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Abstract

Background

The C-reactive protein-triglyceride glucose index (CTI) is a recently introduced index designed to simultaneously assess inflammation (via CRP) and insulin resistance (via the triglyceride-glucose index, TyG), both of which are recognized risk factors for declining testosterone levels in men.

Aim

This study investigates the association between CTI and low testosterone levels in American adult men, aiming to evaluate CTI as a predictor of low testosterone level.

Methods

Data from the 2015–2016 NHANES were used in this cross-sectional study, including men aged 20 and older. Multivariate linear and logistic regression models were employed to analyze the relationship between CTI, total testosterone levels, and the risk of low testosterone level. Receiver operating characteristic (ROC) curves were generated to assess the predictive performance of CTI for low testosterone level.

Outcomes

The primary outcome was testosterone levels, with low testosterone level defined as a serum testosterone level below 300 ng/dL in adult men.

Results

Among 878 participants, 189 had low testosterone level. The mean CTI was significantly higher in the low testosterone level group (9.39 ± 0.09) compared to the non- low testosterone level group (8.62 ± 0.05; P < .0001). After adjusting for covariates, higher CTI was significantly associated with lower total testosterone levels (β = –44.6, 95% CI: –66.34, –22.87, P < .001) and increased low testosterone level risk (OR = 1.84, 95% CI: 1.31, 2.57, P = .002). ROC analysis showed that CTI (AUC = 0.7357, 95% CI: 0.6975, 0.7739) outperformed TyG and VAI in predicting low testosterone level, highlighting its potential clinical value in assessing low testosterone status.

Clinical Implications

Timely monitoring of testosterone levels in individuals with elevated CTI is clinically significant. Additionally, for those with TD, regular assessment of CTI may help in preventing future cardiovascular complications.

Strengths and limitations

This study is the first to explore the relationship between CTI and low testosterone using a large sample from the NHANES database. However, due to the cross-sectional design, causal inference regarding CTI and low testosterone level cannot be drawn.

Conclusions

CTI appears to be a more effective predictor of low testosterone level than TyG, CRP, or VAI, suggesting its usefulness as a simple, low-cost indicator for early TD risk assessment. Further research is needed to verify its clinical applicability across diverse populations.

testosterone deficiency, low testosterone level, C-reactive protein-triglyceride glucose index, inflammation, insulin resistance, NHANES

Introduction

Testosterone is produced and secreted primarily by the Leydig cells in the testes and is an essential steroid hormone for men. Normal levels of testosterone have various important physiological functions, such as regulating male reproductive and sexual abilities (erectile function, libido), cognitive abilities, and cardiovascular health.1-3 Testosterone deficiency is defined by two measurements of testosterone levels below 300 ng/dl.4 Approximately 30% of men aged 40 to 79 are affected by testosterone deficiency.5 The prevalence of testosterone deficiency increases with age and the presence of certain chronic conditions such as hypertension, obesity, diabetes, and metabolic syndrome (Mets).6 Numerous studies have pointed out that a decline in total testosterone or testosterone deficiency can severely impact the quality of life in men, significantly increasing the risk of erectile dysfunction (ED), decreased libido, cardiovascular diseases (CVD), sleep disorders, hair loss, and depression.7-10

Currently, Mets (including obesity, dyslipidemia, hypertension, and insulin resistance [IR]) is a risk factor for testosterone deficiency.11 Among these, IR is closely associated with testosterone deficiency in men, as it can reduce the secretion of testosterone by Leydig cells in the testes.12 A cross-sectional study indicated that low testosterone levels in patients with type 1 or type 2 diabetes are independently associated with IR.13 Furthermore, Obesity is considered to have a close association with IR.14 Inflammatory cytokines induced by obesity are closely associated with IR.15,16 In IR, various cytokines and inflammatory mediators, particularly C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukins (IL), are upregulated.15,17 Recently, a systematic analysis also described that inflammation-related indices are independent risk factors for sex hormone metabolism disorders.18 These pro-inflammatory cytokines released by the accumulation of adipose tissue can also inhibit the hypothalamic–pituitary-gonadal axis, thereby reducing testosterone secretion.19 Therefore, many scholars are dedicated to developing new indicators related to obesity or IR to predict testosterone deficiency. In clinical practice, the triglyceride-glucose (TyG) index, which is calculated from fasting blood glucose and fasting triglycerides, is a novel and reliable indicator of IR.20 It has been shown to have better predictive value compared to traditional IR markers such as the triglyceride/HDL-cholesterol ratio and the homeostasis model assessment of IR (HOMA-IR).21-23 The visceral adiposity index (VAI), which can be used to directly assess abdominal fat distribution, has also been shown to have a predictive effect for testosterone deficiency comparable to that of the TyG index.24

