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ORIGINAL ARTICLE
Year : 2019  |  Volume : 22  |  Issue : 10  |  Page : 1417-1422

Changes in thyroid volume and insulin-like growth factor 1 in pre- and post-pubertal obese children


Department of Pediatric Endocrinology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey

Date of Acceptance28-May-2019
Date of Web Publication14-Oct-2019

Correspondence Address:
Asst. Prof. M Karaoglan
Department of Pediatric Endocrinology, Faculty of Medicine, Gaziantep University, Gaziantep
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_262_19

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   Abstract 


Background: There is a mutual dynamic interaction between thyroid volume (TV), insulin-like growth factor-1 (IGF-1), and body mass index (BMI). These covariates undergo a change with the transition into puberty. The heterogeneity of the variates and study populations complicate the evaluation of the role of pure pubertal effect. Objective: The purpose of this study was to investigate the effect of puberty on IGF-1 and TV in a predetermined homogenous population such as obese children. Subjects and Methods: Three hundred and eighty children (202 girls and 178 boys) aged between 6 and 18 were enrolled in this prospective study. The children were assigned to two groups according to their pubertal status, i.e., prepubertal (n = 169) and postpubertal (n = 211). According to age and sex, the obese group (n = 222) was made up of children at and above the 95th percentile, and the control group (n = 158) of children under the 85th percentile. The following parameters were evaluated in all children: BMI, pubertal status, TV, and serum IGF-1, IGFBP-3, and IGF-1:IGFBP-3 molar ratio. Results: In comparison to the prepubertal obese group, the obese group at Tanner stage 2 had a larger mean TV (P = 0.008) and higher IGF-1 level (P = 0.033). There was a positive correlation between IGF-1 and TV both in the prepubertal and pubertal group (r169= 0.369, P = 0.001; r211= 0.316, P = 0.004, respectively), whereas there was no correlation between IGF-1 and BMI (r169= 0.99, P = 0.092; r211= 0.094, P = 0.088, respectively). Conclusion: This study showed that the TV and serum IGF-1 levels were increased in obese children in the early stage of puberty and that there was a positive correlation between these two variables in all children, which shows the specific effect of the early stage of puberty on the increase in TV and IGF-1 levels and suggests that increased TV is associated with the increase in IGF-1 levels in a homogenous group such as obese children.

Keywords: Childhood obesity, insulin-like growth factor-1, puberty, thyroid volume


How to cite this article:
Karaoglan M, Balci O, Keskin M. Changes in thyroid volume and insulin-like growth factor 1 in pre- and post-pubertal obese children. Niger J Clin Pract 2019;22:1417-22

How to cite this URL:
Karaoglan M, Balci O, Keskin M. Changes in thyroid volume and insulin-like growth factor 1 in pre- and post-pubertal obese children. Niger J Clin Pract [serial online] 2019 [cited 2019 Dec 15];22:1417-22. Available from: http://www.njcponline.com/text.asp?2019/22/10/1417/269013




   Introduction Top


Adipose tissue, which has a role in energy metabolism, has close interactions with the thyroid gland and insulin-like growth factors (IGFs). This interaction is affected by many factors including the variables of age, height, weight, gender, race, nutrition, puberty, iodine intake, and IGFBP-3.[1] The majority of previous studies report contradictory results concerning the interactions between the thyroid volume (TV), IGF-1, and body mass index (BMI).[2],[3] Although IGF-1 levels are generally low in obesity, there are also studies reporting normal or high levels.[4],[5]

While exerting a proliferative effect on thyrocytes and increasing the TV, IGF-1 also mediates the effect of the growth hormone on tissues.[5] Moreover, it plays a role in energy metabolism by interacting with the body's adipose tissue.[6] Although the most effective method for evaluating growth at tissue level is the bioactive IGF-1 test, studies employ the IGF-1:IGFBP-3 molar ratio, as measuring IGF-1 is challenging.[4]

Puberty is a period characterized by elevated sex hormone levels due to the activation of the hypothalamic–pituitary–gonadal axis.[7] During this period, sex hormones stimulate growth factors, leading to dramatic changes, such as growth spurts in height, thyroid growth, elevated IGF-1 levels, and increased BMI. The effect of increased BMI on TV and IGF-1 coincides with the specific effect of puberty throughout this period.

