Is there a link between progranulin, obesity, and parameters of the metabolic syndrome in children? Findings from a longitudinal intervention study.

BACKGROUND: The inflammatory cytokine progranulin has been proposed to play a role in obesity and its associated comorbidities such as insulin resistance. OBJECTIVE: In a longitudinal study, we analyzed the links between progranulin, parameters of fat mass, insulin resistance, and metabolic syndrome (MetS) in obese children. METHODS: We measured the following parameters in 88 obese children at baseline, at the end of a 1-year lifestyle intervention and 1-year later (=2 years after baseline): progranulin, bioactive leptin, body mass index-SD score (BMI-SDS), waist circumference, body fat based on skinfold measurements and bioimpedance analyses, lipids, transaminases, insulin resistance index homeostasis model assessment (HOMA), and blood pressure. As a control, we determined progranulin in 23 normal-weight children. RESULTS: The progranulin concentrations did not differ significantly (P = .795) between obese and normal-weight children. Progranulin concentrations decreased significantly during and after the lifestyle intervention in children with and without decrease of BMI-SDS. There was no relationship between progranulin concentrations and pubertal stage or gender. Progranulin was not significantly associated with insulin resistance HOMA, parameters of the MetS or transaminases both in cross-sectional and longitudinal multiple linear regression analyses adjusted to multiple confounders. Progranulin was significantly, negatively related to age (b-coefficient -1.24 ± .97, P = .012, r2 = .07). CONCLUSIONS: Our data do not support the hypothesis that progranulin is an important link between obesity, insulin resistance, and MetS in childhood.

Link between chemerin, central obesity, and parameters of the Metabolic Syndrome: findings from a longitudinal study in obese children participating in a lifestyle intervention.

OBJECTIVE: Chemerin has been suggested as a potential link between obesity and associated comorbidities in humans. Therefore, we studied the relationships between chemerin, parameters of fat mass, and Metabolic Syndrome (MetS) in obese children before and after weight reduction. METHODS: We determined chemerin, bioactive leptin (bioLep), BMI-SDS, waist circumference (WC), body fat based on skinfold measurements and bioimpedance analyses, lipids, transaminases, insulin resistance index HOMA, and blood pressure in 88 obese children participating in a lifestyle intervention at baseline and 1 year later. Furthermore, we determined chemerin concentrations in 23 normal-weight children. RESULTS: Obese children demonstrated significantly (p < 0.001) higher chemerin concentrations compared to normal-weight children (96.2 ± 23.0 versus 63.1 ± 12.4 ng/ml). The chemerin concentrations were not related to age or gender. Prepubertal children had higher (p = 0.024) chemerin concentrations than pubertal children (71.0 ± 13.4 versus 58.0 ± 8.9 ng/ml). Weight loss was associated with a decrease of chemerin (-14.0 ± 22.0 ng/ml; p < 0.001) and an improvement of all parameters of the MetS. Chemerin was significantly related to BMI-SDS, WC, and bioLep in cross-sectional and longitudinal analyses. Chemerin and its changes were significantly related to insulin, HDL-cholesterol, triglycerides and their changes in multiple linear regression analyses adjusted to age, gender, pubertal stage, leptin and BMI. CONCLUSIONS: Since chemerin was related to parameters of central fat mass and MetS both in cross-sectional and longitudinal analyses these findings suggest an impact of chemerin on factors of the MetS in obese children.

Effect of Weight Loss on Puberty Onset in Overweight Children.

OBJECTIVE: To assess the impact of weight changes on the onset of puberty in overweight children. STUDY DESIGN: We evaluated the timing of puberty onset in 160 prepubertal overweight children (aged 11.2 ± 1.0 years) depending on the changes of their weight status in a 1-year lifestyle intervention. We determined body mass index (BMI), pubertal stage, luteinizing hormone (LH), follicle-stimulating hormone, insulin-like growth factor (IGF)-1, insulin-like growth factor binding protein-3, insulin resistance index homeostatic model assessment, and serum gonadotropins at baseline and 1 year later. RESULTS: Puberty onset during the 1-year follow-up was significantly (P = .014) more frequent in girls without BMI-SDS reduction (75.0%) compared with girls with BMI-SDS reduction (45.7%). The start of puberty was significantly (P = .024) more frequent in boys with BMI-SDS reduction (76.9%) compared with boys without BMI-SDS reduction (53.6%). In logistic regression analyses adjusted for baseline age and BMI-SDS, BMI-SDS reduction was associated with a decreased likelihood for puberty onset in girls (OR 0.24; 95% CI 0.07-0.85) and an increased likelihood in boys (OR 3.77; 95% CI 1.34-10.52). Central onset of puberty was confirmed by an increase of LH concentration and LH/follicle-stimulating hormone ratio in both boys and girls. Homeostatic model assessment, IGF-1, and IGF-1/insulin-like growth factor binding protein-3 ratio as marker for free IGF-1 at baseline or their changes were not associated with the onset of puberty. CONCLUSIONS: BMI-SDS reduction in overweight children was associated with earlier gonadotropin-dependent onset of puberty in boys and later onset of puberty in girls, suggesting earlier puberty in obese girls and later puberty in obese boys. We found no evidence that insulin resistance or IGF-1 have an impact on the start of puberty in obese children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00435734.