Recently, Ruan et al. proposed a new index for comprehensively evaluating the severity of inflammation and IR, called the “C-reactive protein-triglyceride glucose index (CTI),” which is calculated from CRP and TyG.25 Research has already explored the application value of CTI in predicting the survival rate of cancer patients.25,26 Is there really a correlation between MHR and low testosterone level? Therefore, we assessed the relationship between CTI and low testosterone level by obtaining data from the nationally representative National Health and Nutrition Examination Survey (NHANES). We also compared the predictive ability of CTI for low testosterone level with several other indicators, including TyG, CRP, and VAI.

Materials and methods

Data source and study population

NHANES measured testosterone levels in men from 2011 to 2016, while CRP was only measured in the 2015–2016 survey during 2011–2016. Therefore, we used the 2015–2016 NHANES data. NHANES is a continuous national survey conducted every two years by the National Center for Health Statistics (NCHS), which is part of the Centers for Disease Control and Prevention (CDC). Experienced medical personnel collect comprehensive data from participants through personal interviews, physical examinations, questionnaires, and laboratory tests. The data clearly represent the nutritional and health status of the non-institutionalized civilian population in the US because multistage sample weights are assigned to each survey participant. All NHANES procedures were approved by the NHANES Institutional Review Board (IRB)/NCHS Research Ethics Review Board (ERB), and all participants provided written informed consent (NCHS IRB/ERB Protocol No. #2011-17).

In the 2015–2016 NHANES, a total of 9 971 participants were included. Subsequently, we excluded 5 079 female participants, 2 145 participants younger than 20 years old, 280 participants with incomplete testosterone data, 1387 participants lacking fasting plasma glucose and serum triglyceride information needed for calculating the TyG index, 2 participants lacking CRP data, and 200 participants missing covariate data. Finally, we included 878 adult male participants, as illustrated in Fig. 1.

The flow chart of selection process for participants of NHANES 2015–2016.
Figure 1

The flow chart of selection process for participants of NHANES 2015–2016.

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Assessment of serum total testosterone level

Participants were asked to fast overnight before their serum testosterone levels were measured. Due to the diurnal fluctuation of testosterone, the CDC collected serum samples between 8:30 AM and 11:30 AM. The concentrations of serum testosterone were measured using isotope dilution liquid chromatography–tandem mass spectrometry (ID-LC–MS/MS). This method involves separating testosterone from binding proteins and eliminating potential interfering substances prior to analysis. According to the American Urological Association guidelines, low testosterone level is defined as total testosterone <300 ng/dl.4

Measurement of C-reactive protein-triglyceride glucose index

The formula for calculating CTI is 0.412 * Ln (CRP) + TyG,25 and the TyG was defined as Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2].27 Blood samples were processed in the morning after 8.5 hours of fasting, and the samples were shipped to laboratories certified by NCHS. CRP levels were measured using the Beckman UniCel analyzer, with a lower detection limit of 0.011 mg/dL. Triglycerides and fasting blood glucose were enzymatically measured using the Roche Modular P and Roche Cobas 6000 chemical analyzers, as well as the hexokinase-mediated reaction on the Roche/Hitachi Cobas C 501 chemical analyzer. All details regarding the analyzers and corresponding methods can be accessed on the NHANES website.

