Associations of Sex Steroid Hormones with C-Reactive Protein Levels in American Children and Adolescents: Evidence from NHANES 2015-2016

doi:10.21203/rs.3.rs-3935965/v1

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Associations of Sex Steroid Hormones with C-Reactive Protein Levels in American Children and Adolescents: Evidence from NHANES 2015-2016

https://doi.org/10.21203/rs.3.rs-3935965/v1

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Background: The relationship between sex steroid hormones and high-sensitivity C-reactive protein(hs-CRP) levels in American children and adolescents is understudied. This research will examine this association.

Methods: The study conducted a data analysis from the National Health and Nutrition Examination Survey (NHANES) 2015-2016, adjusting multiple linear regression models with R 4.2.2 and EmpowerStats. A total of 1,768 children and adolescents were surveyed.Data collection involved measurements of serum levels of testosterone, estradiol, sex hormone-binding globulin (SHBG) and hs-CRP.

Results:With the increase in testosterone, a brief rise (β=0.082, P=0.047) followed by an overall decline (β=-0.028, P=0.023) in hs-CRP was observed in the Male Prepubertal population, while a continuous decline (β=-0.002, P<0.05) was seen in the Male Pubertal group. A positive correlation (β=0.047, P<0.05) was found between testosterone and hs-CRP in the Female Prepubertal population, whereas no significant association (β=0.002, P>0.05) was detected in the Female Pubertal group. A significant inverse correlation was observed between estradiol and hs-CRP solely in the Female Pubertal group (β=-0.002, P<0.05), while no association was found in other populations. An inverse relationship between SHBG and hs-CRP was consistently noted across all groups: Male Prepubertal, Male Pubertal, Female Prepubertal, and Female Pubertal.

Conclusions:This study highlighted sex steroid hormones as a vital indicator affecting high-sensitivity C-reactive protein levels in children and adolescents.

children

adolescents

NHANES

sex steroid hormones

C-reactive protein

C-reactive protein (CRP), predominantly produced by hepatocytes in the liver, is a homopentameric protein involved in the acute-phase inflammatory response, and its expression is noticeably heightened during inflammation, such as that caused by rheumatoid arthritis, specific cardiovascular disorders, and infections.^[1] It has been suggested that sex steroid hormones may participate in inflammation processes, where testosterone is reported to have anti-inflammatory impacts, and estrogen is seen to contribute proinflammatory effects. ^[2] Furthermore, estrogen is speculated to alter CRP concentrations, with evidence indicating a notable impact of hormone replacement therapy (HRT) on CRP levels in the elderly population.^[1]

Prior research has revealed a complicated and varied relationship between sex steroid hormones and CRP levels in adults. In men, there is generally an inverse association between CRP and key hormonal markers like total testosterone, free testosterone, and SHBG, while the relationship with estradiol is often insignificant.^[3] Interestingly, estrogen treatment in certain male groups could potentially elevate CRP levels.^[4] In women, the relationship varies greatly with hormonal and menopausal status, presenting an intricate pattern of positive, negative, or even non-significant correlations between different sex hormones and CRP levels.^[5–7]

To date, only a single study targeting the adolescent population (aged 12–16 years) has examined the relationship between sex hormones and C-reactive protein. It found a negative correlation between testosterone and high-sensitivity C-reactive protein(hs-CRP) in adolescent boys, but no correlation in girls. In both sexes, a negative association was found between SHBG and hs-CRP.^[2]

The study of sex steroid hormones in children and adolescents has been attracting increasing scholarly attention.^{[8, 9]} Concurrently, existing findings regarding the relationship between these hormones and CRP remain contentious. It is noteworthy that there is a significant scarcity of research, particularly in the age group of 6–11 years.To bridge this research gap, our study proposes to harness the 2015–2016 NHANES data. The objective is to elucidate the potential associations between sex steroid hormones and hs-CRP levels within the population of American children and adolescents.

