Abstract
In the recent decades, obesity rates among children and adolescents, especially males, have increased significantly. This worldwide phenomenon is thought to significantly affect the levels of sex hormones. However, the association between waist circumference (a marker of abdominal obesity) and sex hormone levels in children and adolescents is unknown. In this study, 4031 participants aged 6–19 years from the United States National Health and Nutrition Examination Survey (NHANES) in the USA were enrolled in this study. The common confounders of age, race, body mass index, educational level, family income, diabetes, and time of sample collection were also collected. The participants missing any of the above information were excluded from the study. We used multiple linear regression and other multiple statistics to assess the associations between waist circumference and serum testosterone, estradiol, sex hormone-binding globulin (SHBG), free androgen index (FAI), and testosterone/estradiol ratio (T/E2). Waist circumference remained associated with sex hormone levels in children and adolescents after controlling for covariates. As waist circumference increases, testosterone levels in children and adolescents show an overall decline after a brief increase, with the inflection point for waist circumference of 65–66 cm. In addition, waist circumference positively correlates with estradiol levels in male children (β = 0.007, 95% confidence interval: 0.004–0.009). Moreover, circulating SHBG decreases in children and adolescents as waist circumference increases. In conclusion, this study highlighted waist circumference as a vital indicator affecting sex hormone levels in children and adolescents.
Keywords: adolescents, children, NHANES, sex steroid hormones, waist circumference
INTRODUCTION
Child and adolescent obesity has emerged as a severe health threat in recent decades, affecting approximately 330 million people aged 6–19 years worldwide.1,2 Furthermore, obesity in male children and adolescents is more severe in all developed regions. Obesity has long been considered an important cause of sex hormone disorders and persists in all age groups.3,4 Body mass index (BMI) is the primary method for assessing the obesity-related sex hormone disorders among the many indicators.5,6 However, BMI disregards body fat distribution and fails to distinguish between the fat and muscle. Therefore, BMI alone is insufficient to comprehensively understand the risk of obesity-related sex hormone disorders. In contrast, waist circumference, a traditional indicator, is a simple method for evaluating abdominal obesity that is easily standardized and clinically applicable.7 Moreover, waist circumference has an independent significance from BMI in evaluating all-cause mortality, cardiovascular mortality, and so forth.8,9
Precise regulation of sex steroid hormones plays a vital role in the development and maturation of the reproductive system. For example, several studies have shown that adequate testosterone levels are essential for spermatogenesis and the function of cells such as Leydig cells, Sertoli cells, and peritubular myoid cells in the testis.10–12 As a result, changes in sex hormone levels caused by the rising rate of childhood obesity are unavoidably a major cause of early puberty.13–15 In addition, the imbalance in the ratio of testosterone to estradiol (E2) brought on by obesity can lead to problems such as gynecomastia and erectile dysfunction in male adolescents,16,17 which probably causes significant psychological distress. Moreover, several observational studies also indicated that elevated E2 contributes to hypogonadism in obese men.18,19 However, it is unclear how changes in waist circumference relate to the levels of sex steroid hormones.
Given the additional value of waist circumference in identifying high-risk obesity phenotypes, this study aimed to investigate the relationship between waist circumference and sex hormone levels in children and adolescents, from a representative USA population.
PARTICIPANTS AND METHODS
Study design and participants
The National Health and Nutrition Examination Survey (NHANES) assesses the health and nutritional status of adults and children across the USA. Survey results from this project have been studied and recognized by scientists around the world.20–22 All elements of this study were reviewed and approved by the National Center for Health Statistics Ethics Review Board and informed written consent was received from all participants. Under the Data User Agreement, investigators can statistically report and analyze NHANES subject data while complying with relevant statutory requirements. In order to investigate the relationship between waist circumference and sex hormones, differences in the role of waist circumference between genders were compared, and the reasons for the high prevalence of obesity in men were examined. This study included 4031 male and female children and adolescents, aged 6–19 years, with serum total testosterone (TT), E2, and sex hormone-binding globulin (SHBG) data. The detailed selection process is shown in Figure 1.
Figure 1.
Flowchart for selecting the study population. NHANES: National Health and Nutrition Examination Survey.
Measurements of sex hormone indicators
This study selected TT, E2, SHBG, testosterone/estradiol (T/E2), and free androgen index (FAI) as sex hormone indicators. All blood samples collected by NHANES program were stored at −20°C and tested at the National Center for Environmental Health (Atlanta, GA, USA). Testosterone and E2 were prepared by isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS, Pymble, Australia), and total serum testosterone and E2 were routinely quantified by the National Institute of Standards and Technology (NIST) reference method. The determination of SHBG is based on the reaction of SHBG with immune antibodies, and the reaction products are measured by chemiluminescence. The microparticles were captured and measured using a photomultiplier tube on an electrode where the chemiluminescence reaction occurred. The readings are compared to a batch-specific calibration curve. We also calculated the FAI: the value of TT (in ng dl−1) divided by SHBG (in nmol l−1) and T/E2 to indirectly assess the approximate amount of circulating free androgens23 and aromatase activity, respectively.24
Measurements of waist circumference and BMI
All health technicians were trained and tested before the anthropometric measurements were taken. The provided link details instructions on the NHANES anthropometric training methodology (available from: http://www.cdc.gov/nchs/nhanes/nhanes_questionnaires.htm/; last accessed on 2022 March 05). All measuring instruments were calibrated and verified by health technicians and supervisors. BMI was calculated by dividing weight by height squared (in kg m−2). Waist circumference was measured by drawing a horizontal line above the uppermost outer edge of the right iliac bone. The examiner then wrapped the tape measure around the horizontal waistline and recorded the data.