Covariates

We included potential confounding factors that might affect the association between CTI and testosterone. Demographic variables included age, body mass index (BMI), race, educational level, marital status, and poverty to income ratio (PIR). Personal history variables included smoking status (never smoker, former smoker, current smoker) and alcohol intake (no, yes). Additionally, we collected a range of laboratory data such as HDL-C, low-density lipoprotein cholesterol (LDL-C), and uric acid (UA). Medical complications included diabetes mellitus (DM) (no, borderline, yes), hypertension (no, yes), hyperlipidemia (no, yes), and CVD (no, yes). The specific definitions of smoking, alcohol intake, and medical complications can be found in Supplementary Table S1. Additionally, the calculation of VAI is obtained using the formula: VAI = [waist circumference (WC, cm)/(39.68+ 1.88× BMI (kg/m2))] × (TG (mmol/L)/1.03) × (1.31/HDL (mmol/L)).28

Statistical analysis

NHANES used a complex multistage sampling design, applying appropriate sample weights to each participant to obtain unbiased and accurate estimates. Continuous variables were described using the mean and standard error (SE), while categorical variables were expressed as percentages (%) and SE. The baseline characteristics of all participants were grouped based on whether they had low testosterone level. Continuous variables were compared between the two groups using survey-weighted linear regression, while categorical variables were compared using chi-square tests. Weighted multivariate linear regression models (β and 95% confidence interval (CI)) were used to explore the relationship between CTI and total testosterone level. Weighted multivariate logistic regression models (odds ratio (OR) and 95%CI) were used to explore the relationship between CTI and low testosterone level. Three models were assigned to explore the potential impact of covariates on the association (Crude model: unadjusted; Model 1: adjusted for age, race, education, marital status, and PIR were adjusted; Model 2: Model 1+ LDL-c, HDL-c, UA, BMI, smoking, alcohol intake, DM, hypertension, CVD, and hyperlipidemia were adjusted).

CTI was converted from a continuous variable to a categorical variable based on quartiles (Q) for additional analysis. Additionally, smooth curve fitting and generalized additive models were used to evaluate the dose–response relationship between CTI and total testosterone as well as low testosterone level. The predictive ability of CTI, TyG index, CRP, and VAI for low testosterone level was compared by plotting receiver operating characteristic (ROC) curves and their respective areas under the curve (AUC) (Z-test). Subgroup analyses were conducted to further examine the association between CTI and testosterone across different subgroups. All statistical analyses were performed using Empower software (www.empowerstats.com) and R version 4.0.2 (http://www.R-project.org, The R Foundation). A P-value of <.05 was considered statistically significant.

Results

Baseline characteristics

Finally, 878 adult male participants were included in the study, of whom 189 were classified as having low testosterone level (<300 ng/dL). The CTI in the low testosterone level group (9.39 ± 0.09) was significantly higher than in the non- low testosterone level group (8.62 ± 0.05; P < .0001). Additionally, the TyG index and VAI were both higher in the low testosterone level group (P < .0001). Compared to the non- low testosterone level group, participants in the low testosterone level group had significantly higher prevalence of DM (P < .001), hypertension (P = .016), and hyperlipidemia (P = .002). The detailed demographic characteristics are shown in Table 1.

Table 1
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Baseline characteristics of the study population by low testosterone status, weighted.