Study design and participants

The National Health and Nutrition Examination Survey (NHANES) is a sequence of cross-sectional studies carried out in the United States, assessing the health and nutritional conditions of both adults and children. In contrast to other research, NHANES integrates physical exams and interviews for comprehensive data gathering. The ethical aspects of each part of the study were reviewed and approved by the National Center for Health Statistics Ethics Review Board, and every participant gave their written informed consent.^[10] For the purpose of our research, we extracted data from 1,768 children(6–11 years) and adolescents(12–19 years) who had hs-CRP, serum total testosterone (TT), estradiol (E₂), and sex hormone binding globulin (SHBG) records in the 2015–2016 NHANES dataset. The process of our selection is depicted in Fig. 1.

Measurements of sex hormone indicators

In this study, we employed sex hormone markers such as TT, E₂, and SHBG. Prior to being dispatched to the National Center for Environmental Health for analysis, serum samples were processed and stored in vials at a temperature of -20°C. SHBG concentrations were ascertained using immunological antibodies and chemiluminescent readings of the reaction products through a photomultiplier tube. The quantities of TT and E₂ in the serum were established using isotope dilution coupled with high performance liquid chromatography tandem mass spectrometry (ID-LC-MS/MS).

Measurements of high-sensitivity C-reactive protein

The procedure for hs-CRP in the laboratory utilizes a dual-agent immunoturbidimetric system. To begin, a sample is amalgamated with a Tris buffer followed by an incubation period. Afterward, the second reagent, comprising latex particles that are coated with mouse anti-human CRP antibodies, is introduced. Upon exposure to circulating CRP, the latex particles tend to clump together, leading to the formation of immune complexes. These formed complexes induce an increase in the scattering of light, which is directly proportional to the CRP concentration. The resulting light absorption from the scattered light is then measured against a pre-established CRP standard curve to determine the concentration of CRP.^[11]

Covariates

The selection of covariates in this study was based on previous research on sex hormones^{[3, 6, 7]}, and included age (continuous), race (Mexican American, other Hispanic, Non-Hispanic white, Non-Hispanic black, Non-Hispanic Asian, or other race), education level (6th and below 6th grade, above 6th grade), poverty income ratio (PIR, continuous), body mass index (BMI, continuous), diabetes (categorical), session of blood sample collection (morning, afternoon, or evening), total cholesterol(TC, continuous), and physical activity(non-activity, 0.1–0.9 hour / week, 0.1–0.9 hour / week, 1.0-3.4 hour / week, 3.5–5.9 hour / week, and ≥ 6 hour / week). To identify participants with diabetes, any of the following characteristics were used: (a) hemoglobin A1C concentration ≥ 6.5% or a fasting plasma glucose level ≥ 126 mg/dL; (b) for those who answered "yes" to the following questions: ‘Take diabetic pills to lower blood sugar?’ or ‘Doctor told you have diabetes?’ or ‘Taking insulin now?’.^[12]

Adjustment for Pubertal Status

It is noteworthy that segmenting the participants aged 6–19 years into categories of children and adolescents based purely on age could result in blending prepubescent and pubescent individuals within each group. Consequently, this could give rise to unusually high or low concentrations of sex hormones within each category, which could skew the relationships between sex hormones and hs-CRP during regression analysis. In addition, the influence of sex hormones on hs-CRP may vary with puberty status. In an effort to mitigate this concern, we subdivided the participants into two categories, namely pubertal and prepubertal groups, based on their serum sex hormone levels and menarcheal status. Participants who displayed levels of TT ≥ 50 ng/dL (in the case of males) or E₂ ≥ 20 pg/mL (in the case of females), or had initiated menstrual cycles (applicable to females), were classified under the 'pubertal group'. The remaining participants, who did not meet these criteria, were assigned to the 'prepubertal group'.^[13]

Statistical analyses

We used sampling weights to adjust for selection probabilities, oversampling, non-response, and differences between the sample and the entire US population. Given the right-skewed distribution of hs-CRP, we performed a natural logarithmic transformation on the hs-CRP values.Weighted univariate linear regression was employed to ascertain the correlations between sex steroid hormones and hs-CRP. We used weighted multivariable linear regression models to examine the relationship between sex hormones and hs-CRP, adjusting for various confounding factors. We performed trend tests to see if the effects of different ranges of sex hormones on hs-CRP were consistent. We adopted the Generalized Additive Model(GAM) to detect the non-linear association. If the relationship between sex hormones and hs-CRP was non-linear, a two-piecewise linear regression model was implemented to estimate the threshold effect of sex steroid hormones on hs-CRP. Subgroup analyses were conducted via stratified linear regression models, with the modification and interaction within subgroups assessed through the likelihood ratio test. We analyzed the data using the R software (version 4.2.2) and EmpowerStats (http://www.empowerstats.com). We considered a P-value < 0.05 as statistically significant.

