Original article https://doi.org/10.6065/apem.2017.22.2.108 Ann Pediatr Endocrinol Metab 2017;22:108-114
The association between skeletal maturation and adrenal androgen levels in obese children and adolescents Sung Eun Kim, MD, Joon Weon Jang, MD, Moon Bae Ahn, MD, Shin-Hee Kim, MD, Won Kyoung Cho, MD, PhD Kyoung Soon Cho, MD, So Hyun Park, MD, PhD, Min Ho Jung, MD, PhD, Byoung Kyu Suh, MD, PhD Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea
Purpose: This study aimed to investigate the association between skeletal maturation and adrenal androgen levels in obese children and adolescents. Methods: Fifty-three children and adolescents (aged 7–15 years) diagnosed as obese or overweight were investigated. Anthropometric measurements, bone age (BA) determination, serum biochemical analyses, and hormonal measurements were performed. The difference between BA and chronological age (BA–CA, dBACA) was calculated and used to represent the degree of advanced skeletal maturation. Results: Thirty-one subjects were classified into the obese group and 22 subjects into the overweight group. Insulin resistance as calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) was significantly higher in the obese group than in the overweight group (4.03±2.20 vs. 2.86±1.11, P=0.026). The skeletal maturation of the obese group was advanced, but the dBACA did not differ between the obese and overweight groups statistically (1.43±1.35 vs. 0.91±1.15, P=0.141). Serum dehydroepiandrosterone sulfate (DHEA-S) levels were significantly higher in subjects with dBACA>1 compared to those with dBACA≤1 (104.3±62.2 vs. 59.6±61.0, P=0.014). Correlation analyses demonstrated that dBACA was positively correlated with body mass index standard deviation scores (r=0.35, P=0.010), fasting insulin (r=0.36, P=0.009), HOMA-IR (r=0.30, P=0.031), and insulin-like growth factorbinding protein-3 (r=0.331, P=0.028). In multivariate linear regression analysis, HOMA-IR (P=0.026) and serum DHEA-S (P=0.032) were positively correlated with the degree of advanced skeletal maturation. Conclusion: Advanced skeletal maturation is associated with increased insulin resistance and elevated DHEA-S levels in obese children and adolescents. Keywords: Obesity, Androgens, Dehydroepiandrosterone sulfate, Child
Received: 12 September, 2016 Revised: 14 October, 2016 Accepted: 23 October, 2016 Address for correspondence: Min Ho Jung, MD, PhD Department of Pediatrics, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 10 63(yuksam)-ro, Yeongdeungpo-gu, Seoul 07345, Korea Tel: +82-2-3779-1131 Fax: +82-2-783-2589 E-mail:
[email protected] https://orcid.org/0000-0001-51887041
Introduction The prevalence of obesity in children and adolescents has been increasing worldwide and its development at an earlier age is reportedly associated with a greater risk of comorbidities and complications1,2). In particular, obesity during childhood is known to be linked to advanced pubertal development3,4). Moreover, several studies have found that obese children have bone ages (BAs) that exceed their chronological ages (CAs), which leads to relatively tall stature before puberty and during early puberty, though not to tall adult height5,6). Skeletal maturation is regulated by genetic, nutritional, and hormonal factors 7) and hormones including growth hormone, insulin-like growth factor (IGF), cortisol, estrogen, and androgens are known to influence the process7-9). Children and adults with obesity demonstrate alterations in steroid hormone synthesis10,11) and studies have revealed the influence of steroid hormones on advanced skeletal maturation in obese children and
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©2017 Annals of Pediatric Endocrinology & Metabolism
ISSN: 2287-1012(Print) ISSN: 2287-1292(Online)
Kim SE, et al. • Investigation of skeletal maturation and adrenal androgen in obesity
adolescents. Increased levels of cortisol and testosterone have been observed in obese children10,12). However, the question as to which hormonal factors are most essential for stimulating skeletal maturation in this condition remains controversial7,13). Thus far, little information is available pertaining to the influence of adrenal androgens including dehydroepiandro sterone sulfate (DHEA-S) on advanced skeletal maturation. Therefore, the purpose of this study was to investigate the association between skeletal maturation and adrenal androgen levels in obese children and adolescents.