CharacteristicsTotal participants (N = 878)Low testosterone levelP value
No (N = 689)Yes (N = 189)
Age, years48.50 ± 0.7747.83 ± 1.0951.22 ± 1.19.11
BMI, kg/m229.57 ± 0.3228.38 ± 0.3334.43 ± 0.70<.0001
Total testosterone. ng/dl460.59 ± 10.52518.98 ± 9.97222.94 ± 6.97<.0001
FBG, mg/dL113.20 ± 1.10109.25 ± 1.08129.30 ± 3.44<.0001
UA, mg/dL6.07 ± 0.055.94 ± 0.056.59 ± 0.06<.0001
HDL-c, mg/dL50.09 ± 0.8051.57 ± 0.9344.02 ± 0.81<.0001
LDL-c, mg/dL113.38 ± 1.48113.33 ± 1.57113.56 ± 3.08.94
CRP, mg/dL3.19 ± 0.222.82 ± 0.194.71 ± 0.74.024
Fasting triglycerides, mg/dL116.56 ± 2.99108.56 ± 2.88149.12 ± 7.59<.0001
TyG8.60 ± 0.038.51 ± 0.0328.98 ± 0.05<.0001
VAI1.67 ± 0.061.4911 ± 0.05642.40 ± 0.12<.0001
CTI8.77 ± 0.058.62 ± 0.059.39 ± 0.09<.0001
PIR3.11 ± 0.123.11 ± 0.133.10 ± 0.13.96
Race, %.34
 Mexican American8.17 ± 0.028.00 ± 2.268.86 ± 2.76
 Non-Hispanic White67.68 ± 0.0967.03 ± 3.7170.30 ± 5.20
 Non-Hispanic Black8.58 ± 0.018.57 ± 1.798.65 ± 2.40
 Other races15.57 ± 0.0216.40 ± 1.9612.20 ± 2.59
Educational level, %.50
 Below high school14.69 ± 0.0215.41 ± 3.2311.73 ± 2.05
 High school23.30 ± 0.0322.54 ± 2.4826.39 ± 5.10
 Above high school62.01 ± 0.0762.04 ± 4.5561.90 ± 5.08
Marital status, %.62
 Living alone30.15 ± 0.0230.67 ± 2.8528.03 ± 4.24
 Married or living with a partner69.85 ± 0.0769.33 ± 2.8571.97 ± 4.24
Age group, %.18
 20–40 y32.12 ± 0.0334.03 ± 3.3224.34 ± 3.63
 40–60 y38.53 ± 0.0336.63 ± 2.6046.24 ± 4.22
 ≥60 y29.35 ± 0.0329.33 ± 2.5029.41 ± 3.38
BMI group, %<.0001
 <25 kg/m223.78 ± 0.0228.56 ± 2.384.35 ± 1.78
 25 -30 kg/m235.58 ± 0.0338.10 ± 1.3125.31 ± 2.80
 ≥30 kg/m240.64 ± 0.0533.34 ± 2.5570.34 ± 3.13
Alcohol intake, %.512
 No8.31 ± 0.027.80 ± 2.0310.39 ± 3.69
 Yes91.69 ± 0.0792.20 ± 2.0389.61 ± 3.69
Smoking, %<.001
 Never46.94 ± 0.0448.88 ± 3.3739.02 ± 4.01
 Former32.41 ± 0.0428.01 ± 2.4950.32 ± 5.84
 Now20.65 ± 0.0223.11 ± 2.2610.66 ± 2.69
DM, %<.001
 No55.56 ± 0.0561.52 ± 2.4831.32 ± 4.92
 Borderline24.86 ± 0.0322.96 ± 2.0832.58 ± 4.79
 Yes19.58 ± 0.0215.52 ± 1.5236.09 ± 4.53
Hypertension, %.016
 No58.30 ± 0.0661.59 ± 2.9844.91 ± 5.34
 Yes41.70 ± 0.0338.41 ± 2.9855.09 ± 5.34
Hyperlipidemia, %.002
 No31.53 ± 0.0336.13 ± 2.7312.77 ± 3.90
 Yes68.47 ± 0.0663.87 ± 2.7387.23 ± 3.90
CVD.17
 No90.22 ± 0.0791.05 ± 1.6986.84 ± 2.23
 Yes9.78 ± 0.028.95 ± 1.6913.16 ± 2.23