The purpose of this study is to reveal the net effect of puberty on IGF-1 and TV in a group of obese children who exhibit homogeneity in terms of BMI, i.e., one of the three variables which closely interact with each other.


   Materials and Methods Top


Three hundred and eighty children aged between 6 and 18 were enrolled in this single-center prospective cross-sectional study. The study was approved by the Clinical Trials Ethics Committee of Gaziantep University with decision no. 22.01.2013/42. Informed written consent was obtained from the parents of all children. The children were divided into two groups, i.e., prepubertal and pubertal. One hundred and sixty-nine participants were prepubertal children (92 girls, 77 boys), and 211 participants were pubertal (110 girls, 101 boys). Among the 380 children included in this study, 222 (116 girls, 106 boys) were included in the obese group, and 158 in the normal weight group. According to age and gender, children with a BMI in the 3rd–85th percentile were enrolled in the control group, and children over +2 standart deviation score (SDS) were enrolled in the obese group.[8] 102 and 120 of the obese children (n = 222) were prepubertal and pubertal, respectively, whereas 67 and 91 of the children in the control group (n = 158) were prepubertal and pubertal, respectively. The following exclusion criteria were used in the study: (1) Autoimmune thyroiditis, thyroid nodules or cysts, (2) defects in thyroid synthesis, (3) subclinical hypothyroidism (T4 normal, thyroid stimulating hormone [TSH] between 5 and 10 mU/L) (4) iodine deficiency or excess, (5) children being underweight (<3rd percentile) according to growth charts,[8] (6) Cushing's syndrome, (7) syndromes associated with obesity 22 children who met the criteria given above were excluded from the study. BMI was calculated according to the following formula: BMI = weight/height 2 (kg/m 2). Pubertal status was determined according to Tanner scoring. Stage 2 was considered pubertal (in boys; testicular volume: At least 4 ml, in girls; breast development at least B2). All children were examined by the same pediatric endocrinologist (MK) and their height and weight were measured using a wall-mounted stadiometer in accordance with the standard measurement rules.

Blood samples for tests were collected at 8.00 a.m. The following parameters were assayed in all children: Free T4, TSH, anti-TPO, anti-TG, IGF-1, IGFBP-3, urinary iodine excretion. Blood samples were stored at −20°C until being analyzed. Serum IGF-1 and IGFBP-3 assays were analyzed using a solid-phase, enzyme-labeled chemiluminescent immunometric assay using the IMMULITE ® 2000 kit (DPC, USA). The IGF-1:IGFBP-3 molar ratio was calculated using conversion into nmol/L (IGF-1; ng/mL × 0.1307 = nmol/L, IGFBP-3; ng/mL × 0.03478 = nmol/L).

All the children underwent a thyroid ultrasound scan, which was performed using a VF13-5 (13-5 MHz) linear transducer and a Siemens Sonoline Antares ultrasound machine (Siemens Medical Solutions USA Inc., Malvern, PA, USA). TV was estimated using the ellipsoid formula: Length × width × depth × π/6. We measured the total volume of both thyroid lobes.

Statistical analysis

Data that showed continuous distribution was analyzed using the Kolmogorov–Smirnov test. The Student's t-test was conducted to compare two independent variables with a normal distribution. Nonnormal variables were analyzed using the Mann–Whitney U-test. The relationship between two categorical variables was determined using the Chi-square test. The correlation between other variables was analyzed using Pearson's correlation coefficient. All percentages, frequencies, and means ± standard deviations were analyzed as descriptive statistics. The IBM SPSS Statistics for Windows, Version 22.0., (IBM Corp., Armonk, NY, USA) was used for all the statistical analyses. A value of P < 0.05 was accepted as statistically significant. The independent samples t-test was used with the SPSS software version 22 program.


   Results Top


The mean ages of prepubertal (n = 169) and pubertal (n = 211) children were 95.32 ± 11.77 (range 71.78–118.33) and 154.93 ± 16.52 months (range 119.23–188.54), respectively [Table 1]. There was no statistically significant difference between the prepubertal and pubertal group in terms of age (P = 0.727, P = 0.606, respectively). Similarly, there was no difference between the two groups in terms of male and female sex (P = 0.854, P = 0.253, respectively). The comparison of prepubertal (109.23 ± 45.34 mcg/g/cr/creatinine) and pubertal (114.43 ± 70.53 mcg/g/creatinine) obese children with their control group did not reveal any significant differences between mean urinary iodine values (P = 0.776, P = 0.678, respectively) [Table 1].
Table 1: Clinical and laboratory characteristics of prepubertal and pubertal obese children

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The mean BMI values of prepubertal and pubertal obese children were 28.38 ± 2.29 (range 23.17–33.36) and 29.13 ± 2.36 (range 23.84–33.59), respectively. The mean BMI SDS values of the two groups were 2.68 ± 0.73 and 2.85 ± 1.1, respectively [Table 1].

