Publications by authors named "Nina Lass"

30 Publications

  • Page 1 of 1

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

Horm Res Paediatr 2020 9;93(5):279-286. Epub 2020 Oct 9.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Children Datteln, University of Witten/Herdecke, Datteln, Germany,

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.
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http://dx.doi.org/10.1159/000509786DOI Listing
October 2020

Sex Hormone Profile in Pubertal Boys With Gynecomastia and Pseudogynecomastia.

J Clin Endocrinol Metab 2020 04;105(4)

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel/Christian-Albrechts University of Kiel, Kiel, Germany.

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 ± 2 years) with breast enlargement and 84 healthy boys (mean age 14 ± 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.
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http://dx.doi.org/10.1210/clinem/dgaa044DOI Listing
April 2020

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

Pediatr Obes 2020 05 16;15(5):e12605. Epub 2019 Dec 16.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

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 vs. 232 ± 99 ng ml ). Omentin-1 concentrations increased significantly (P < .001) in children with obesity and substantial weight loss (35 ± 55 ng ml ), while omentin-1 concentrations did not change significantly (P = .750) in children with obesity without weight loss (-5 ± 108 ng ml ) 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 ). 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.
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http://dx.doi.org/10.1111/ijpo.12605DOI Listing
May 2020

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

Pediatr Diabetes 2019 12 18;20(8):1047-1055. Epub 2019 Sep 18.

Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

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, r = .07).

Conclusions: Our data do not support the hypothesis that progranulin is an important link between obesity, insulin resistance, and MetS in childhood.
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http://dx.doi.org/10.1111/pedi.12915DOI Listing
December 2019

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

Endocr Connect 2018 Oct;7(10):1020-1030

Steroid Research & Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus-Liebig-University Giessen, Giessen, Germany.

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 (β-coefficient: 0.09 ± 0.07, P = 0.020) and longitudinal analyses (β-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.
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http://dx.doi.org/10.1530/EC-18-0233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198195PMC
October 2018

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

Int J Obes (Lond) 2018 10 20;42(10):1743-1752. Epub 2018 Jul 20.

Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

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.
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http://dx.doi.org/10.1038/s41366-018-0157-3DOI Listing
October 2018

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.

Clin Chim Acta 2018 May 21;480:225-229. Epub 2018 Feb 21.

Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cca.2018.02.020DOI Listing
May 2018

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

J Pediatr Endocrinol Metab 2017 Jul;30(7):749-757

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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.
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http://dx.doi.org/10.1515/jpem-2017-0098DOI Listing
July 2017

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

Clin Endocrinol (Oxf) 2017 Aug 29;87(2):185-193. Epub 2017 May 29.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University Hospital of Schleswig-Holstein, UKSH, Campus Kiel/Christian Albrechts University of Kiel, CAU, Kiel, Germany.

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.
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http://dx.doi.org/10.1111/cen.13358DOI Listing
August 2017

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

Endocr Connect 2017 May 3;6(4):213-224. Epub 2017 Apr 3.

Division of Pediatric Endocrinology and DiabetesDepartment of Pediatrics, University Hospital of Schleswig - Holstein, UKSH, Campus Kiel/Christian Albrechts University of Kiel, CAU, Kiel, Germany.

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.
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http://dx.doi.org/10.1530/EC-17-0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435851PMC
May 2017

Effect of Weight Loss on Puberty Onset in Overweight Children.

J Pediatr 2017 05 24;184:143-150.e1. Epub 2017 Feb 24.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA; Division of Endocrinology, Department of Pediatrics, University of Washington, Seattle, WA.

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.
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http://dx.doi.org/10.1016/j.jpeds.2017.01.066DOI Listing
May 2017

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

Horm Res Paediatr 2017 10;87(2):73-80. Epub 2017 Jan 10.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

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.
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http://dx.doi.org/10.1159/000450643DOI Listing
June 2017

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

Clin Endocrinol (Oxf) 2016 Dec 3;85(6):868-873. Epub 2016 Oct 3.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

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 (β-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 (β-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.
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http://dx.doi.org/10.1111/cen.13235DOI Listing
December 2016

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.

Horm Res Paediatr 2016 12;86(2):117-125. Epub 2016 Aug 12.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

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.
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http://dx.doi.org/10.1159/000448283DOI Listing
April 2017

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

Pediatr Diabetes 2017 Sep 12;18(6):485-491. Epub 2016 Jul 12.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Witten, Germany.