Covariates
The covariates were selected based on previously published studies on sex hormones.25,26 The covariates for this study were obtained from demographic surveys, physical examinations, laboratory data, and questionnaires. Demographic survey factors included age (continuous), gender (male or female), race (non-Hispanic White, non-Hispanic Black, Mexican American, other Hispanic, or other races), educational level (6th and below 6th grade, or above 6th grade), and Household income (less than USA dollar [USD] 20 000, USD 20 000 or more than USD 20 000). Furthermore, the potential effects of age and gender were considered. All participants were divided into four categories: male children (6–11 years), male adolescents (12–19 years), female children (6–11 years), and female adolescents (12–19 years).27 BMI was collected for the physical examination. The 5th, 85th, and 95th percentiles of age and sex were used as cutoffs for children and adolescents in the 2000 Centers for Disease Control (CDC) growth charts (available from: https://www.cdc.gov/; last accessed on 2022 March 05) which classified BMI as underweight, normal weight, overweight, and obese. Since sex hormone levels fluctuate throughout the day, the time of venipuncture blood collection was also considered as a covariate (morning, afternoon, or evening).25 The factors examined in the questionnaire were self-reported history of diabetes (diabetes, borderline, or nondiabetic).
Statistical analyses
The continuous variables were expressed using mean ± standard deviation (normal distribution), median with quartile 1–3 (Q1–Q3; skewed distribution), and categorical variables were expressed using percentages. Since sex hormone indicators are generally right-skewed, they were log-transformed to improve the normality in descriptive and regression analyses. Moreover, we have presented the distribution of the transformed variables with density plots (Supplementary Figure 1 (1.1MB, tif) ). Trends in abdominal circumference were fitted using linear regression by four subgroups of male children, male adolescents, female children, and female adolescents. Using the Spearman correlation coefficient, we also examined the correlation between waist circumference, BMI, and sex hormone metrics.
Multivariate regression analyses were used to estimate the relationship between waist circumference and sex hormone indicators in the four subgroups. The models were adjusted for age, BMI category, race, educational level, family income, diabetes, and time of sample collection. We also ran trend tests, dividing waist circumference into quartiles and using the lowest quartile as a reference to see if the effect of different waist circumferences on sex hormones was consistent. If nonlinearity was detected, we used a two-segment logistic regression model to test the threshold effect of waist circumference on sex hormones indexes and calculate the inflection point. We further performed a log-likelihood ratio test by comparing the two-segment logistic regression model with the one-line logistic regression model. Moreover, we used the generalized summation models to plot the fitted curves between waist circumference and sex hormone indicators. All statistical analyses were performed using R software version 4.0.0 for Windows (The R Foundation for Statistical Computing, Vienna, Austria), and P < 0.05 was considered statistically significant.
RESULTS
Baseline characteristics
We included 4031 children and adolescents aged 6–19 years from 20 146 individuals in two cycles of NHANES 2013–2014 and 2015–2016. The age (mean±standard deviation [s.d.]) of male children, male adolescents, female children, and female adolescents was 8.5 ± 1.7 years, 15.3 ± 2.2 years, 8.6 ± 1.7 years, and 15.4 ± 2.2 years, respectively (Table 1). Adolescent testosterone and E2 levels increased significantly compared to children, and the difference in T/E2 between male and female individuals during adolescence became more pronounced. The majority (79.2%) of subjects underwent sex hormone testing in the daytime. In addition, we observed that the waist circumference of children and adolescents has been increasing in a slow trend over the last 20 years (Figure 2), and the Spearman correlation coefficient showed that waist circumference was more closely related to sex hormone levels than BMI in all children and adolescents (Supplementary Figure 2 (1.4MB, tif) ).
Table 1.