Baseline characteristics

The study population(Table 1), stratified by gender and age groups, exhibited significant disparities in levels of testosterone, estradiol, SHBG, age, and BMI (all P<0.001). Testosterone and estradiol levels were notably higher in adolescents, while SHBG was highest in children. BMI differed significantly between children and adolescents. Most participants were of normal weight (58.26%) and non-diabetic (99.38%).Importantly, pubertal status significantly differed between children and adolescents (P<0.001), with a noteworthy proportion of female children (21.85%) already in puberty. This finding prompted us to mainly categorize our population based on pubertal status for subsequent analysis.

Weighted univariate analysis

The Supplementary Table 1 analysis revealed that testosterone, estradiol, SHBG, age, race, BMI, diabetes status, and examination time were significantly associated with hs-CRP levels across prepubertal and pubertal males and females. Notably, the association strength did not significantly differ between groups, barring estradiol ,race, examination time, and BMI.

Association between testosterone and high-sensitivity C-reactive protein

In Male Prepubertal subjects, testosterone exhibited no significant link with hs-CRP (Table 2). A threshold effect was evident at a testosterone level of 8.90 ng/dl(Supplementary Table 2), associating positively below(β=0.082, P=0.047) and negatively above(β=-0.028, P=0.023) this threshold (Figure 2). Stratified analysis (Supplementary Table 3) revealed significant negative correlations in Mexican American(β=-0.027, P<0.05) and Other Hispanic groups(β=-0.044, P<0.05), while the Other Race group showed a positive correlation(β=0.073, P<0.05).

In Male Pubertal subjects, a consistent negative association was evident between testosterone and hs-CRP levels (β=-0.002, P<0.05, Table 2). Supplementary Table 2 revealed a threshold effect at 224.00 ng/dl, where above this level, the association was more pronounced(β=-0.003, P<0.001) (Figure 2). The results of the stratified analysis (Supplementary Table 3) also support the negative correlation between testosterone and hs-CRP.

For Female Prepubertal subjects, a significant positive association was found between testosterone and hs-CRP in the fully-adjusted model in Table 2 (β=0.047, P<0.05). However, the piecewise linear regression model in Supplementary Table 2 failed to detect any significant threshold effect(Supplementary Figure 1). In the stratified analysis for the Female Prepubertal group(Supplementary Table 3), a significant negative relationship is demonstrated in overweight children (β=-0.077, P<0.05).

For Female Pubertal subjects, no significant association between testosterone and CRP was found in all models in Table 2, and likewise, no significant threshold effect was detected in Supplementary Table 2 and Supplementary Figure 1. In the stratified analysis of female pubertal development, a significant negative association was observed among Mexican American children(β=-0.016, P<0.05) and those engaging in over 6 hours of physical activity per week(β=-0.048, P<0.05). Conversely, a significant positive relationship was found in Non-Hispanic Asian children (β=0.023, P<0.05).

Association between estradiol and high-sensitivity C-reactive protein

In conducting multivariate regression analysis(Table 2) and threshold effect analysis(Supplementary Table 2), we did not identify significant associations between estradiol and hs-CRP in Male Prepubertal, Male Pubertal, and Female Prepubertal cohorts(Figure 2, Supplementary Figure 1).However,upon conducting stratified analyses within these three populations, we identified several subgroups where the relationship between estradiol and hs-CRP exhibited statistically significant associations. These included both positive and negative correlations (Supplementary Table 4).