Weight loss in obese girls with polycystic ovarian syndrome is associated with a decrease in Anti-Muellerian Hormone concentrations.

OBJECTIVE: The Anti-Muellerian Hormone (AMH) has been reported as surrogate marker of antral follicles, which are the origins of hyperandrogenism in polycystic ovarian syndrome (PCOS). Therefore, AMH may be useful for the diagnosis of PCOS. The objective was to study the longitudinal changes in AMH concentrations in girls with and without PCOS. DESIGN: This is a longitudinal study of obese girls participating in a 1-year lifestyle intervention. PATIENTS: Forty obese girls aged 13-16 years (50% with PCOS) were included in the study. Girls with and without PCOS were matched to age, BMI and change in weight status. MEASUREMENTS: AMH, gonadotropins, androstenedione, testosterone, oestradiol and sex hormone-binding globulin (SHBG) were determined. RESULTS: Obese girls with PCOS demonstrated significantly (P<.001) higher AMH concentrations (5.8±3.1 ng/mL) compared to obese girls without PCOS (2.4±1.4 ng/mL). None of the girls without PCOS had AMH concentrations ≥6 ng/mL and none of the PCOS girls showed AMH concentrations ≤3 ng/mL. Weight loss in girls with PCOS was associated with a significant drop in AMH concentrations (-1.4±1.8 ng/mL, P=.045). AMH was significantly related to testosterone (cross-sectional: b-coefficient 3.7±1.7, P=.001, longitudinal: b-coefficient 0.54±0.47, P=.026) and luteinizing hormone (LH) (cross-sectional: b-coefficient 0.05±0.04, P=.039, longitudinal: b-coefficient 0.005±0.004, P=.039), but not to any other analysed parameter in multiple linear regression analyses adjusted to multiple confounders. CONCLUSIONS: AMH was increased in adolescent girls with PCOS and normalized with weight loss. AMH was cross-sectionally and longitudinally related to hyperandrogenism.

Betatrophin: no relation to glucose metabolism or weight status in obese children before and after lifestyle intervention.

OBJECTIVE: The influences of obesity, glucose metabolism, gender, and puberty on betatrophin levels and the longitudinal relationships between weight loss, metabolic changes and betatrophin have not yet been studied in childhood. METHODS: Cross-sectional and longitudinal analysis of weight status (standard deviation score-body mass index (SDS-BMI)), homeostasis model assessment insulin resistance (HOMA-IR), gender, and pubertal stage were evaluated in 69 obese children (51% female, age 11.9 ± 2.0 years) participating in lifestyle intervention over a 1-year period. An oral glucose tolerance test was performed in 53 of the 69 children. Twenty normal weight children (50% female, age 12.3 ± 3.0 years) served as controls. RESULTS: Circulating betatrophin did not differ significantly between obese and lean children (1.99 ± 0.90 vs 2.35 ± 0.28, mean ± SD, P = .155). At baseline, betatrophin did not differ in obese patients with vs without glucose intolerance (1.89 ± 0.96 vs 2.031 ± 0.91 ng/mL; P = .591) and obese with (delta SDS-BMI >0.4) vs without successful obesity intervention (1.89 ± 0.94 vs. 2.07 ± 0.87 ng/mL; P = 0.396). In multiple linear regression analyses, pubertal stage was associated with betatrophin (b: 0.48, P = .027), while gender, age, BMI, blood pressure, fasting glucose, HOMA-IR, triglycerides, LDL- and HDL-cholesterol were not related to betatrophin at baseline. At the end of the 1-year intervention, changes of betatrophin were not significantly associated with any parameter after controlling for multiple covariates including age and changes of pubertal stages. CONCLUSIONS: Our data do not support a relationship between betatrophin and weight status or glucose tolerance, insulin resistance, and lipid metabolism in children.

Copeptin in obese children and adolescents: relationships to body mass index, cortisol and gender.