Characteristics of the three populations
| Characteristic | Total participants | Male | Female | ||
|---|---|---|---|---|---|
|
|
|
||||
| Children | Adolescents | Children | Adolescents | ||
| Participants (n) | 4031 | 981 | 1091 | 918 | 1041 |
| Age (year), mean±s.d. | 12.2±4.0 | 8.5±1.7 | 15.3±2.2 | 8.6±1.7 | 15.4±2.2 |
| BMI (kg m−2), mean±s.d. | 21.86±6.16 | 18.78±4.22 | 24.09±6.35 | 19.23±4.48 | 24.74±6.44 |
| Waist circumference (cm), mean±s.d. | 74.74±16.44 | 65.33±12.32 | 82.74±16.48 | 66.51±12.14 | 82.49±14.79 |
| Testosterone (ng dl−1), median (IQR) | 17.90 (4.41–117.97) | 3.57 (2.08–6.30) | 383.00 (233.00–512.50) | 5.01 (2.90–9.77) | 24.00 (17.60–32.20) |
| Estradiol (pg ml−1), median (IQR) | 12.80 (2.12–31.80) | 2.12 (2.11–2.12) | 19.20 (12.00–26.00) | 2.12 (2.11–12.80) | 52.95 (29.90–110.00) |
| SHBG (nmol l−1), median (IQR) | 56.16 (33.60–93.84) | 93.66 (62.35–134.50) | 33.38 (22.62–47.25) | 77.84 (49.67–111.45) | 50.29 (32.60–74.70) |
| T/E2, median (IQR) | 13.84 (5.71–115.45) | 15.56 (9.09–26.64) | 186.76 (137.30–248.22) | 10.00 (5.73–16.41) | 4.43 (2.11–7.34) |
| FAI, median (IQR) | 1.16 (0.20–9.10) | 0.14 (0.06–0.36) | 43.47 (24.64–60.53) | 0.23 (0.10–0.67) | 1.67 (1.04–2.66) |
| BMI category (children/adolescents), n (%) | |||||
| Underweight (BMI < 5th percentile) | 121 (3.0) | 28 (2.8) | 43 (3.9) | 25 (2.7) | 25 (2.4) |
| Normal weight (BMI: 5th to < 85th percentiles) | 2322 (57.6) | 586 (59.7) | 630 (57.7) | 532 (57.9) | 574 (55.1) |
| Overweight (BMI: 85th to < 95th percentiles) | 723 (17.9) | 153 (15.6) | 184 (16.9) | 178 (19.4) | 208 (20.0) |
| Obesity (BMI ≥ 95th percentile) | 865 (21.5) | 214 (21.8) | 234 (21.4) | 183 (19.9) | 234 (22.5) |
| Gender, n (%) | |||||
| Male | 2072 (51.4) | 981 (100.0) | 1091 (100.0) | 0 (0) | 0 (0) |
| Female | 1959 (48.6) | 0 (0) | 0 (0) | 918 (100.0) | 1041 (100.0) |
| Race, n (%) | |||||
| Mexican American | 931 (23.1) | 210 (21.4) | 230 (21.1) | 238 (25.9) | 253 (24.3) |
| Other Hispanic | 471 (11.7) | 117 (11.9) | 116 (10.6) | 108 (11.8) | 130 (12.5) |
| Non-Hispanic white | 1094 (27.1) | 275 (28.0) | 324 (29.7) | 231 (25.2) | 264 (25.4) |
| Non-Hispanic black | 941 (23.3) | 238 (24.3) | 255 (23.4) | 221 (24.1) | 227 (21.8) |
| Other race | 594 (14.7) | 141 (14.4) | 166 (15.2) | 120 (13.1) | 167 (16.0) |
| Education level, n (%) | |||||
| 6th and below 6th grade | 2227 (55.2) | 978 (99.7) | 177 (16.2) | 915 (99.7) | 157 (15.1) |
| Above 6th grade | 1804 (44.7) | 3 (0.3) | 914 (83.8) | 3 (0.3) | 884 (84.9) |
| Income, n (%) | |||||
| <USD 20 000 | 798 (19.8) | 182 (18.5) | 223 (20.4) | 196 (21.3) | 197 (18.9) |
| USD 20 000 or more | 3233 (80.2) | 799 (81.4) | 868 (79.6) | 722 (78.6) | 844 (81.1) |
| Diabetes, n (%) | |||||
| Yes | 15 (0.4) | 4 (0.4) | 3 (0.3) | 3 (0.3) | 5 (0.5) |
| No | 3998 (99.2) | 974 (99.3) | 1084 (99.3) | 912 (99.3) | 1028 (98.7) |
| Borderline | 18 (0.4) | 3 (0.3) | 4 (0.4) | 3 (0.3) | 8 (0.8) |
| Session of blood sample collection, n (%) | |||||
| Morning | 1743 (43.2) | 374 (38.1) | 517 (47.4) | 358 (39.0) | 494 (47.4) |
| Afternoon | 1450 (36.0) | 385 (39.2) | 385 (35.3) | 353 (38.4) | 327 (31.4) |
| Evening | 838 (20.8) | 222 (22.6) | 189 (17.3) | 207 (22.5) | 220 (21.1) |
s.d.: standard deviation; BMI: body mass index; IQR: interquartile range; SHBG: sex hormone-binding globulin; FAI: free androgen index; T/E2: testosterone/estradiol; USD: USA dollar
Figure 2.
Trends in waist circumference change in children and adolescents from 2000 to 2018.
Association between waist circumference and testosterone
Multiple linear regression found a positive association between waist circumference and children’s testosterone levels after adjusting for covariates (Table 2 and Supplementary Table 1). Although the overall association between waist circumference and testosterone was weak for male and female adolescents, trend test analysis found that as waist circumference increased, testosterone tended to increase when Q2, Q3 and Q4 were compared to Q1 (both P < 0.05). Then, we conducted threshold effect analysis and plotted fitted curves based on the relationship between waist circumference and testosterone. We found that testosterone levels first increased (all P < 0.001) and then decreased (P = 0.068 for male children; P < 0.001 for male adolescents; P = 0.020 for female children; and P = 0.370 for female adolescents) with increasing waist circumference in children and adolescents (Figure 3, Supplementary Table 2 and Supplementary Figure 3 (1.6MB, tif) ). This trend was more pronounced among male children and adolescents. Moreover, due to the circadian rhythm of sex hormone levels, we performed a stratified analysis according to the time of venous blood collection (morning, afternoon, or evening), with essentially similar results as above (Supplementary Table 3).