In the Female Pubertal group, a significant negative correlation was observed between estradiol and hs-CRP(β=-0.002, P<0.05), and this inverse relationship was more pronounced when estradiol was less than or equal to 183 pg/ml(β=-0.004, P=0.001). In the Female Pubertal group, a significant positive correlation was observed between estradiol and hs-CRP when physical activity was between 3.5-5.9 hours per week(β=0.017, P<0.05, Supplementary Table 4).

Association between SHBG and high-sensitivity C-reactive protein

From Table 2, for each subgroup, there exists a significant negative association between SHBG and hs-CRP, with the relationship holding across various models adjusting for different sets of covariates(all P<0.05). For the Male Prepubertal, Male Pubertal, Female Prepubertal, and Female Pubertal groups, the β coefficients suggest a stronger negative correlation below the respective inflection points of 72.09, 25.74, 149.10, and 56.48 nmol/l (Supplementary Table 2, Figure 2, and Supplementary Figure 1).

The results from stratified analysis also support a negative correlation between SHBG levels and hs-CRP(Supplementary Table 5). However, a notable exception is observed in the 'Above 6th grade' group within the Female Prepubertal population, where a positive correlation is identified(β=0.035, P<0.05).

Our research uncovers a distinct gender and age-related difference in the relationship between testosterone and hs-CRP. In Male Prepubertal group, an initial increase in testosterone levels leads to a transient surge in hs-CRP (β = 0.082, P = 0.047), subsequently resulting in an overall decline (β=-0.028, P = 0.023). Contrarily, in Male Pubertal, hs-CRP levels consistently decrease under the influence of testosterone (β=-0.002, P < 0.05). In Female Prepubertal, a significant positive correlation between testosterone and hs-CRP is observed (β = 0.047, P < 0.05). However, no significant correlation is found in Female Pubertal (β = 0.002, P > 0.05). Previous studies commonly support the negative correlation between testosterone and CRP in both adolescent^[2] and adult males^{[3, 14]}, to some extent, validating the hypothesis that testosterone has anti-inflammatory properties in males. In females, the relationship between testosterone and CRP appears diverse, even contrary. The research conducted by de Dios O and colleagues did not identify any correlation between testosterone and hs-CRP in female adolescents aged between 12 and 16 years^[2]. In postmenopausal women, some studies have reported a positive correlation between serum testosterone levels and CRP.^[6] However, there are also studies concluding an inverse relationship between serum testosterone levels and CRP in postmenopausal women.^{[7, 15]} The level of testosterone plays a crucial role in modulating inflammatory processes, which is achieved by suppressing the expansion, differentiation, and function of adipocytes, curtailing the formation of cytokines (leptin, IL-6, TNF-α, MCP-1, resistin), and concurrently promoting the secretion of adiponectin.^[16] Future research is necessary to explore the interaction mechanisms between testosterone and hs-CRP.

Our study found a negative correlation between estradiol and hs-CRP (β=-0.002, P < 0.05) solely within the Female Pubertal population. No such correlation was observed in the Male Prepubertal, Male Pubertal, and Female Prepubertal groups. Previous studies on adult females have indicated that the relationship between estradiol and CRP is negative pre-menopause^{[5, 17]}, but turns positive post-menopause^{[6, 15]}. This suggests a potentially complex and dynamic relationship between these variables across different stages of life. Throughout the inflammatory reaction, pro-inflammatory cytokines prompt the synthesis of NO in cells like monocytes, macrophages, and neutrophils. During the process of phagocytosis, NO, when discharged by tissue macrophages, operates as a positive feedback entity, catalyzing the attraction of additional phagocytes. Physiological levels of estrogen maintained the nCRP-facilitated decrease in NO production in LPS-stimulated monocytes, concurrently, estrogen countered the mCRP-induced increase of NO production in the same cells.^[18] This aligns with earlier research demonstrating that estrogen attenuates pro-inflammatory responses, which includes the production of NO and inflammatory cytokines.