OBJECTIVE: Copeptin has been reported to be associated with stress, obesity and the metabolic syndrome (MetS) in adults. However, data in childhood are scarce. Therefore, we studied the relationships between copeptin, cortisol, puberty and parameters of the MetS in children. DESIGN: Cross-sectional study. PATIENTS: A total of 51 obese children (10·8 ± 3·2 years, 39% male, 45% prepubertal, body mass index standard deviation score (BMI-SDS) 2·77 ± 0·56) and 24 lean children of similar age, gender and pubertal stage. MEASUREMENTS: Copeptin, serum cortisol, 24-h urinary free cortisol, BMI-SDS and, as parameters of the MetS, insulin resistance index (HOMA), HbA1c, uric acids, blood pressure and lipids. RESULTS: Copeptin levels were significantly (P = 0·047) higher in obese children (5·8 ± 2·8pmol/l) compared to lean children (4·6 ± 2·2pmol/l). BMI-SDS (ß-coefficient 0·38 ± 0·35, P =0·033), but not any parameter of the MetS, was significantly related to copeptin in multiple linear regression analyses adjusted for age, gender and pubertal stage. A 24-h urinary free cortisol (ß-coefficient 0·13 ± 0·06, P < 0·001), but not serum cortisol, was significantly related to copeptin in multiple linear regression analyses adjusted for age, gender, pubertal stage and BMI-SDS. Pubertal boys (6·6 ± 2·8pmol/l) demonstrated significantly (P = 0·042) higher copeptin levels compared to pubertal girls (4·8 ± 2·6pmol/l), while copeptin concentrations did not differ between prepubertal girls and boys. CONCLUSIONS: Copeptin levels are related to 24-h urinary free cortisol in obese children. Pubertal boys, but not prepubertal boys, demonstrated higher copeptin levels than girls, suggesting that sex hormones are involved in the regulation of copeptin levels. Further studies are necessary to understand the relationship between obesity, cortisol, gender, pubertal stage and copeptin levels.

Changes in the serum metabolite profile in obese children with weight loss.

PURPOSE: Childhood obesity is an increasing problem and is accompanied by metabolic disturbances. Recently, we have identified 14 serum metabolites by a metabolomics approach (FIA-MS/MS), which showed altered concentrations in obese children as compared to normal-weight children. Obese children demonstrated higher concentrations of two acylcarnitines and lower levels of three amino acids, six acyl-alkyl phosphatidylcholines, and three lysophosphatidylcholines. The aim of this study was to analyze whether these alterations normalize in weight loss. METHODS: We analyzed the changes of these 14 metabolites by the same metabolic kit as in our previous study in serum samples of 80 obese children with substantial weight loss (BMI-SDS reduction >0.5) and in 80 obese children with stable weight status all participating in a 1-year lifestyle intervention. RESULTS: In the children without weight change, no significant changes of metabolite concentrations could be observed. In children with substantial weight loss, glutamine, methionine, the lysophosphatidylcholines LPCaC18:1, LPCaC18:2, and LPCa20:4, as well as the acyl-alkyl phosphatidylcholine PCaeC36:2 increased significantly, while the acylcarnitines C12:1 and C16:1, proline, PCaeC34:1, PCaeC34:2, PCaeC34:3, PCaeC36:3, and PCaeC38:2 did not change significantly. CONCLUSIONS: The changes of glutamine, methionine, LPCaC18:1, LPCaC18:2, LPCa20:4, and PCaeC36:2 seem to be related to the changes of dieting or exercise habits in lifestyle intervention or to be a consequence of overweight since they normalized in weight loss. Further studies should substantiate our findings.

Thyroid Volume and Thyroid Function Parameters Are Independently Associated with Weight Status in Overweight Children.

BACKGROUND: A relation between thyroid-stimulating hormone (TSH), insulin resistance - both of which are related to obesity - and thyroid volume has been suggested. Therefore, we analyzed thyroid volume and structure in relation to thyroid function parameters, weight status, and insulin resistance. METHODS: This is a cross-sectional study in which weight status (BMI-SDS), thyroid function parameters (TSH, free tri-iodothyronine [fT3], and free thyroxine [fT4]), insulin resistance index (HOMA-IR), and thyroid volume (ultrasound) were determined in 617 overweight children (aged 10.4 ± 2.2 years, 50% male, BMI-SDS 2.5 ± 0.6) and in 27 normal-weight children of a similar age and gender. Furthermore, changes in thyroid volume and structure, and thyroid function parameters were analyzed in 83 obese children (51% male, mean age 10.3 ± 2.2) at baseline and at the end of a 1-year lifestyle intervention. RESULTS: Overweight children had a significant greater thyroid volume (4.2 ± 1.8 vs. 4.1 ± 0.5 mL) and higher TSH (3.1 ± 1.5 vs. 2.4 ± 1.1 mU/L) and fT3 (4.4 ± 0.7 vs. 4.1 ± 0.5 pg/mL) concentrations compared to normal-weight children. In multiple linear regression analyses adjusted to multiple confounders, thyroid volume was significantly related to BMI-SDS (b coefficient 0.44 ± 0.10, r2 = 0.41) but not to any thyroid function parameter or HOMA-IR. Changes in BMI-SDS were significantly associated with changes in thyroid volume (r = 0.22). The changes in thyroid volume were not correlated to changes of any thyroid function parameter or HOMA-IR. CONCLUSIONS: Thyroid volume is positively correlated to weight status in childhood obesity and the change is reversible after weight loss independently of thyroid function parameters and insulin resistance. Further studies are needed to understand why thyroid volume is increased reversibly in overweight children.