Table 2.
Association between sex hormones and waist circumference in children and adolescents
| Variable | Male children, β (95% CI) P | Male adolescents, β (95% CI) P |
|---|---|---|
| Waist circumference (exposure to testosterone) | 0.041 (0.032–0.050) <0.001 | −0.006 (−0.011–−0.002) 0.006 |
| Q1 | Reference | Reference |
| Q2 | 0.11 (0.03–0.20) 0.009 | 0.22 (0.10–0.34) <0.001 |
| Q3 | 0.02 (−0.11–0.14) 0.763 | 0.20 (0.08–0.33) 0.001 |
| Q4 | −0.15 (−0.35–0.04) 0.116 | 0.18 (0.04–0.32) 0.011 |
| Waist circumference (exposure to estradiol) | 0.007 (0.004–0.009) <0.001 | −0.003 (−0.007–0.000) 0.089 |
| Q1 | Reference | Reference |
| Q2 | 0.05 (0.03–0.08) <0.001 | 0.09 (0.01–0.18) 0.036 |
| Q3 | 0.05 (0.03–0.08) 0.001 | 0.14 (0.04–0.23) 0.004 |
| Q4 | 0.12 (0.09–0.15) <0.001 | 0.13 (0.03–0.23) 0.010 |
| Waist circumference (exposure to SHBG) | −0.012 (−0.015–−0.009) <0.001 | −0.007 (−0.010–−0.005) <0.001 |
| Q1 | Reference | Reference |
| Q2 | −0.04 (−0.07–−0.00) 0.048 | −0.11 (−0.18–−0.05) <0.001 |
| Q3 | −0.13 (−0.18–−0.08) <0.001 | −0.17 (−0.24–−0.10) <0.001 |
| Q4 | −0.17 (−0.25–−0.09) <0.001 | −0.27 (−0.35–−0.20) <0.001 |
| Waist circumference (exposure to FAI) | 0.053 (0.043–0.063) <0.001 | −0.000 (−0.006–0.005) 0.878 |
| Q1 | Reference | Reference |
| Q2 | 0.14 (0.05–0.24) 0.004 | 0.27 (0.12–0.41) <0.001 |
| Q3 | 0.14 (−0.00–0.29) 0.057 | 0.31 (0.16–0.46) <0.001 |
| Q4 | 0.02 (−0.20–0.24) 0.887 | 0.38 (0.22–0.55) <0.001 |
| Waist circumference (exposure to T/E2) | 0.036 (0.027–0.044) <0.001 | −0.004 (−0.006–−0.001) 0.011 |
| Q1 | Reference | Reference |
| Q2 | 0.11 (0.03–0.18) 0.005 | 0.11 (0.04–0.19) 0.004 |
| Q3 | 0.02 (−0.09–0.13) 0.664 | 0.06 (−0.02–0.14) 0.145 |
| Q4 | −0.17 (−0.34–−0.00) 0.045 | 0.03 (−0.06–0.12) 0.497 |
Model adjust for age, race, BMI, education level, family income, diabetes, and session of blood sample collection. Q1: quartile 1; Q2: quartile 2; Q3: quartile 3; Q4: quartile 4; CI: confidence interval; BMI: body mass index; SHBG: sex hormone-binding globulin; FAI: free androgen index; T/E2: testosterone/estradiol
Supplementary Table 1.