CharacteristicsTotal participants (N = 878)Low testosterone levelP value
No (N = 689)Yes (N = 189)
Age, years48.50 ± 0.7747.83 ± 1.0951.22 ± 1.19.11
BMI, kg/m229.57 ± 0.3228.38 ± 0.3334.43 ± 0.70<.0001
Total testosterone. ng/dl460.59 ± 10.52518.98 ± 9.97222.94 ± 6.97<.0001
FBG, mg/dL113.20 ± 1.10109.25 ± 1.08129.30 ± 3.44<.0001
UA, mg/dL6.07 ± 0.055.94 ± 0.056.59 ± 0.06<.0001
HDL-c, mg/dL50.09 ± 0.8051.57 ± 0.9344.02 ± 0.81<.0001
LDL-c, mg/dL113.38 ± 1.48113.33 ± 1.57113.56 ± 3.08.94
CRP, mg/dL3.19 ± 0.222.82 ± 0.194.71 ± 0.74.024
Fasting triglycerides, mg/dL116.56 ± 2.99108.56 ± 2.88149.12 ± 7.59<.0001
TyG8.60 ± 0.038.51 ± 0.0328.98 ± 0.05<.0001
VAI1.67 ± 0.061.4911 ± 0.05642.40 ± 0.12<.0001
CTI8.77 ± 0.058.62 ± 0.059.39 ± 0.09<.0001
PIR3.11 ± 0.123.11 ± 0.133.10 ± 0.13.96
Race, %.34
 Mexican American8.17 ± 0.028.00 ± 2.268.86 ± 2.76
 Non-Hispanic White67.68 ± 0.0967.03 ± 3.7170.30 ± 5.20
 Non-Hispanic Black8.58 ± 0.018.57 ± 1.798.65 ± 2.40
 Other races15.57 ± 0.0216.40 ± 1.9612.20 ± 2.59
Educational level, %.50
 Below high school14.69 ± 0.0215.41 ± 3.2311.73 ± 2.05
 High school23.30 ± 0.0322.54 ± 2.4826.39 ± 5.10
 Above high school62.01 ± 0.0762.04 ± 4.5561.90 ± 5.08
Marital status, %.62
 Living alone30.15 ± 0.0230.67 ± 2.8528.03 ± 4.24
 Married or living with a partner69.85 ± 0.0769.33 ± 2.8571.97 ± 4.24
Age group, %.18
 20–40 y32.12 ± 0.0334.03 ± 3.3224.34 ± 3.63
 40–60 y38.53 ± 0.0336.63 ± 2.6046.24 ± 4.22
 ≥60 y29.35 ± 0.0329.33 ± 2.5029.41 ± 3.38
BMI group, %<.0001
 <25 kg/m223.78 ± 0.0228.56 ± 2.384.35 ± 1.78
 25 -30 kg/m235.58 ± 0.0338.10 ± 1.3125.31 ± 2.80
 ≥30 kg/m240.64 ± 0.0533.34 ± 2.5570.34 ± 3.13
Alcohol intake, %.512
 No8.31 ± 0.027.80 ± 2.0310.39 ± 3.69
 Yes91.69 ± 0.0792.20 ± 2.0389.61 ± 3.69
Smoking, %<.001
 Never46.94 ± 0.0448.88 ± 3.3739.02 ± 4.01
 Former32.41 ± 0.0428.01 ± 2.4950.32 ± 5.84
 Now20.65 ± 0.0223.11 ± 2.2610.66 ± 2.69
DM, %<.001
 No55.56 ± 0.0561.52 ± 2.4831.32 ± 4.92
 Borderline24.86 ± 0.0322.96 ± 2.0832.58 ± 4.79
 Yes19.58 ± 0.0215.52 ± 1.5236.09 ± 4.53
Hypertension, %.016
 No58.30 ± 0.0661.59 ± 2.9844.91 ± 5.34
 Yes41.70 ± 0.0338.41 ± 2.9855.09 ± 5.34
Hyperlipidemia, %.002
 No31.53 ± 0.0336.13 ± 2.7312.77 ± 3.90
 Yes68.47 ± 0.0663.87 ± 2.7387.23 ± 3.90
CVD.17
 No90.22 ± 0.0791.05 ± 1.6986.84 ± 2.23
 Yes9.78 ± 0.028.95 ± 1.6913.16 ± 2.23