Link between omentin-1, obesity and insulin resistance in children: Findings from a longitudinal intervention study.

OBJECTIVE: The adipokine omentin-1 has been suggested to be inversely associated with obesity and insulin resistance in humans. We studied the relationships between omentin-1, parameters of fat mass, insulin resistance, lipids and blood pressure in children with obesity in a longitudinal study. METHODS: We analysed omentin-1 concentrations in 23 normal-weight children and in 82 children with obesity participating in a one-year lifestyle intervention. In the children with obesity, omentin-1, bioactive and conventional leptin, thyroid hormones (thyroid-stimulating hormone, free thyroxine 4, free triiodothyronine), body mass index, waist circumference, body fat based on skin-fold measurements and bioimpedance analyses, lipids, insulin resistance as homeostatic model assessment of insulin resistance (HOMA-IR) and blood pressure were determined at baseline and 1 year later. Furthermore, we measured omentin-1 concentrations 1 year after the end of the lifestyle intervention. RESULTS: The omentin-1 concentrations were significantly (P = .008) lower in children with obesity compared to normal-weight children (296 ± 108 ng ml-1 vs. 232 ± 99 ng ml-1 ). Omentin-1 concentrations increased significantly (P < .001) in children with obesity and substantial weight loss (35 ± 55 ng ml-1 ), while omentin-1 concentrations did not change significantly (P = .750) in children with obesity without weight loss (-5 ± 108 ng ml-1 ) during the intervention. Substantial weight loss after the end of intervention led to a significant (P < .001) increase of omentin-1 concentrations (+64 ± 14 ng ml-1 ). Omentin-1 was significantly and negatively associated with HOMA-IR both in cross-sectional (r = -.27, P = .006) and longitudinal analyses (r = -.33, P = .001). Omentin-1 concentrations were not related to pubertal stage, sex or thyroid hormones. CONCLUSIONS: Our data do support the hypothesis that omentin-1 is reversibly decreased in obesity and is a link between obesity and insulin resistance.

Sex Hormone Profile in Pubertal Boys With Gynecomastia and Pseudogynecomastia.

CONTENT: Gynecomastia (defined by proliferation of glandular elements) and pseudogynecomastia (defined by adipose tissue) are frequent in pubertal boys. An association with sex hormones and the growth hormone axis has been discussed. OBJECTIVE: The objective of this work is to compare sex hormones, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor binding protein 3 (IGFBP-3) between boys with gynecomastia and pseudogynecomastia (separation by ultrasound). DESIGN: An observational study was performed. SETTING: The setting of this study was an outpatient clinic. PARTICIPANTS: A total of 124 pubertal boys (mean age 14 ±â€…2 years) with breast enlargement and 84 healthy boys (mean age 14 ±â€…2 years) without breast enlargement participated in this study. INTERVENTIONS: No interventions were performed. MAIN OUTCOME MEASURES: Measurements were taken for sex hormones (progesterone, estradiol [E2], estriol, estrone, androstendione, testosterone [T], dihydrotestosterone) measured by liquid chromatography-tandem mass spectrometry, as well as gonadotropins, prolactin, IGF-1, and IGFBP-3. RESULTS: Eighty-six boys suffered from gynecomastia and 38 from pseudogynecomastia. In boys with gynecomastia, the E2/T ratio (median 22, interquartile range [IQR] 8-75) was significantly (P < .05) higher compared to boys with pseudogynecomastia (median 12, IQR 5-21) or healthy controls without breast enlargement (median 18, IQR 6-44) even after adjustment for testes volume. T concentrations were significantly (P < .05) lower in boys with gynecomastia (median 1.8, IQR 0.7-4.2 nM/L) compared to boys with pseudogynecomastia (median 4.3, IQR 1.4-6.9 nM/L) or healthy controls without breast enlargement (median 3.1, IQR 0.6-7.6 nM/L). Boys with gynecomastia did not differ from boys with pseudogynecomastia according to other sex hormones, prolactin, IGF-1, or IGFBP-3 concentrations. CONCLUSIONS: True gynecomastia is characterized by a relative T deficiency to E2 concentrations in contrast to pseudogynecomastia.