Association between sex hormones and waist circumference in female children and adolescents
| Exposure | Female children, β (95% CI) P | Female adolescents, β (95% CI) P |
|---|---|---|
| Waist circumference (exposure to testosterone) | 0.027 (0.021–0.032) <0.001 | −0.001 (−0.003–0.002) 0.699 |
| Q1 | Reference | Reference |
| Q2 | 0.10 (0.05–0.15) <0.001 | 0.17 (0.08–0.26) <0.001 |
| Q3 | 0.06 (−0.02–0.13) 0.137 | 0.14 (0.05–0.23) 0.003 |
| Q4 | −0.06 (−0.18–0.07) 0.369 | 0.14 (0.04–0.24) 0.007 |
| Waist circumference (exposure to estradiol) | 0.034 (0.027–0.042) <0.001 | 0.001 (−0.005–0.006) 0.798 |
| Q1 | Reference | Reference |
| Q2 | 0.11 (0.04–0.19) 0.002 | 0.16 (−0.03–0.35) 0.105 |
| Q3 | 0.03 (−0.08–0.14) 0.591 | 0.13 (−0.06–0.33) 0.179 |
| Q4 | −0.08 (−0.25–0.09) 0.355 | 0.10 (−0.11–0.31) 0.351 |
| Waist circumference (exposure to SHBG) | −0.014 (−0.017–−0.011) <0.001 | −0.007 (−0.010–−0.004) <0.001 |
| Q1 | Reference | Reference |
| Q2 | −0.09 (−0.13–−0.06) <0.001 | −0.09 (−0.20–0.02) 0.109 |
| Q3 | −0.21 (−0.27–−0.16) <0.001 | −0.14 (−0.25–−0.03) 0.013 |
| Q4 | −0.29 (−0.38–−0.20) <0.001 | −0.22 (−0.34–−0.10) <0.001 |
| Waist circumference (exposure to FAI) | 0.041 (0.034–0.047) <0.001 | 0.006 (0.002–0.010) 0.002 |
| Q1 | Reference | Reference |
| Q2 | 0.19 (0.13–0.26) <0.001 | 0.28 (0.14–0.41) <0.001 |
| Q3 | 0.27 (0.17–0.36) <0.001 | 0.30 (0.16–0.44) <0.001 |
| Q4 | 0.24 (0.08–0.40) 0.003 | 0.38 (0.23–0.53) <0.001 |
| Waist circumference (exposure to T/E2) | 0.003 (−0.002–0.009) 0.248 | −0.001 (−0.006–0.004) 0.710 |
| Q1 | Reference | Reference |
| Q2 | −0.01 (−0.08–0.05) 0.715 | 0.01 (−0.16–0.19) 0.894 |
| Q3 | 0.03 (−0.07–0.12) 0.579 | 0.01 (−0.17–0.19) 0.910 |
| Q4 | 0.03 (−0.12–0.18) 0.731 | 0.04 (−0.15–0.24) 0.649 |
Model adjust for: age; race; BMI; education level; family income; diabetes; session of blood sample collection. Q1: quartile 1; Q2: quartile 2; Q3: quartile 3; Q4: quartile 4; CI: confidence interval; BMI: body mass index; SHBG: sex hormone-binding globulin; FAI: free androgen index; T/E2: testosterone/estradiol
Figure 3.
Nonlinear dose-response relationships between waist circumference and sex hormone indices in child and adolescent males. Estimated values and corresponding 95% confidence intervals of log-transformed sex hormone indices are represented by solid and dashed lines, respectively. SHBG: sex hormone-binding globulin; FAI: free androgen index; T/E2: testosterone/estradiol
Supplementary Table 2.
Threshold effect analysis of waist circumference on testosterone (ng/dl) using piecewise binary logistic regression models
| Group | Inflection point (cm) | Group | β (95% CI) P | P for log likelihood ratio test |
|---|---|---|---|---|
| Male children | 66.3 | ≤66.3 | 0.02 (0.01–0.03) <0.001 | <0.001 |
| >66.3 | −0.01 (−0.02–0.00) 0.068 | |||
| Male adolescents | 64.9 | ≤64.9 | 0.05 (0.03–0.06) <0.001 | <0.001 |
| >64.9 | −0.01 (−0.01–−0.00) <0.001 | |||
| Female children | 66.3 | ≤66.3 | 0.01 (0.00–0.01) 0.003 | <0.001 |
| >66.3 | −0.01 (−0.01–−0.00) 0.020 | |||
| Female adolescents | 65.3 | ≤65.3 | 0.03 (0.01–0.05) <0.001 | <0.001 |
| >65.3 | −0.00 (−0.00–0.00) 0.370 |
Model adjust for: age; race; BMI; education level; family income; diabetes; session of blood sample collection. CI: confidence interval; BMI: body mass index
Supplementary Table 3.
Stratified analysis of the relationship between sex hormones and waist circumference based on the session of blood sample collection
| Exposure | Male children, β (95% CI) P | Male adolescents, β (95% CI) P | Female children, β (95% CI) P | Female adolescents, β (95% CI) P |
|---|---|---|---|---|
| Testosterone (morning) | −0.009 (−0.025–0.006) 0.245 | −0.005 (−0.011–0.001) 0.099 | −0.000 (−0.007–0.007) 0.999 | −0.001 (−0.005–0.003) 0.620 |
| Estradiol (morning) | 0.004 (−0.002–0.010) 0.237 | −0.005 (−0.009–0.000) 0.059 | −0.002 (−0.013–0.009) 0.721 | 0.001 (−0.007–0.010) 0.770 |
| SHBG (morning) | −0.014 (−0.020–−0.008) <0.001 | −0.006 (−0.009–−0.002) 0.002 | −0.013 (−0.018–−0.008) <0.001 | −0.010 (−0.015–−0.005) <0.001 |
| T/E2 (morning) | −0.013 (−0.026–0.000) 0.058 | 0.000 (−0.004–0.004) 0.989 | 0.002 (−0.007–0.012) 0.631 | −0.002 (−0.010–0.006) 0.547 |
| FAI (morning) | 0.003 (−0.015–0.021) 0.706 | −0.002 (−0.008–0.005) 0.662 | 0.013 (0.004–0.022) 0.003 | 0.008 (0.002–0.014) 0.010 |