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.
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http://dx.doi.org/10.1111/pedi.12412DOI Listing
September 2017

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

J Clin Endocrinol Metab 2016 08 10;101(8):3171-9. Epub 2016 Jun 10.

Vestische Kinder- und Jugendklinik Datteln (T.R., N.L., C.T., J.R.), Department of Pediatric Endocrinology, Diabetes, and Nutrition Medicine, University of Witten-Herdecke, D-45711 Datteln, Germany; Institute for Epidemiology and Medical Biometry (S.L., R.W.H.), Zentralinstitut für Biomedizinische Technik, University of Ulm, D-89081 Ulm, Germany; and German Center for Diabetes Research (S.L., R.W.H.), D-85764 Neuherberg, Germany.

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.
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http://dx.doi.org/10.1210/jc.2016-1885DOI Listing
August 2016

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

J Diabetes Res 2016 21;2016:2108909. Epub 2015 Dec 21.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten-Herdecke, Dr. Friedrich Steiner Strasse 5, 45711 Datteln, Germany.

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.
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http://dx.doi.org/10.1155/2016/2108909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736430PMC
December 2016

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

Horm Res Paediatr 2015 8;84(4):240-7. Epub 2015 Aug 8.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

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.
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http://dx.doi.org/10.1159/000437305DOI Listing
September 2016

Irisin and its relation to insulin resistance and puberty in obese children: a longitudinal analysis.

J Clin Endocrinol Metab 2015 May 17;100(5):2123-30. Epub 2015 Mar 17.

Department of Pediatric Endocrinology, Diabetes, and Nutrition Medicine (T.R., N.L.), Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, D-45711 Datteln, Germany; and Seattle Children's Research Institute (C.E., C.L.R.), University of Washington, Seattle, Washington 98105.

Context: Irisin is a recently identified myokine affecting metabolic and glucose homeostasis. However, the role of irisin in obesity and its metabolic consequences are controversial, and data in children are scarce.

Objective: To study the relationships between irisin, insulin resistance, and puberty before and after weight loss in obese children with and without impaired glucose tolerance.

Design: One-year follow-up study in obese children participating in a lifestyle intervention.

Setting: Primary care.

Patients: Forty obese children and 20 normal-weight children of similar age, gender, and pubertal stage.

Intervention: A 1-year outpatient intervention program based on exercise, behavior, and nutrition therapy.

Main Outcomes Measures: Fasting serum irisin, weight status (body mass index [BMI] SD score), and the following parameters of the metabolic syndrome: insulin resistance index (homeostasis model of assessment), blood pressure, and lipids.

Results: The irisin levels were the highest in obese children with impaired glucose tolerance, followed by obese children with normal glucose tolerance, and levels were lowest in normal-weight children (P < .001). In a multiple linear regression analysis, baseline irisin was significantly associated with pubertal stage, high-density lipoprotein-cholesterol, and homeostasis model of assessment, but not to age, gender, BMI, or any other parameter of the metabolic syndrome. The irisin concentrations were significantly (P = .010) lower in the prepubertal compared to the pubertal children. In longitudinal analyses, changes of irisin were significantly associated with entry into puberty, change of fasting glucose, and 2-hour glucose in an oral glucose tolerance test, but not with change of BMI or any other parameter.

Conclusions: Irisin levels are related to pubertal stage and insulin resistance but not to weight status in childhood.
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http://dx.doi.org/10.1210/jc.2015-1208DOI Listing
May 2015

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

J Clin Endocrinol Metab 2015 Jan;100(1):301-8

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine (T.R., B.W., C.K., N.L.), Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, 58448 Witten, Germany; and Institute for Epidemiology and Medical Biometry (R.W.H.), Central Institute for Biomedical Technology, CAQM, University of Ulm, 89081 Ulm, Germany.

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.
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http://dx.doi.org/10.1210/jc.2014-2674DOI Listing
January 2015

Carotid intima-media thickness in children treated with growth hormone.

J Pediatr Endocrinol Metab 2015 Sep;28(9-10):985-91

Background: There is an ongoing discussion whether high doses of growth hormone (GH) may lead to cardiovascular diseases. Therefore, we studied the relationships between GH treatment and carotid intima-media thickness (cIMT), which is predictive of the development of atherosclerosis.