Higher steroid sulfation is linked to successful weight loss in obese children.

Objective Little information is available on the steroid sulfates profile in obese children. Therefore, we examined whether sulfated steroids are linked with weight status and associated comorbidities in obese children. Methods We analyzed 66 obese children (mean age 10.5 ± 2.5 years, 57.6% female, 53.9% prepubertal, mean BMI 27.0 ± 4.6 kg/m2, 50% with BMI-SDS reduction >0.5, 50% without BMI-SDS reduction) who participated in an outpatient 1-year intervention program based on exercise, behavior and nutrition therapy. We measured intact sulfated steroids (cholesterol sulfate (CS), pregnenolone sulfate (PregS), 17αOH pregnenolone sulfate (17OH-PregS), 16αOH dehydroepiandrosterone sulfate (16OH-DHEAS), DHEAS, androstenediol-3-sulfate, androsterone sulfate and epiandrosterone sulfate) by LC-MS/MS, and insulin resistance index HOMA, lipids, blood pressure at baseline and 1 year later. Results All sulfated steroids except 17OH-PregS, 16OH-DHEAS, androsterone sulfate and epiandrosterone sulfate were higher in boys compared to girls. Concentrations of CS before intervention were higher in children who lost weight. After 1 year of treatment, both groups showed increased levels of DHEAS, 16OH-DHEAS and androstenediol-3-sulfate, but PregS was only increased in children with weight loss. None of the steroid sulfates was significantly related to cardiovascular risk factors or HOMA except 17OH-PregS, which was associated with systolic blood pressure both in cross-sectional (ß-coefficient: 0.09 ± 0.07, P = 0.020) and longitudinal analyses (ß-coefficient: 0.06 ± 0.04, P = 0.013) in multiple linear regression analyses. Conclusions Since higher steroid sulfation capacity was associated with successful weight intervention in children disruption of sulfation may be associated with difficulties to lose weight. Future studies are necessary to prove this hypothesis.

Bioactive leptin is stronger related to parameters of fat mass and distribution than conventionally measured leptin: Findings from a longitudinal study in obese children participating in a lifestyle intervention.

OBJECTIVE: This study analyzed the relationships between bioactive leptin, conventionally measured leptin, and parameters of fat mass and distribution in obese children before and after weight reduction. METHODS: We determined bioactive leptin (bioLep), conventional measured leptin (conLep), weight, height, body fat based on skinfold measurements and bioimpedance analyses, waist circumference (wc), and pubertal stage in 88 obese children participating in a lifestyle intervention at baseline and one year later. RESULTS: We identified no child with homozygous or heterozygous status for bioinactive leptin mutations. The baseline associations between bioLep and BMI (r = 0.53), BMI-SDS (r = 0.48), body fat (bioimpedance: r = 0.61, skinfold thickness: r = 0.49), wc (r = 0.42), and waist to height ratio (whr) (r = 0.39) were stronger than the associations between conLep and BMI (r = 0.50), BMI-SDS (r = 0.44), body fat (bioimpedance: r = 0.57, skinfold thickness: r = 0.41), wc (r = 0.41), and whr (r = 0.37). The changes of bioLep were stronger related to changes of BMI-SDS (r = 0.54), body fat (bioimpedance r = 0.59, skinfold thickness: r = 0.37), wc (r = 0.22), and whr (r = 0.21) than the associations between changes of conLep and changes of BMI-SDS (r = 0.48), body fat (bioimpedance: r = 0.56, skinfold thickness: r = 0.43), wc (r = 0.20), and whr (r = 0.20). The same findings were observed in multiple linear regression analyses adjusted to multiple confounders. In contrast to changes of conLep (r = 0.22), the changes of bioLep during intervention were not related to weight regain after the end of intervention. BioLep concentrations did not differ between prepubertal girls and boys, but were higher in pubertal girls compared to pubertal boys (p = 0.031). CONCLUSIONS: Bioactive leptin was stronger related to fat mass and distribution compared to conventionally measured leptin.

Impact of discontinuation of growth hormone treatment on lipids and weight status in adolescents.