| Testosterone (afternoon) | 0.002 (−0.009–0.013) 0.714 | −0.013 (−0.020–−0.005) <0.001 | 0.001 (−0.007–0.008) 0.894 | −0.002 (−0.007–0.004) 0.570 |
| Estradiol (afternoon) | 0.001 (−0.003–0.005) 0.590 | −0.004 (−0.009–0.001) 0.119 | 0.001 (−0.011–0.012) 0.927 | −0.000 (−0.011–0.010) 0.951 |
| SHBG (afternoon) | −0.009 (−0.014–−0.004) <0.001 | −0.009 (−0.013–−0.005) <0.001 | −0.012 (−0.018–−0.006) <0.001 | −0.004 (−0.010–0.001) 0.101 |
| T/E2 (afternoon) | −0.001 (−0.011–0.009) 0.839 | −0.009 (−0.013–−0.004) <0.001 | 0.000 (−0.010–0.010) 0.954 | −0.001 (−0.010–0.009) 0.870 |
| FAI (afternoon) | 0.011 (−0.002–0.023) 0.095 | −0.004 (−0.013–0.005) 0.414 | 0.011 (−0.000–0.022) 0.055 | 0.003 (−0.004–0.011) 0.354 |
| Testosterone (evening) | 0.005 (0.000–0.009) 0.043 | −0.004 (−0.007–−0.001) 0.011 | 0.010 (0.006–0.014) <0.001 | 0.001 (−0.001–0.004) 0.219 |
| Estradiol (evening) | 0.002 (0.001–0.003) <0.001 | 0.004 (0.002–0.006) <0.001 | 0.006 (0.002–0.011) 0.007 | −0.001 (−0.006–0.004) 0.756 |
| SHBG (evening) | −0.015 (−0.017–−0.013) <0.001 | −0.007 (−0.009–−0.006) <0.001 | −0.016 (−0.018–−0.013) <0.001 | −0.011 (−0.013–−0.008) <0.001 |
| T/E2 (evening) | 0.002 (−0.002–0.007) 0.281 | −0.007 (−0.009–−0.005) <0.001 | 0.004 (−0.001–0.008) 0.095 | 0.002 (−0.003–0.006) 0.414 |
| FAI (evening) | 0.020 (0.015–0.025) <0.001 | 0.003 (−0.001–0.007) 0.101 | 0.026 (0.021–0.031) <0.001 | 0.012 (0.008–0.015) <0.001 |
Model adjust for: age; race; BMI; education level; family income; diabetes. CI: confidence interval; BMI: body mass index; SHBG: sex hormone binding globulin; FAI: free androgen index; T/E2: testosterone/estradiol
Association between waist circumference and E2
The relationship between waist circumference and E2 was gender- and age-specific. Multifactorial regression models showed a positive association between waist circumference and E2 levels in male children with a β = 0.007 (95% confidence interval [CI]: 0.004–0.009; P < 0.05). The linear regression, threshold analysis, and fitted curves showed an inflection point between waist circumference and E2 levels in male adolescents. The waist circumference and E2 levels were positively correlated for waist circumference ≤69.2 cm (P < 0.001) and negatively correlated for waist circumference >69.2 cm (P < 0.001; Supplementary Table 4). The analysis of the threshold effect also showed that E2 levels tended to decrease (β = −0.01, 95% CI: −0.02–−0.00; P < 0.05) when the waist circumference of female children exceeded 66.5 cm (Supplementary Table 4). However, waist circumference had almost no effect on E2 levels in female adolescents (P = 0.798).
Supplementary Table 4.
Threshold effect analysis of waist circumference on estradiol (ng/dl) using piecewise binary logistic regression models
| Group | Inflection point (cm) | Group | β (95% CI) P | P for log likelihood ratio test |
|---|---|---|---|---|
| Male children | 88.1 | ≤88.1 | 0.00 (0.00–0.01) 0.015 | 0.045 |
| >88.1 | 0.01 (0.00–0.01) 0.001 | |||
| Male adolescents | 69.2 | ≤69.2 | 0.01 (0.01–0.02) <0.001 | <0.001 |
| >69.2 | −0.00 (−0.01–−0.00) 0.005 | |||
| Female children | 66.5 | ≤66.5 | 0.01 (−0.00–0.01) 0.122 | <0.001 |
| >66.5 | −0.01 (−0.02–−0.00) 0.006 |
Model adjust for: age; race; BMI; education level; family income; diabetes; session of blood sample collection. CI: confidence interval; BMI: body mass index
Association between waist circumference and SHBG and FAI
SHBG is a carrier of sex hormones in the circulation, and it has about four times the affinity for testosterone than E2.28 Commonly, SHBG and free androgen levels, and to a lesser extent FAI, have a negative correlation. Our study found that SHBG tended to decrease with increasing waist circumference in female children, and male and female adolescents when waist circumference was ≤85.6 cm, ≤96.5 cm, and ≤110.8 cm, respectively (all P < 0.05; Supplementary Table 5). In addition, male children had a significant negative correlation between waist circumference and SHBG after waist circumference exceeded 57.0 cm (P < 0.001). The results of the threshold analysis also showed that FAI increased as waist circumference increased for male and female children and adolescents when waist circumference was ≤71.6 cm, ≤65.9 cm, ≤78.2 cm, and ≤110.8 cm, respectively (all P < 0.05; Supplementary Table 6). However, when the waist circumference of female adolescents exceeded 110.8 cm, FAI decreased (P = 0.029) with a further increase in waist circumference.