Methods: We measured cIMT in 38 children with supraphysiological doses of GH (mean age 10.9 ± 2.2 years; 47% male; GH indication: small for gestational age, n = 31; Turner syndrome, n = 5; SHOX deficiency, n = 2) and in 38 age- and gender-matched healthy children without GH treatment. Furthermore, we examined cIMT in 61 children with physiological doses of GH (mean age 12.0 ± 3.1 years; 64% male; GH indication: GH deficiency) and in 61 age- and gender-matched healthy children without GH treatment. Moreover, we analyzed blood pressure, lipids, HbA1c, IGF-1, and IGFBP-3 in children treated with GH.

Results: The cIMT levels did not differ significantly between children with and without GH treatment either in high-dose GH treatment or in physiological GH doses. In backwards linear regression analyses, cIMT was significantly related to HbA1c, but not to age, gender, BMI, pubertal stage, indication of GH treatment, duration or doses of GH treatment, IGF-1, IGFBP-3, or to any cardiovascular risk factor.

Conclusions: We found no evidence that GH treatment is associated with changes in cIMT.
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http://dx.doi.org/10.1515/jpem-2014-0180DOI Listing
September 2015

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

Eur J Nutr 2015 Mar 17;54(2):173-81. Epub 2014 Apr 17.

Department of Pediatric Endocrinology, Diabetes, and Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten/Herdecke, Dr. F. Steiner Str. 5, 45711, Datteln, Germany,

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.
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http://dx.doi.org/10.1007/s00394-014-0698-8DOI Listing
March 2015

Relationships between 24-hour urinary free cortisol concentrations and metabolic syndrome in obese children.

J Clin Endocrinol Metab 2014 Jul 26;99(7):2391-9. Epub 2014 Mar 26.

Department of Pediatric Endocrinology (T.R., B.W., C.K., N.L.), Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Witten, Germany; Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics (A.K., M.W., P.-M.H.), University Hospital of Schleswig Holstein, Campus Kiel/Christian, Albrechts University of Kiel, Kiel, Germany.

Context: Clinical features of Metabolic Syndrome (MetS) and Cushing's Syndrome are similar, suggesting a pathogenetic role of hypothalamus-pituitary-adrenal axis in MetS.

Objective: The aim of the study was to determine whether MetS diagnosis and specific clusters of MetS components (waist circumference, dyslipidemia, hypertension, and impaired glucose metabolism) are associated with serum cortisol (SC) or 24-h urinary free cortisol (UFC) levels.

Design And Setting: We conducted cross-sectional analyses of data from our obesity cohort. We studied 264 obese children (age, 11.0 ± 2.8 years; male, 48%; BMI, 28.2 ± 5.4 kg/m(2)). We examined UFC, SC, homeostasis model assessment (HOMA), and features of MetS (waist circumference, blood pressure, fasting lipids, and glucose).

Results: Slightly increased UFC concentrations were measured in 30.7% of the children. Obese children with MetS had significantly (P = .003) higher UFC levels compared with obese children without MetS. Girls demonstrated significantly higher UFC concentrations compared with boys independent of pubertal stage. UFC and SC levels were significantly related to features of MetS, but the associations were stronger for UFC. In multivariate analyses adjusted for age, sex, and body mass index, none of the features of MetS but HOMA index was correlated with UFC, whereas SC demonstrated no significant association to any parameter of MetS or HOMA.

Conclusions: Our findings support the hypothesis that changes in the hypothalamus-pituitary-adrenal axis are related to MetS in obesity. UFC seems to be a suitable marker for this relationship. Norm values for UFC adapted to obese children may help to avoid unnecessary dexamethasone suppression tests.
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http://dx.doi.org/10.1210/jc.2013-4398DOI Listing
July 2014

Short stature before puberty: which children should be screened for SHOX deficiency?

Horm Res Paediatr 2013 18;80(4):273-80. Epub 2013 Sep 18.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

Objective: We studied the prevalence of deficiency in the short stature homeobox containing gene (SHOX) in prepubertal short-statured children and analyzed the clinical and radiological signs.