BACKGROUND: While the main role of growth hormone (GH) replacement therapy in children is to promote linear growth, GH has also an effect on lipids and body composition. There is an ongoing discussion whether discontinuation of GH treatment is associated with deterioration of lipids. METHODS: We analyzed weight status [as body mass index-standard deviation score (BMI-SDS)], insulin like growth factor (IGF)-1, triglycerides, total, low-density liporptoein (LDL)- and high-density lipoprotein (HDL)-cholesterol at the end of GH treatment and in mean 6 months later in 90 adolescents (53 with GH deficiency, 16 with Turner syndrome [TS] and 21 born small-for-gestational age [SGA]). RESULTS: After stopping GH treatment, total cholesterol (+10±24 mg/dL vs. -4±13 mg/dL) and LDL-cholesterol (+15±20 mg/dL vs. -6±12 mg/dL) increased significantly higher in severe (defined by GH peak in stimulation test <3 ng/mL) compared to moderate GHD. In patients with TS, total cholesterol (+19±9 mg/dL), LDL-cholesterol (+9±12 mg/dL) and HDL-cholesterol (+4.3±3.5 mg/dL) increased significantly. In adolescents born SGA, triglycerides increased (+34±51 mg/dL) and HDL-cholesterol decreased significantly (-3.8±7.1 mg/dL). In multiple linear regression analyses, changes of total and LDL-cholesterol were significantly negatively related to peak GH in stimulation tests, but not to gender, age at GH start, duration of GH treatment, observation time, changes of BMI-SDS or IGF-1 after the end of GH treatment. The BMI-SDS did not change after the end of GH treatment. CONCLUSIONS: Discontinuation of GH treatment leads to a deterioration of lipids in TS, SGA and severe but not moderate GHD.

Carotid Intima-Media Thickness in Children Treated with Growth Hormone: A Follow-Up Study over Three Years.

BACKGROUND: There is an ongoing discussion whether high doses of growth hormone (GH) may lead to cardiovascular diseases. Therefore, we studied the longitudinal relationships between GH treatment and carotid intima-media thickness (cIMT), which is predictive of the development of atherosclerosis. METHODS: We measured blood pressure, lipids, hemoglobin HbA1c, IGF-1, IGFBP-3, and cIMT in 28 children treated with supraphysiological doses of GH (mean age 9.8 ± 2.2 years, 39% males) and 36 children suffering from GH deficiency (GHD) and treated with physiological doses of GH (mean age 9.7 ± 2.2 years, 72% males) in a longitudinal study over 3 years. RESULTS: The cIMT values did not change significantly in the observation period in children with GHD (Δmaximum and Δmean cIMT 0.0 ± 0.1 mm). The mean (+0.1 ± 0.1 mm) but not the maximum cIMT (0.0 ± 0.1 mm) increased significantly (p = 0.049) in the children treated with supraphysiological doses of GH. Blood pressure, lipids, and HbA1c were not related to cIMT, while IGF-1, IGFBP-3, body mass index expressed as a standard deviation score, and treatment duration correlated significantly with cIMT. CONCLUSIONS: We did not find any robust evidence that GH treatment is associated with changes in cIMT. Further studies are necessary to analyze the impact of IGF-1 and IGFBP-3 concentrations on cIMT.

Longitudinal analyses of the steroid metabolome in obese PCOS girls with weight loss.

OBJECTIVE: The underlying mechanisms of polycystic ovarian syndrome (PCOS) are not fully understood yet. The aim of the study was to get functional insights into the regulation of steroid hormones in PCOS by steroid metabolomics. DESIGN: This is a longitudinal study of changes of steroid hormones in 40 obese girls aged 13-16 years (50% with PCOS) participating in a 1-year lifestyle intervention. Girls with and without PCOS were matched to age, BMI and change of weight status. METHODS: We measured progesterone, 17-hydroxyprogesterone, 17-hydroxyprogenolon, 11-deoxycorticosterone, 21-deoxycorticosterone, deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol, cortisone, androstenedione, testosterone, dehydroepiandrostendione-sulfate (DHEA-S), estrone and estradiol by LC-MS/MS steroid profiling at baseline and one year later. RESULTS: At baseline, obese PCOS girls demonstrated significantly higher androstenedione and testosterone concentrations compared to obese girls without PCOS, whereas the other steroid hormones including glucocorticoids, mineralocorticoids, estrogens and precursors of androgens did not differ significantly. Weight loss in obese PCOS girls was associated with a significant decrease of testosterone, androstenedione, DHEA-S, cortisol and corticosterone concentrations. Weight loss in obese non-PCOS girls was associated with a significant decrease of DHEA-S, cortisol and corticosterone concentrations, whereas no significant changes of testosterone and androstenedione concentrations could be observed. Without weight loss, no significant changes of steroid hormones were measured except an increase of estradiol in obese PCOS girls without weight loss. CONCLUSIONS: The key steroid hormones in obese adolescents with PCOS are androstenedione and testosterone, whereas glucocorticoids, mineralocorticoids, estrogens and precursors of androgens did not differ between obese girls with and without PCOS.