Abbreviations: BMI, body mass index; FBG, fasting blood glucose; UA, uric acid; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; CRP, C-reactive protein; TyG, triglyceride-glucose; VAI, visceral adiposity index; CTI, C-reactive protein-triglyceride glucose index; PIR, poverty-to-income ratio; DM, diabetes mellitus; CVD, cardiovascular disease.

Note: Continuous variables are presented as weighted means with standard errors; categorical variables are presented as weighted percentages with standard errors.

Table 1
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Baseline characteristics of the study population by low testosterone status, weighted.

CharacteristicsTotal participants (N = 878)Low testosterone levelP value
No (N = 689)Yes (N = 189)
Age, years48.50 ± 0.7747.83 ± 1.0951.22 ± 1.19.11
BMI, kg/m229.57 ± 0.3228.38 ± 0.3334.43 ± 0.70<.0001
Total testosterone. ng/dl460.59 ± 10.52518.98 ± 9.97222.94 ± 6.97<.0001
FBG, mg/dL113.20 ± 1.10109.25 ± 1.08129.30 ± 3.44<.0001
UA, mg/dL6.07 ± 0.055.94 ± 0.056.59 ± 0.06<.0001
HDL-c, mg/dL50.09 ± 0.8051.57 ± 0.9344.02 ± 0.81<.0001
LDL-c, mg/dL113.38 ± 1.48113.33 ± 1.57113.56 ± 3.08.94
CRP, mg/dL3.19 ± 0.222.82 ± 0.194.71 ± 0.74.024
Fasting triglycerides, mg/dL116.56 ± 2.99108.56 ± 2.88149.12 ± 7.59<.0001
TyG8.60 ± 0.038.51 ± 0.0328.98 ± 0.05<.0001
VAI1.67 ± 0.061.4911 ± 0.05642.40 ± 0.12<.0001
CTI8.77 ± 0.058.62 ± 0.059.39 ± 0.09<.0001
PIR3.11 ± 0.123.11 ± 0.133.10 ± 0.13.96
Race, %.34
 Mexican American8.17 ± 0.028.00 ± 2.268.86 ± 2.76
 Non-Hispanic White67.68 ± 0.0967.03 ± 3.7170.30 ± 5.20
 Non-Hispanic Black8.58 ± 0.018.57 ± 1.798.65 ± 2.40
 Other races15.57 ± 0.0216.40 ± 1.9612.20 ± 2.59
Educational level, %.50
 Below high school14.69 ± 0.0215.41 ± 3.2311.73 ± 2.05
 High school23.30 ± 0.0322.54 ± 2.4826.39 ± 5.10
 Above high school62.01 ± 0.0762.04 ± 4.5561.90 ± 5.08
Marital status, %.62
 Living alone30.15 ± 0.0230.67 ± 2.8528.03 ± 4.24
 Married or living with a partner69.85 ± 0.0769.33 ± 2.8571.97 ± 4.24
Age group, %.18
 20–40 y32.12 ± 0.0334.03 ± 3.3224.34 ± 3.63
 40–60 y38.53 ± 0.0336.63 ± 2.6046.24 ± 4.22
 ≥60 y29.35 ± 0.0329.33 ± 2.5029.41 ± 3.38
BMI group, %<.0001
 <25 kg/m223.78 ± 0.0228.56 ± 2.384.35 ± 1.78
 25 -30 kg/m235.58 ± 0.0338.10 ± 1.3125.31 ± 2.80
 ≥30 kg/m240.64 ± 0.0533.34 ± 2.5570.34 ± 3.13
Alcohol intake, %.512
 No8.31 ± 0.027.80 ± 2.0310.39 ± 3.69
 Yes91.69 ± 0.0792.20 ± 2.0389.61 ± 3.69
Smoking, %<.001
 Never46.94 ± 0.0448.88 ± 3.3739.02 ± 4.01
 Former32.41 ± 0.0428.01 ± 2.4950.32 ± 5.84
 Now20.65 ± 0.0223.11 ± 2.2610.66 ± 2.69
DM, %<.001
 No55.56 ± 0.0561.52 ± 2.4831.32 ± 4.92
 Borderline24.86 ± 0.0322.96 ± 2.0832.58 ± 4.79