Methods: Screening for SHOX deficiency was performed in 449 prepubertal short-statured children (54% females, aged 4-10 years) by direct sequencing and multiplex ligation probe-dependent amplification. Children with SHOX deficiency were compared to 1:2 age- and gender-matched prepubertal children without SHOX deficiency with respect to left-hand radiographs and anthropometrics including different ratios to height and proposed scores.

Results: We identified 22 (4.9%) patients with SHOX deficiency (64% point mutations). Children with SHOX deficiency demonstrated a mesomelic shortening of extremities. Lower leg lengths but not forearm length was reduced in children <8 years with SHOX deficiency. 36% of all children and none of the children <8 years with SHOX deficiency demonstrated any typical radiologic sign. Increased sitting height-to-height ratio and decreased extremities-to-trunk ratio demonstrated the best positive and negative predictive values to identify SHOX deficiency.

Conclusions: Screening for SHOX deficiency seems rational, especially in children with increased sitting height-to-height ratio or decreased extremities-to-trunk ratio. These criteria were also valid in young children.
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http://dx.doi.org/10.1159/000354989DOI Listing
June 2014

Steroid hormone profiles in prepubertal obese children before and after weight loss.

J Clin Endocrinol Metab 2013 Jun 23;98(6):E1022-30. Epub 2013 May 23.

Department of Pediatric Endocrinology, Diabetes, and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, D-45711 Datteln, Germany.

Context: Little information is available on the steroid hormone profiles in obese children and their changes after weight loss.

Objective: We compared liquid chromatography-tandem mass spectrometry of serum steroid hormone profiles between obese and normal-weight children and studied the differential effects of weight loss on these hormones.

Design: This study was a cross-sectional comparison between obese and normal-weight children and a longitudinal 1-year follow-up study during lifestyle intervention in obese children.

Setting: The setting of the study was primary care.

Patients: Forty obese prepubertal (mean age 8.5 ± 2.1 years, 48% female, mean body mass index 24.8 ± 3.5 kg/m(2)) and 40 normal-weight children matched for gender, age, and pubertal stage.

Intervention: The study consisted of an outpatient 1-year intervention program based on exercise, behavior, and nutrition therapy.

Main Outcomes Measures: Progesterone, 17-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, aldosterone, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, T, dihydrotestosterone, insulin resistance index of the homeostasis model assessment, and blood pressure were measured.

Results: Prepubertal obese children showed significantly increased androgens (DHEAS, androstenedione, T), mineralocorticoid precursor corticosterone, and glucocorticoids (11-deoxycortisol, cortisol, cortisone) compared with normal-weight children. In contrast to 20 obese children without weight loss, the 20 obese children with substantial weight loss demonstrated a significant decrease of cortisol, cortisone, and corticosterone. Androstenedione and T decreased but DHEAS remained elevated. Changes of the homeostasis model assessment correlated significantly positively with changes of cortisol (r = 0.38) and cortisone (r = 0.43) in partial regression analyses adjusted to changes of weight status.

Conclusions: In obese prepubertal children, the increased androgens, mineralocorticoid precursors, and glucocorticoids were responsive to weight loss in contrast to DHEAS, suggesting that DHEAS does not seem to be regulated by changes in body mass index.
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http://dx.doi.org/10.1210/jc.2013-1173DOI Listing
June 2013

Treatment with gonadotropin-releasing hormone analogues: different impact on body weight in normal-weight and overweight children.

Horm Res Paediatr 2012 21;78(5-6):304-11. Epub 2012 Dec 21.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

Objective: We studied the effect of gonadotropin-releasing hormone analogues (GnRHa) on weight gain as a possible side effect.

Methods: We analyzed longitudinally changes in BMI-SDS in 92 children [median age 8.0 years (IQR 7.1-8.9), 88% females, mean BMI-SDS 0.69 ± 1.30] with idiopathic central precocious puberty or early puberty treated with GnRHa. Furthermore, 25 overweight children with GnRHa were compared to 25 overweight children without GnRHa matched by age, gender, degree of overweight, and pubertal stage.

Results: The matched overweight children without GnRHa demonstrated a significant increase in their BMI-SDS in the course of 1 year (+0.18 ± 0.22). Normal-weight children treated with GnRHa demonstrated a significant increase in BMI-SDS in the course of 1 year (+0.32 ± 0.66) in contrast to overweight children treated with GnRHa who showed a stable BMI-SDS (-0.02 ± 0.27). This significant difference in changes in BMI-SDS between normal-weight and overweight children treated with GnRHa was also observed at the end of GnRHa treatment and 6 months later (p < 0.001).