Supplementary Table 5.
Threshold effect analysis of waist circumference on sex hormone binding globulin (nmol/l) using piecewise binary logistic regression models
| Group | Inflection point (cm) | Group | β (95% CI) P | P for log likelihood ratio test |
|---|---|---|---|---|
| Male children | 57.0 | ≤57.0 | −0.00 (−0.01–0.00) 0.450 | 0.015 |
| >57.0 | −0.01 (−0.01–−0.01) <0.001 | |||
| Male adolescents | 96.5 | ≤ 96.5 | −0.01 (−0.01–−0.01) <0.001 | <0.001 |
| >96.5 | −0.00 (−0.00–0.00) 0.234 | |||
| Female children | 85.6 | ≤85.6 | −0.01 (−0.02–−0.01) <0.001 | 0.002 |
| >85.6 | −0.01 (−0.01–0.00) 0.058 | |||
| Female adolescents | 110.8 | ≤110.8 | −0.01 (−0.01–−0.01) <0.001 | <0.001 |
| >110.8 | 0.01 (−0.00–0.01) 0.073 |
Model adjust for: age; race; BMI; education level; family income; diabetes; session of blood sample collection. CI: confidence interval; BMI: body mass index
Supplementary Table 6.
Threshold effect analysis of waist circumference on free androgen index using piecewise binary logistic regression models
| Group | Inflection point (cm) | Group | β (95% CI) P | P for log likelihood ratio test |
|---|---|---|---|---|
| Male children | 71.6 | ≤71.6 | 0.02 (0.01–0.03) <0.001 | <0.001 |
| >71.6 | 0.00 (−0.01–0.01) 0.958 | |||
| Male adolescents | 65.9 | ≤65.9 | 0.05 (0.03–0.07) <0.001 | <0.001 |
| >65.9 | −0.00 (−0.01–0.00) 0.305 | |||
| Female children | 78.2 | ≤78.2 | 0.02 (0.01–0.02) <0.001 | <0.001 |
| >78.2 | −0.00 (−0.01–0.01) 0.813 | |||
| Female adolescents | 110.8 | ≤110.8 | 0.01 (0.00–0.01) <0.001 | <0.001 |
| >110.8 | −0.01 (−0.02–−0.00) 0.029 |
Model adjust for: age; race; BMI; education level; family income; diabetes; session of blood sample collection. CI: confidence interval; BMI: body mass index
Association between waist circumference and T/E2
To some extent, T/E2 reflects the activity of aromatase, a key enzyme in converting testosterone to E2. The piecewise binary logistic regression showed a trend of increasing (both P < 0.05) and then decreasing (both P < 0.05) T/E2 in male children and adolescents with increasing waist circumference, and the turning points were 70.0 cm and 64.2 cm, respectively (Supplementary Table 7). However, waist circumference did not show a statistically significant association with T/E2 in female children and adolescents after adjusting for covariates (for female children, P = 0.248; for female adolescents, P = 0.710; Supplementary Table 1).
Supplementary Table 7.
Threshold effect analysis of waist circumference on testosterone/estradiol using piecewise binary logistic regression models
| Group | Inflection point (cm) | Group | β (95% CI) P | P for log likelihood ratio test |
|---|---|---|---|---|
| Male children | 70.0 | ≤70.0 | 0.01 (0.00–0.02) 0.005 | <0.001 |
| >70.0 | −0.01 (−0.02–−0.01) <0.001 | |||
| Male adolescents | 64.2 | ≤64.2 | 0.02 (0.01–0.04) 0.007 | 0.001 |
| >64.2 | −0.00 (−0.01–−0.00) 0.002 |
Model adjust for: age; race; BMI; education level; family income; diabetes; session of blood sample collection. CI: confidence interval; BMI: body mass index
DISCUSSION
New epidemiological evidence suggests that waist circumference in children and adolescents is increasing worldwide at a more pronounced trend than BMI and poses severe public health problems.29,30 Our findings also reflected this phenomenon, as the waist circumference of children and adolescents has been increasing slowly over the last decade. Moreover, many studies have shown a better correlation between abdominal circumference and visceral fat, a risk factor for total mortality independent of BMI.9,31
However, few studies have investigated the association between abdominal circumference and sex hormones in children and adolescents, and the effect of abdominal circumference on sex hormones remains elusive. A cross-sectional study showed that waist circumference was negatively associated with testosterone, SHBG, and both independent of BMI in community adult men.32 The waist circumference was also more closely related to men’s sex hormone levels than BMI or waist-to-hip ratio. Another cross-sectional study of adult Pomeranian women suggested no association between waist circumference and testosterone and E2, and only a weak negative association with SHBG.33 Moreover, a study of obese adolescent females reported a positive association between waist circumference and testosterone.34 However, the study had a small sample size (n = 160), which reduced the reliability of the findings, and all participants were obese, which may have led to biased results. The obesity epidemic and the decline in male fertility have paralleled each other, and previous studies using BMI to assess obesity have found that high BMI is associated with hypogonadism, reduced sperm count, and infertility.35 Moreover, Yang et al.36 considered the altered sex hormone levels brought about by obesity as the key to impaired fertility. Our study showed that waist circumference remained associated with sex hormone levels in children and adolescents after adjusting for BMI. Therefore, waist circumference is an influential endocrine factor related to sex hormone levels, independent of height and weight. Until now, waist circumference has not been widely monitored, which may lead to a portion of the population with normal BMI (<25 kg m−2) but high waist circumference being overlooked. Recently, Batsis and Villareal37 reviewed the consequences of patients with sarcopenic obesity (high abdominal circumference and normal BMI), including lipid metabolism disorders, insulin resistance, reduced bone mineral density, and endocrine disruption. Considering that the risk of being overweight at the age of 35 years is more significant if one is obese in childhood or adolescence,38 waist circumference should also be an independent indicator of obesity. Our results also support the development of a novel waist circumference classification system for children and adolescents from the perspective of sex hormone levels, which could take full advantage of its unique benefits in managing obesity-related sex hormone disorders. Moreover, this may open up new ideas for the government to control the obesity rates during this period.