Materials and methods 1. Subjects
Fifty-three children and adolescents (age range, 7–15 years; 32 male and 21 female patints) diagnosed as obese or overweight were investigated at the Department of Pediatrics, Yeouido St. Mary's Hospital between December 2014 and December 2015. Obesity was defined as body mass index (BMI) ≥ 95th percentile for age and sex according to the 2007 Korean National Growth Charts14). Overweight status was defined as a BMI between the 85th and 94th percentile for age and sex. Key exclusion criteria included chronic diseases (including cardiovascular, gastrointestinal, or respiratory disease), endocrine disorders requiring hormonal treatment, small for gestational age, idiopathic short stature, precocious puberty, premature adrenarche, and history of chronic drug use. Informed consent was given by all participants. Precocious puberty was defined by the onset of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys15). Premature adrenarche was defined as the appearance of sexual hair before the age of 8 years in girls and 9 years in boys. The study was reviewed and approved by the local Institutional Review Board.
considered consistent with puberty. In defining pubertal stage, breast and gonadal stage were adopted preferentially if they were not corresponding with pubic hair stage. 3. Laboratory evaluation and bone age determination
Venous blood samples were taken after 10- to 12-hour overnight fasting. Serum concentrations of glucose, insulin, total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were analyzed. Hormonal measurements including cortisol, luteinizing hormone, follicle-stimulating hormone (FSH), estradiol, testosterone, and DHEA-S were performed. insulinlike growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured using an immunoradiometric assay. Dyslipidemia was defined as having one or more of the following abnormal lipid levels: total cholesterol ≥200 mg/ dL, LDL-C ≥130 mg/dL, HDL-C ≤35 mg/dL, and triglycerides ≥150 mg/dL (based on the Third Report of the National Cholesterol Education Program17) and the American Diabetes Association18)). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using this equation: HOMA-IR = fasting insulin (μU/mL) × fasting glucose (mmol/ L)/22.519). BA was estimated from a radiograph of the left hand and wrist, using the Greulich and Pyle method20). BA was read by a pediatric endocrinologist and a pediatric radiologist, and the mean of both readings was taken. Readers were permitted to read BAs as between two of the standard radiographs if they did not assume that either standard was an adequate match. If the difference of the readings was greater than 6 months, the readers discussed to determine the exact BA. The difference between the BA and CA (BA–CA, dBACA) was calculated and was used as a variable representing the degree of advanced skeletal maturation. dBACA>1 was considered significantly advanced skeletal maturation.
2. Anthropometric measurements 4. Statistical analysis
Anthropometric measurements for the subjects included height, weight, and waist circumference (WC). Height was measured with a Harpenden's stadiometer. Weight and height were recorded to the nearest 0.1 kg and 0.1 cm, respectively. BMI was calculated as kg/m 2. WC was measured halfway between the lowest rib and the superior border of the iliac crest at the end of expiration to the nearest 0.1 cm. Waist-height ratio (WHR) was also calculated. The standard deviation scores (SDSs) for height, weight, and BMI were determined using the 2007 Korean National Growth Charts14). Pubertal development (sexual maturity rating) was evaluated by the standards of Marshall and Tanner16). In males, sexual maturity rating was based on testicular enlargement and the development of pubic hair. In females, it was based on breast changes combined with the development of pubic hair. A testicular volume of ≥4 mL in males and stage 2–5 breast development in females were
Values of measured parameters are expressed as mean±stan dard deviation. Statistical analyses were performed using SPSS ver. 18 (SPSS Inc., Chicago, IL, USA). Continuous variables were compared by t-test or Mann-Whitney U-test, as appropriate. Differences in proportions were tested using Fisher exact test. Pearson correlation coefficients were calculated to examine the relationship of the BMI SDS and dBACA to anthropometric and biochemical variables. For the variables that did not show normal distribution, correlations were evaluated with Spearman rank-order correlation coefficients. Multivariate linear regression analyses were conducted for the dependent variable, dBACA (degree of advanced skeletal maturation), including CA, the state of obesity, the state of puberty, and HOMA-IR as independent variables. P