Conclusions: Change in weight status differed between overweight and normal-weight children during GnRHa treatment. We found no increased risk for the side effect of weight gain in overweight children treated with GnRHa.
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http://dx.doi.org/10.1159/000346145DOI Listing
July 2013

TSH and free triiodothyronine concentrations are associated with weight loss in a lifestyle intervention and weight regain afterwards in obese children.

Eur J Endocrinol 2013 Mar 15;168(3):323-9. Epub 2013 Feb 15.

Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Hospital for Children and Children Datteln, University of Witten/Herdecke, Dr F Steiner Street 5, D-45711 Datteln, Germany.

Objective: The impact of thyroid hormones on weight loss in lifestyle interventions and on weight regain afterwards is unknown. Therefore, we studied the relationships between TSH, free triiodothyronine (fT₃), free thyroxine (fT₄), and weight status, as well as their changes during and after a lifestyle intervention in obese children.

Materials And Methods: We evaluated the weight status as BMI-SDS in 477 obese children (mean age 10.6±2.7 years, 46% male, mean BMI 28.1±4.5  kg/m²) participating in a 1-year lifestyle intervention in a 2-year longitudinal study. Changes in BMI-SDS at 1 and 2 years were correlated with TSH, fT₃, and fT₄ concentrations at baseline and their changes during the intervention.

Results: A decrease in BMI-SDS during the intervention period (-0.32±0.38; P<0.001) was significantly positively associated with baseline TSH and fT₃ in multiple linear regression analyses adjusted for age, sex, pubertal stage, and baseline BMI-SDS. An increase in BMI-SDS after the end of the intervention (+0.05±0.36; P=0.011) was significantly related to the decreases in TSH and fT₃ during the intervention in multiple linear regression analyses adjusted for change in BMI-SDS during the intervention. In contrast to children with weight maintenance, children with weight regain after the end of the intervention demonstrated a decrease in their TSH levels (-0.1±1.6 vs +0.2±1.6  mU/l; P=0.03) and fT₃ (-0.2±1.1 vs +0.3±1.6  pg/ml; P<0.001) during the intervention.

Conclusions: The decreases in TSH and fT₃ concentrations during the lifestyle intervention were associated with weight regain after the intervention. Future studies should confirm that the decreases in TSH and fT₃ levels associated with weight loss are related to the change in metabolism such as resting energy expenditure.
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http://dx.doi.org/10.1530/EJE-12-0981DOI Listing
March 2013

Quality of life in children and adolescents with growth hormone deficiency: association with growth hormone treatment.

Horm Res Paediatr 2012 14;78(2):94-9. Epub 2012 Aug 14.

Department of Pediatric Nutrition Medicine, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Datteln, Germany.

Background: Quality of life (QoL) as it is related with growth hormone deficiency (GHD) is a matter of controversy.

Methods: We analyzed QoL in 95 children aged 8-18 years with isolated GHD (72% male) treated with growth hormone (GH). These children were compared to 190 age- and gender-matched healthy children with similar height [height <10th percentile; control group 1 (CG1)] and age- and gender-matched 285 healthy children of normal stature (control group 2: CG2). QoL was measured by the KINDL® questionnaire referring to six domains (physical well-being, emotional well-being, self-esteem, family, friends, and school).

Results: QoL was significantly reduced in CG1 (effect-size 0.21) compared to CG2, while QoL was not significantly altered in children with GHD. In multiple linear regression analyses adjusted to age, gender, BMI, migration background, and socioeconomic status, decreasing height-SDS was associated with poorer QoL (especially emotional well-being), and treatment with GH was related significantly to better self-esteem. Increase of height-SDS in children treated with GH was associated positively with QoL and all its subscales except family and school.

Conclusions: These findings suggest psychological consequences of short stature in children and an improvement of QoL in children treated with GH with the focus on self-esteem and emotional well-being.
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http://dx.doi.org/10.1159/000341151DOI Listing
February 2013

Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls.

J Clin Endocrinol Metab 2011 Nov 31;96(11):3533-40. Epub 2011 Aug 31.