Our study reveals a consistent negative correlation between SHBG and hs-CRP in both children and adolescents. This finding is not isolated, as it aligns with the results of prior research. Such negative correlation between SHBG and C-reactive protein has been confirmed in various populations, including adolescents^[2], adult males^[3], premenopausal women^[17], and postmenopausal women^[7]. SHBG, secreted by the liver into the bloodstream, avidly binds to both androgens and estrogens, thereby regulating their bioavailability. BMI has been traditionally considered a primary determinant of circulating SHBG concentration, with a reported consistent negative correlation between BMI and plasma SHBG levels.^[19] Lower serum SHBG concentrations in overweight individuals serve as a biomarker of metabolic syndrome^[20] and indicate an increased risk of type 2 diabetes(T2D)^[21] and cardiovascular diseases(CVD)^[22]. Obesity-related endocrine mechanisms and chronic inflammation are associated with the reduction of SHBG prior to puberty, suggesting that lower SHBG levels could indicate an earlier onset of puberty.^[23] Reviews have proposed that the subtle inflammation and changes in pro-inflammatory/anti-inflammatory cytokines (i.e., TNFα, IL-1β, and adiponectin) occurring in obesity and T2D may be the primary cause of decreased SHBG levels, rather than hyperinsulinemia.^[22] It remains to be elucidated whether the decrease in SHBG is merely a biomarker, or if it actively participates in the inflammatory response process related to CRP, and subsequently contributes to the pathogenesis of obesity, T2D, fatty liver, and cardiovascular diseases.

Our study possesses several strengths. First, we have filled a research gap in exploring the relationship between sex steroid hormones and hs-CRP in children populations(6–11 years). Additionally, we categorized children and adolescents into prepubertal and pubertal groups based on hormone levels, offering a more reliable demographic foundation for researching the association between sex steroid hormones and hs-CRP. Furthermore, the data utilized in our study was obtained from the NHANES database, ensuring the accuracy of serum hormone and hs-CRP measurements. We also weighted our data to ensure that our final results would be representative of the overall health status of children and adolescents in the United States. Nevertheless, there are some limitations in our study. Even though we adjusted for potential confounders, there might still be unadjusted factors that could influence our results. The lack of data on gonadotropin-releasing hormone, gonadotropins, and crucial enzymes involved in hormone responses restricted us from further delving into the underlying biological mechanisms. Importantly, it should be noted that our study is cross-sectional, thereby preventing us from establishing a causal relationship between sex steroid hormones and hs-CRP.

The present study illuminates the potential implication of sex steroid hormones as a key indicator modulating high-sensitivity C-reactive protein levels in the children and adolescent population.

Author Contributions:

ZSZ and XYZ designed this research. ZSZ , XGL, CYW, SZZ and XYZ performed the research. XGL and CYW conducted statistical analyses. ZSZ wrote the first draft of the manuscript. SZZ and XYZ revised the manuscript for intellectual content. All authors have reviewed and approved the final version of the manuscript.

Conflict of Interest Statement:

The authors declare no conflicts of interest.

Funding: None.

Acknowledgments:

We would like to express our sincere gratitude to the investigators who conducted the original NHANES study, as well as the USA National Center for Health Statistics for sharing the data.

Statement :

The manuscript has been read and approved by all the authors. The requirements for authorship have been met. Each author believes that the manuscript represents honest work.

The ethics declaration:

This study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving human subjects were approved by each institute’s ethics committe.

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Tables 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

Tables.docx
SupplementaryMaterials.docx
Supplementary Figure 1: Curve fitting relationships between sex steroid hormones and high-sensitivity C-reactive protein in female children and adolescents. The solid and dashed lines in the graph represent the estimated values and corresponding 95% confidence intervals of high-sensitivity C-reactive protein, respectively. SHBG: sex hormone‑binding globulin; Curve adjusted for age, race, education level, poverty income ratio, diabetes status, sample collection session, and total cholesterol.

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Associations of Sex Steroid Hormones with C-Reactive Protein Levels in American Children and Adolescents: Evidence from NHANES 2015-2016

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Version 1

Abstract

Figures

INTRODUCTION

PARTICIPANTS AND METHODS

Study design and participants

Measurements of sex hormone indicators

Measurements of high-sensitivity C-reactive protein

Covariates

Adjustment for Pubertal Status

Statistical analyses

RESULTS

DISCUSSION

CONCLUSIONS

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

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