There was no statistically significant difference between the mean TV of obese (5.61 ± 2.87 cm 3; range 1.98–7.28 cm 3) and control (5.36 ± 1.38 cm 3; range 2.67–7.45 cm 3) groups in the prepubertal group (P = 0.603) [Table 1]. However, the mean TV of the pubertal obese group (9.67 ± 2.32 cm 3; range 5.53–12.34 cm 3) was higher in comparison to that of the control group (7.28 ± 1.22 cm 3; range 4.35–10.24 cm 3) [Figure 1]. Evaluating the pubertal obese group according to Tanner stage, the increase in TV was statistically significant only at stage 2 (P = 0.007).
Figure 1: The mean thyroid volume of and control groups in prepubertal and pubertal children. *TV: Thyroid Volume (prepubertal TV, P = 0.603; pubertal TV, P = 0.007)

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Similarly, there was no statistically significant difference between the mean IGF-1 levels of obese (224.61 ± 77.45 ng/ml) and control (192.35 ± 72.81 ng/ml) groups in the prepubertal group (P = 0.951) [Figure 2]. However, the mean IGF-1 level of pubertal obese children (462.3 ± 112.17 ng/ml) was higher than the mean IGF-1 level of the pubertal control group (324.17 ± 101.78 ng/ml) (P = 0.023) [Figure 3]. Evaluating the pubertal obese group according to Tanner stage, we found that IGF-1 levels were only statistically significant at stage 2 (P = 0.008) [Table 2]. Comparison of the mean IGFBP-3 and IGF-1:IGFBP-3 molar ratio values with their control groups showed that the differences were not significant in the prepubertal obese group, whereas there was a higher difference in the pubertal obese group (P = 0.042, P = 0.031, respectively) [Table 2].
Figure 2: Serum mean IGF-1 levels of and control groups in prepubertal and pubertal children (prepubertal IGF-1, P = 0.951; pubertal IGF-1, P = 0.023)

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Figure 3: Serum mean IGF-1:IGFBP-3 levels of and control groups in prepubertal and pubertal children (prepubertal IGF-1: IGFBP-3, P = 0.693; pubertal IGF-1:IGFBP-3, P = 0.031)

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Table 2: Thyroid volumes and serum insulin-like growth factor-1 levels according to pubertal stages

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Considering the correlations between TV, BMI and IGF-1 in both the prepubertal and pubertal groups, there was no correlation between IGF-1 and BMI (rpre-pubertal = 0.099, P = 0.092; rpubertal = 0.094, P = 0.088, respectively), whereas there was a positive correlation between IGF-1 and TV in both groups (rpre-pubertal = 0.369, P = 0,001; rpubertal = 0.316, P = 0.04) [Table 3].
Table 3: Pearson correlation and P scores of insulin-like growth factor-1 with thyroid volume and body mass index in prepubertal and pubertal children

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   Discussion Top


This study conducted on obese children has two main findings:First, serum IGF-1 and TV exhibit a significant increase in the early stage of puberty. Second, there is a significant correlation between elevated IGF-1 level and increased TV, and this correlation is independent of puberty. These results show the specific effect of puberty on elevated IGF-1 level and TV spurt, independent of the effect of BMI. Furthermore, they indicate that IGF-1 plays a role, independent of puberty, in increased TV in both the pre- and post-pubertal stage.

TV increases during puberty, especially between the ages of 11 and 15.[7] The significant spurt in TV is especially seen at the age of 12 and in the following period, during which TV exhibits a two-fold increase compared to the younger ages.[9] This period/interval coincides with the “pubertal growth spurt” in both genders. This dramatic increase is seen in the early phases of puberty in girls and in later stages in boys.

