Setting: We conducted an observational, cross-sectional study at an outpatient clinical research center., Patients: Patients included 36 boys (8-17 yr): 12 with CDGM (short stature, delayed bone age and puberty, and no other pathology) and 12 height-matched (pre- or early-pubertal) and 12 age-matched (pubertal) healthy controls., Main Outcome Measures: Outcome measures included doubly labeled water studies (TEE), serum nutritional/hormonal markers, dual-energy x-ray absorptiometry, dietary analysis, and indirect calorimetry (REE)., Results: Nutritional markers were comparable among the groups. CDGM subjects had bone mineral density lower than age-matched controls (P < 0.01) but comparable with height-matched controls. Even though REE did not differ between groups, CDGM subjects had 25% higher caloric intake adjusted for fat-free mass (FFM) than height-matched controls (P < 0.05) and 78% higher caloric intake per kilogram FFM compared with age-matched controls (P < 0.00001). CDGM subjects had 46% (P < 0.05) and 91% (P < 0.001) higher TEE per kilogram FFM than height- and age-matched controls, respectively. CDGM subjects had lower IGF-I and testosterone than age-matched controls (P < 0.001) but levels were comparable with height-matched controls., Conclusions: Boys with CDGM have higher rates of overall energy expenditure compared with age- and size-matched controls. This increased metabolism may result in impaired tempo of growth. Additional studies are needed to determine whether augmenting nutrition to match their energy needs (with or without hormonal therapy) can improve linear and ponderal growth in patients with CDGM.