 Yes19.58 ± 0.0215.52 ± 1.5236.09 ± 4.53
Hypertension, %.016
 No58.30 ± 0.0661.59 ± 2.9844.91 ± 5.34
 Yes41.70 ± 0.0338.41 ± 2.9855.09 ± 5.34
Hyperlipidemia, %.002
 No31.53 ± 0.0336.13 ± 2.7312.77 ± 3.90
 Yes68.47 ± 0.0663.87 ± 2.7387.23 ± 3.90
CVD.17
 No90.22 ± 0.0791.05 ± 1.6986.84 ± 2.23
 Yes9.78 ± 0.028.95 ± 1.6913.16 ± 2.23
CharacteristicsTotal participants (N = 878)Low testosterone levelP value
No (N = 689)Yes (N = 189)
Age, years48.50 ± 0.7747.83 ± 1.0951.22 ± 1.19.11
BMI, kg/m229.57 ± 0.3228.38 ± 0.3334.43 ± 0.70<.0001
Total testosterone. ng/dl460.59 ± 10.52518.98 ± 9.97222.94 ± 6.97<.0001
FBG, mg/dL113.20 ± 1.10109.25 ± 1.08129.30 ± 3.44<.0001
UA, mg/dL6.07 ± 0.055.94 ± 0.056.59 ± 0.06<.0001
HDL-c, mg/dL50.09 ± 0.8051.57 ± 0.9344.02 ± 0.81<.0001
LDL-c, mg/dL113.38 ± 1.48113.33 ± 1.57113.56 ± 3.08.94
CRP, mg/dL3.19 ± 0.222.82 ± 0.194.71 ± 0.74.024
Fasting triglycerides, mg/dL116.56 ± 2.99108.56 ± 2.88149.12 ± 7.59<.0001
TyG8.60 ± 0.038.51 ± 0.0328.98 ± 0.05<.0001
VAI1.67 ± 0.061.4911 ± 0.05642.40 ± 0.12<.0001
CTI8.77 ± 0.058.62 ± 0.059.39 ± 0.09<.0001
PIR3.11 ± 0.123.11 ± 0.133.10 ± 0.13.96
Race, %.34
 Mexican American8.17 ± 0.028.00 ± 2.268.86 ± 2.76
 Non-Hispanic White67.68 ± 0.0967.03 ± 3.7170.30 ± 5.20
 Non-Hispanic Black8.58 ± 0.018.57 ± 1.798.65 ± 2.40
 Other races15.57 ± 0.0216.40 ± 1.9612.20 ± 2.59
Educational level, %.50
 Below high school14.69 ± 0.0215.41 ± 3.2311.73 ± 2.05
 High school23.30 ± 0.0322.54 ± 2.4826.39 ± 5.10
 Above high school62.01 ± 0.0762.04 ± 4.5561.90 ± 5.08
Marital status, %.62
 Living alone30.15 ± 0.0230.67 ± 2.8528.03 ± 4.24
 Married or living with a partner69.85 ± 0.0769.33 ± 2.8571.97 ± 4.24
Age group, %.18
 20–40 y32.12 ± 0.0334.03 ± 3.3224.34 ± 3.63
 40–60 y38.53 ± 0.0336.63 ± 2.6046.24 ± 4.22
 ≥60 y29.35 ± 0.0329.33 ± 2.5029.41 ± 3.38
BMI group, %<.0001
 <25 kg/m223.78 ± 0.0228.56 ± 2.384.35 ± 1.78
 25 -30 kg/m235.58 ± 0.0338.10 ± 1.3125.31 ± 2.80
 ≥30 kg/m240.64 ± 0.0533.34 ± 2.5570.34 ± 3.13
Alcohol intake, %.512
 No8.31 ± 0.027.80 ± 2.0310.39 ± 3.69
 Yes91.69 ± 0.0792.20 ± 2.0389.61 ± 3.69
Smoking, %<.001
 Never46.94 ± 0.0448.88 ± 3.3739.02 ± 4.01
 Former32.41 ± 0.0428.01 ± 2.4950.32 ± 5.84
 Now20.65 ± 0.0223.11 ± 2.2610.66 ± 2.69
DM, %<.001
 No55.56 ± 0.0561.52 ± 2.4831.32 ± 4.92
 Borderline24.86 ± 0.0322.96 ± 2.0832.58 ± 4.79
 Yes19.58 ± 0.0215.52 ± 1.5236.09 ± 4.53
Hypertension, %.016
 No58.30 ± 0.0661.59 ± 2.9844.91 ± 5.34
 Yes41.70 ± 0.0338.41 ± 2.9855.09 ± 5.34
Hyperlipidemia, %.002
 No31.53 ± 0.0336.13 ± 2.7312.77 ± 3.90
 Yes68.47 ± 0.0663.87 ± 2.7387.23 ± 3.90
CVD.17
 No90.22 ± 0.0791.05 ± 1.6986.84 ± 2.23
 Yes9.78 ± 0.028.95 ± 1.6913.16 ± 2.23