Progressive Decline in Height Standard Deviation Scores in the First 5 Years of Life Distinguished Idiopathic Growth Hormone Deficiency from Familial Short Stature and Constitutional Delay of Growth.

BACKGROUND: Familial short stature (FSS) and constitutional delay of growth (CDG) are the most frequent norm variants in children presenting with short stature. Knowing the growth patterns of these entities in the first years of life might be helpful to distinguish them from growth hormone deficiency (GHD) or other chronic diseases. METHODS: We studied the height in the first 5 years of life in 26 children with FSS, in 38 children with CDG and in 14 children with idiopathic GHD. RESULTS: Height standard deviation scores (SDS) did not change between birth and 6 months of life, while height SDS decreased significantly afterwards in GHD, FSS, and CDG. The loss of height SDS was higher in the first 2 years of life than between 2 and 5 years of life in children with CDG (-0.92 vs. -0.11; p = 0.003) or FSS (-0.79 vs. -0.01; p = 0.002). In idiopathic GHD, the loss of height SDS did not differ between the first 2 years of life and the next 3 years (-0.78 vs. -0.77; p = 0.821). CONCLUSION: Children with FSS and CDG showed a decline in height SDS mainly in the first 2 years of life, whereas the height SDS of children with idiopathic GHD decreased almost continuously over the first 5 years of life.

Tyrosine Is Associated with Insulin Resistance in Longitudinal Metabolomic Profiling of Obese Children.

In obese children, hyperinsulinaemia induces adverse metabolic consequences related to the risk of cardiovascular and other disorders. Branched-chain amino acids (BCAA) and acylcarnitines (Carn), involved in amino acid (AA) degradation, were linked to obesity-associated insulin resistance, but these associations yet have not been studied longitudinally in obese children. We studied 80 obese children before and after a one-year lifestyle intervention programme inducing substantial weight loss >0.5 BMI standard deviation scores in 40 children and no weight loss in another 40 children. At baseline and after the 1-year intervention, we assessed insulin resistance (HOMA index), fasting glucose, HbA1c, 2 h glucose in an oral glucose tolerance test, AA, and Carn. BMI adjusted metabolite levels were associated with clinical markers at baseline and after intervention, and changes with the intervention period were evaluated. Only tyrosine was significantly associated with HOMA (p < 0.05) at baseline and end and with change during the intervention (p < 0.05). In contrast, ratios depicting BCAA metabolism were negatively associated with HOMA at baseline (p < 0.05), but not in the longitudinal profiling. Stratified analysis revealed that the children with substantial weight loss drove this association. We conclude that tyrosine alterations in association with insulin resistance precede alteration in BCAA metabolism. This trial is registered with ClinicalTrials.gov Identifier NCT00435734.

Which Amount of BMI-SDS Reduction Is Necessary to Improve Cardiovascular Risk Factors in Overweight Children?