IGF-1 increases the proliferation of thyroid cells by means of mitogenic effects. It also induces TSH activation, which promotes thyroid growth.[10] The proliferative effect of IGF-1 plays a key role in puberty. Although IGF-1 does not have an effect on the onset of puberty in obese children, it contributes to the development of insulin resistance and metabolic syndrome in obese individuals during puberty.[11] The results of this study show that elevated IGF-1 levels can be encountered in association with childhood obesity. In our study, the mean IGF level was significantly higher in the pubertal obese group (P = 0.023). Contrary to our findings, it is reported in the literature that obese children generally have low serum IGF-1 levels. Our findings were inconsistent with the literature and this may stem from the fact that the majority of pubertal obese children (n = 124) in our study were at Tanner stage 2. The mean age of the children included in the Tanner stage 2 obese group was 12.5, which coincides with the growth spurt seen in puberty.

This study has shown the positive correlation between TV and IGF-1 in prepubertal and pubertal children. This result indicates that puberty may contribute to thyroid gland growth, irrespective of the stage of puberty. Therefore, we think that increased TV in puberty may stem from the mitogenic effect of IGF-1 rather than fat accumulation. In a recent report, it was reported that lean body mass is correlated with thyroid size and that larger TV is associated with lean body mass in males.[12]

It was reported that sex steroids play a role in thyroid growth by activating the pituitary-thyroid axis.[7] This study found that the thyroid gland contains sex steroid receptors and that both estrogen and androgen have a positive effect on thyroid growth. This proliferative effect is higher in girls due to estrogen. It has been shown that estrogens may have an effect on the growth of thyroid cells.[13] As it is known, women are more susceptible to enlarged thyroid gland disorders such as goiter, cysts, and nodules.

Recent studies on obese adult populations have reported that BMI is associated with TV.[2] Boas et al.[3] demonstrated that TV increases with age and BMI in prepubertal children. In contrast to previous studies, the present study did not find a relationship between BMI and TV after comparing the control group and the study group. This inconsistent finding might be due to the heterogeneous study populations.[14],[15] Previous studies have reported a significant relationship between TV and BMI; however, these studies included obese patients with thyroid disorders, such as subclinical hypothyroidism, nodules, or autoimmune thyroiditis.[16],[17] Another reason could be the relatively small study population in this study. Furthermore, the BMI difference in the study groups may also have affected the results. This study only included obese children in order to prevent negative outcomes that may stem from heterogeneous populations.[18]

Total IGF-1 does not reflect the free bioactive form of IGF-1. In clinical practice, the molar ratio of IGF-1: IGFBP-3 is used instead of IGF-1.[14] In this study, we found that serum IGF-1: IGFBP-3 ratio was higher in the group of pubertal obese children. We are of the opinion that high mean serum IGF-1, IGFBP-3 and IGF-1:IGFBP-3 molar ratio levels stem from the fact that the mean age of the pubertal obese group was around 12 years. This age, as mentioned before, coincides with Tanner stage 2, which overlaps with growth spurt in the majority (n = 124), i.e., 58.7%, of our study group. In the above-mentioned study,[14] high IGFBP-3 and IGF: IGFBP-3 molar ratio was found to be significant only around 11–12-years old. The changing relationship between BMI and IGF-1 can be observed when IGF-1 and IGFBP-3 levels are corrected with respect to the pubertal stages.

Although our study is limited in that the obese population was relatively small, it shows the net effect of puberty on the increase in TV and IGF-1 levels in a homogeneous obese group, in which the BMI variable was fixed and predetermined.


   Conclusion Top


Consequently, this study shows that thyroid size and serum IGF-1 level are increased and there is a significant correlation between IGF-1 and TV in the early stage of puberty in obese children. These results show that puberty plays a specific role in increased thyroid growth and elevated serum IGF-1 levels, and highlight the effect of IGF-1 on the increase in TV independent of puberty.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Dahl M, Ohrt JD, Fonvig CE, Kloppenborg JT, Pedersen O, Hansen T, et al. Subclinical hypothyroidism in Danish lean and obese children and adolescents. J Clin Res Pediatr Endocrinol 2017;9:8-16.  Back to cited text no. 12
    
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Marwaha RK, Garg MK, Gupta S, Khurana AK, Narang A, Shukla M, et al. Assessment of insulin like growth factor-1 and IGF binding protein-3 in healthy İndian girls from Delhi and their correlation with age, pubertal status, obesity and thyroid hormonal status. J Pediatr Endocrinol Metab 2017;30:739-47.  Back to cited text no. 14
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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