Department of Pediatric Endocrinology, Diabetes, and Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten/Herdecke, Dr. F. Steiner Strasse 5, D-45711 Datteln, Germany.

Context: Polycystic ovarian syndrome (PCOS) is associated with cardiovascular risk factors (CRF). Lifestyle intervention is regarded as therapy of choice even if studies in adolescent girls with PCOS are scarce.

Objective: Our objective was to analyze the impact of lifestyle intervention on menses irregularities, hyperandrogenemia, CRF, and intima-media thickness (IMT) in adolescent girls with PCOS.

Patients: Patients included 59 obese girls with PCOS aged 12-18 yr.

Intervention: Intervention was a 1-yr lifestyle intervention based on nutrition education, exercise training, and behavior therapy.

Main Outcome Measures: Menses cycles, IMT, waist circumference, blood pressure, fasting lipids, insulin, glucose, testosterone, dehydroepiandrosterone sulfate, androstenedione, and SHBG were evaluated.

Results: In contrast to the 33 girls without weight loss, the 26 girls reducing their body mass index during the lifestyle intervention (by a mean of -3.9 kg/m(2)) improved most CRF and decreased their IMT (by a mean of -0.01 cm). Testosterone concentrations decreased (by a mean of -0.3 nmol/liter) and SHBG concentrations increased (by a mean of +8 ng/ml) significantly in girls with weight loss in contrast to girls with increasing weight. The prevalence of amenorrhea (-42%) and oligoamenorrhea (-19%) decreased in the girls with weight loss. The changes in insulin in the 1-yr follow-up were significantly correlated to changes in testosterone (r = 0.38; P = 0.002) and SHBG (r = -0.35; P = 0.048). A linear regression model with changes in IMT as dependent variable demonstrated a significant association with changes in blood pressure and weight status but not with changes in testosterone.

Conclusions: Weight loss due to lifestyle intervention is effective to treat menses irregularities, normalize androgens, and improve CRF and IMT in obese adolescent girls with PCOS.
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http://dx.doi.org/10.1210/jc.2011-1609DOI Listing
November 2011

Body mass index patterns over 5 y in obese children motivated to participate in a 1-y lifestyle intervention: age as a predictor of long-term success.

Am J Clin Nutr 2010 May 10;91(5):1165-71. Epub 2010 Mar 10.

Vestische Kinderklinik Datteln, Institute of Pediatric Nutrition Medicine, University of Witten-Herdecke, Datteln, Germany.

Background: Long-term outcome after lifestyle interventions in obese children is largely unknown but important to improving intervention.

Objective: The aim was to identify predictors of long-term changes in body mass index (BMI) after lifestyle intervention.

Design: Annual changes in the BMI SD score (BMI-SDS) over 5 y in 663 obese children (aged 4-16 y) motivated to participate in an outpatient lifestyle intervention were analyzed. Child-specific longitudinal curves based on multilevel growth curve models (MLMs) over 5 y were estimated depending on patient characteristics (age and sex).

Results: The mean decrease in BMI-SDS was 0.36 (95% CI: 0.33, 0.39) at the end of the 1-y intervention and 0.46 (95% CI: 0.36, 0.55) 4 y after the intervention. Change in BMI-SDS in the intervention period predicted long-term outcome after 5 y (P < 0.001). MLMs identified age but not sex as a predictor of the outcome: the youngest children (<8 y) at the onset of the intervention had the greatest decrease in BMI-SDS over 5 y, and the oldest children (>13 y) had the least decrease in BMI-SDS (P < 0.05). Whereas there was a larger reduction in BMI-SDS during the intervention in children aged 8-10 y than in children aged 11-12 y, long-term decrease in BMI-SDS was greater in 11-12-y-old children (P < 0.001).

Conclusions: Younger age was associated with the best long-term outcome after participation in the lifestyle intervention, which supports the need for early intervention in childhood obesity. Children aged 8-10 y may need modified intervention, because BMI-SDS increased more in the older children in the long term. However, mean BMI-SDS was significantly lower 4 y after the end of the intervention than at baseline in all age groups. This study was registered at clinicaltrials.gov as NCT00435734.
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http://dx.doi.org/10.3945/ajcn.2009.28705DOI Listing
May 2010