CONTEXT: Knowing the changes of cardiovascular risk factors (CRFs) in relation to weight loss would be helpful to advise overweight children and their parents and to decide whether drugs should be prescribed in addition to lifestyle intervention. OBJECTIVE: The objective of the study was to determine the body mass index (BMI)-SD score (SDS) reduction to improve CRFs in overweight children. DESIGN: This was a prospective observation study. SETTING: The study was conducted at a specialized outpatient obesity clinic. PATIENTS: A total of 1388 overweight children (mean BMI 27.9 ± 0.1 kg/m(2), mean age 11.4 ± 0.1 y, 43.8% male, 45.5% prepubertal) participated in the study. INTERVENTION: The study included a 1-year lifestyle intervention. MAIN OUTCOME MEASURES: We studied changes of blood pressure (BP), fasting high-density lipoprotein- and low-density lipoprotein-cholesterol, triglycerides, glucose, and homeostasis model assessment (HOMA) of insulin resistance index. Change of weight status was determined by δBMI-SDS based on the recommended percentiles of the International Task Force of Obesity. RESULTS: BMI-SDS change was associated with a significant improvement of all CRFs except fasting glucose and low-density lipoprotein-cholesterol after adjusting for multiple confounders such as baseline CRFs, age, gender, BMI, pubertal stage, and its changes. BMI-SDS reduction of 0.25-0.5 was related to a decrease of systolic blood pressure (BP) (-3.2 ± 1.4 mm Hg), diastolic BP (-2.2 ± 1.1 mm Hg), triglycerides (-6.9 ± 5.8 mg/dL), HOMA (-0.5 ± 0.3), and triglyceride/high-density lipoprotein)-cholesterol (-0.3 ± 0.2), whereas high-density lipoprotein (HDL)-cholesterol increased (+1.3 ± 1.2 mg/dL). A reduction of greater than 0.5 BMI-SDS led to more pronounced improvement (systolic BP -6.0± 1.3 mm Hg, diastolic BP -5.1 ± 1.3 mm Hg, triglycerides -16.4 ± 7.1 mg/dL, HDL-cholesterol +1.6 ± 1.5 mg/dL, HOMA -0.9 ± 0.3). Per 0.1 BMI-SDS reduction in systolic BP (-1.0 mm Hg), diastolic BP (-0.8 mm Hg), triglycerides (-2.3 mg/dL), HOMA (-0.2), and triglyceride/HDL-cholesterol (-0.5) decreased significantly, whereas HDL-cholesterol (0.2 mg/dL) increased significantly in linear regression analyses and accounted for multiple confounders. CONCLUSIONS: A BMI-SDS reduction of 0.25 or greater significantly improved hypertension, hypertriglyceridemia, and low HDL-cholesterol, whereas a BMI-SDS greater than 0.5 doubled the effect.

Low Treatment Adherence in Pubertal Children Treated with Thyroxin or Growth Hormone.

BACKGROUND: Treatment outcome depends largely on treatment adherence (TA). However, studies analyzing TA in chronic endocrine diseases are scarce and controversial in childhood. PATIENTS AND METHODS: We studied TA in 103 children treated subcutaneously with growth hormone (GH) and 97 children treated orally with thyroxin. TA was calculated based on the prescription refill rates. The number of GH injections was recorded by an autoinjector device in 23 children treated with GH. RESULTS: The correlation between recorded TA and calculated TA based on prescription refill rates was very good (p < 0.001, r = 0.83). TA was lower (p < 0.01) in pubertal children compared to prepubertal children and in children self-administering their medication compared to those whose drug was administered by their parents, both in GH- and thyroxin-treated children. Overall, 67% of the pubertal children treated with GH and 58% of the pubertal children treated with thyroxin missed at least 1 dose per week. TA was higher (p < 0.001) in children with thyroxin treatment compared to children treated with recombinant human GH (8 vs. 26% missed >3 doses/week). DISCUSSION: Puberty and self-administration of drugs were negative predictors of TA. Therefore, in puberty, prevention and treatment efforts should be undertaken to improve TA, especially when adolescents administer their drugs themselves.

Strong effect of pubertal status on metabolic health in obese children: a longitudinal study.

CONTEXT: The concept of metabolic healthy obese (MHO) status has been proposed also for children. However, it is unclear whether this is a stable status in childhood. OBJECTIVE: The aim was to analyze the changes of MHO status over time. DESIGN AND SETTING: This is 1-year longitudinal analysis of our obesity cohort. PARTICIPANTS: All obese children of our outpatient obesity clinic with 1-year follow-up were included. INTERVENTIONS: Standard care intervention was used. MAIN OUTCOME MEASURES: We examined body mass index (BMI), waist circumference, pubertal stage, blood pressure, fasting lipids, glucose, and insulin resistance index homeostasis model assessment (HOMA). MHO status was defined by absence of cardiovascular risk factors. RESULTS: A total of 2017 obese children (mean age, 11.6 ± 2.8 y; 45% male; BMI, 28.5 ± 5.3 kg/m(2); BMI-z score, 2.4 ±0.5) were enrolled onto the study, and 49.3% of the children were MHO at baseline. After 1 year, the majority of the MHO remained MHO (68.0%). MHO children were significantly younger, more frequently prepubertal, and less overweight compared with metabolic unhealthy obese (MUO) children (all P < .05). In the longitudinal analyses, entering into puberty (OR, 1.9; 95% confidence interval, 1.3-2.8]; P = .004) doubled the risk for switching from MHO to MUO, whereas changing from mid to late puberty nearly tripled the likelihood for switching from MUO to MHO (OR 3.1 [2.1-4.5], P < .001) in multiple logistic regression analyses adjusted for age, sex, and changes of body mass index standard deviation score (BMI-SDS). CONCLUSIONS: MHO is a stable status in childhood obesity as long as pubertal status remains stable. Due to the strong association between puberty and MUO status, the concept of MHO is questionable, at least in pubertal children.