Our study found that as waist circumference increased, testosterone levels showed an overall decreasing trend after a brief increase and that the inflection point for waist circumference was between 65 cm and 66 cm. Therefore, we inferred that the increase in adipocytes caused by the gain in waist circumference leads to an additional secretion of leptin. Leptin can increase the release of testosterone by stimulating gonadotropin-releasing hormone neurons in the hypothalamus to release luteinizing hormone and by directly stimulating the testes.4 However, excess leptin can cause leptin resistance in the hypothalamus and inhibit androgen synthesis in testicular Leydig cell cells.39 In addition, increased fat increases the enzyme aromatase, a key enzyme in converting testosterone to E2, further decreasing testosterone levels.40
Only a few studies examined serum E2 levels in obese children, but there were no differences, most likely due to screening instrument limitations and small sample sizes.41,42 Our study found a positive correlation between waist circumference and E2 concentration in male children, a positive correlation with E2 concentration in male adolescents with waist circumference less than 65 cm, and a negative correlation beyond 65 cm. Considering that 80% of E2 in men is converted from testosterone, changes in E2 are influenced by the testosterone concentration. However, the ovaries of adolescent women also begin to produce E2, which may make the role of obesity masked. Moreover, this result is consistent with another study of estrogen in obese women during puberty.43
This study also has multiple strengths and some limitations. First, this study used continuous values of waist circumference rather than just truncated values, which allowed us to comprehensively examine the relationship between waist circumference and sex hormones. Furthermore, we divided the participants into four categories for a comprehensive analysis of the relationship between waist circumference and sex hormones, and considered the effects of several confounding factors, especially BMI.8 Finally, the large sample size (over 4000 individuals) also contributed to the credibility of our results. This study discovered novel links between waist circumference and sex hormones in children and adolescents. However, it was limited by cross-sectional studies that struggled to establish causality. Moreover, prospective cohort studies are still needed to clarify the effect of waist circumference on sex hormones. Second, only the most common sex hormone indicators were studied in this study, and FAI and T/E2 were used to indirectly reflect free androgen content and aromatase activity. In addition, the lack of data on gonadotropins, gonadotropin-releasing hormones, and key enzymes of sex hormone synthesis affected further mechanistic studies. Third, this study only used a single-sex hormone test result as the basis for evaluation. Although we considered gender, age, and diurnal fluctuations, we could not entirely exclude the effects of potential confounding factors on sex hormone levels.
CONCLUSIONS
The present study highlighted waist circumference as a vital indicator of the influence of sex hormone levels in children and adolescents. When assessing the effects of obesity on growth and development in children and adolescents, the findings supported measuring waist circumference rather than just BMI.
AUTHOR CONTRIBUTIONS
AMX and ZJW designed this research. ZYW, BCL, JJX, SYL and TTZ performed the research. ZYW and BCL conducted statistical analyses. ZYW wrote the first draft of the manuscript. AMX and ZJW revised the manuscript for intellectual content. All authors read and approved the final manuscript.
COMPETING INTERESTS
All authors declare no competing interests.
Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.
Distribution of (a) total, (b) testosterone, (c) estradiol, (d) SHBG, (e) FAI and (f) T/E2 after stratification according to age and gender.
The correlation between waist circumference, BMI, and sex hormone metrics using the Spearman correlation coefficient according to (a) male children, (b) male adolescents, (c) female children and (d) female adolescents.
Nonlinear dose-response relationships between waist circumference and sex hormone indices in child and adolescent females.
ACKNOWLEDGMENTS
We sincerely appreciate the investigators who conducted the original NHANES study and the USA National Center for Health Statistics for sharing the data.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Distribution of (a) total, (b) testosterone, (c) estradiol, (d) SHBG, (e) FAI and (f) T/E2 after stratification according to age and gender.
The correlation between waist circumference, BMI, and sex hormone metrics using the Spearman correlation coefficient according to (a) male children, (b) male adolescents, (c) female children and (d) female adolescents.
Nonlinear dose-response relationships between waist circumference and sex hormone indices in child and adolescent females.