Abbreviations: BMI, body mass index; FBG, fasting blood glucose; UA, uric acid; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; CRP, C-reactive protein; TyG, triglyceride-glucose; VAI, visceral adiposity index; CTI, C-reactive protein-triglyceride glucose index; PIR, poverty-to-income ratio; DM, diabetes mellitus; CVD, cardiovascular disease.

Note: Continuous variables are presented as weighted means with standard errors; categorical variables are presented as weighted percentages with standard errors.

Association between C-reactive protein-triglyceride glucose index and total testosterone, and low testosterone level

As shown in Table 2, there is a significant negative association between CTI and total testosterone (Crude model, β = –84.1, 95% CI: –98.99, –69.21, P < .0001; Model 1, β = –82.74, 95% CI: –99.02, –66.46, P < .0001; Model 2, β = –44.6, 95% CI: –66.34, –22.87, P < .001). Subsequently, after dividing CTI into quartiles, this association remained significant in both the Crude model and Model 1 (P < .05). In the fully adjusted Model 2, our results showed that higher CTI is significantly associated with lower levels of total testosterone (Q3 vs Q1: β = –98.57, 95% CI: –145.38, –51.75, P < .001; Q4 vs Q1: β = –118.46, 95% CI: –170.99, –65.93, P < .001). Then, the positive association between CTI and low testosterone level was significant in all models (Crude model, OR = 2.70, 95% CI: 2.26, 3.24, P < .0001; Model 1, OR = 2.69, 95%CI: 2.17, 3.34, P < .0001; Model 2, OR = 1.84, 95% CI: 1.31, 2.57, P = .002). n the fully adjusted model, participants with higher levels of CTI had a significantly increased risk of low testosterone level compared to those in the lowest quartile (Q3 vs. Q1: OR = 4.92, 95% CI: 1.44–16.82, P = .01; Q4 vs. Q1: OR = 5.94, 95% CI: 1.94–18.17, P = .004; Table 2). In all three models, the estimated values of Q1–Q4 are progressively higher with a significant trend (P for trend <.01). As shown in Fig. 2, the results of the smooth curve fitting indicated a linear relationship between CTI and total testosterone as well as low testosterone level. As CTI increases, total testosterone levels gradually decrease, while the risk of low testosterone level significantly increases.

Table 2
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The association between CTI and total testosterone and low testosterone level from NHANES 2015–2016 study, weighted.

ExposureCrude modelModel 1Model 2
Total testosterone (ng/dl), β (95%CI); P-value
CTI (Continuous)–84.1(–98.99, –69.21)<0.0001–82.74(–99.02, –66.46)<0.0001–44.6(–66.34, –22.87)<0.001
CTI quartile
 Quartile 1refrefref
 Quartile 2–102.81(–168.32, –37.30)0.01–102.6(–184.47, –20.72)0.03–44.62(–101.66, 12.41)0.12
 Quartile 3–182.07(–225.54, –138.60)<0.0001–179.86(–232.28, –127.43)<0.001–98.57(–145.38, –51.75)<0.001
 Quartile 4–212.15(–261.50, –162.81)<0.0001–206.94(–268.07, –145.81)<0.001–118.46(–170.99, –65.93)<0.001
P for trend<0.0001<0.0001<0.001
Low testosterone level, OR (95%CI); P-value
CTI (Continuous)2.70 (2.26, 3.24)<0.00012.69 (2.17, 3.34)<0.00011.84 (1.31, 2.57)0.002
CTI quartile
 Quartile 1refrefref
 Quartile 26.50 (2.05, 20.63)0.0046.30 (1.42, 27.94)0.032.70 (0.74, 9.85)0.12
 Quartile 312.99 (4.73, 35.65)<0.00113.19 (3.63, 48.01)0.014.92 (1.44,16.82)0.01
 Quartile 421.17 (7.21, 62.17)<0.000120.59 (4.94, 85.88)0.0045.94 (1.94,18.17)0.004
P for trend<0.0001<0.0010.001
ExposureCrude modelModel 1Model 2
Total testosterone (ng/dl), β (95%CI); P-value
CTI (Continuous)–84.1(–98.99, –69.21)<0.0001–82.74(–99.02, –66.46)<0.0001–44.6(–66.34, –22.87)<0.001
CTI quartile
 Quartile 1refrefref
 Quartile 2–102.81(–168.32, –37.30)0.01–102.6(–184.47, –20.72)0.03–44.62(–101.66, 12.41)0.12
 Quartile 3–182.07(–225.54, –138.60)<0.0001–179.86(–232.28, –127.43)<0.001–98.57(–145.38, –51.75)<0.001
 Quartile 4–212.15(–261.50, –162.81)<0.0001–206.94(–268.07, –145.81)<0.001–118.46(–170.99, –65.93)<0.001
P for trend<0.0001<0.0001<0.001
Low testosterone level, OR (95%CI); P-value
CTI (Continuous)2.70 (2.26, 3.24)<0.00012.69 (2.17, 3.34)<0.00011.84 (1.31, 2.57)0.002
CTI quartile
 Quartile 1refrefref
 Quartile 26.50 (2.05, 20.63)0.0046.30 (1.42, 27.94)0.032.70 (0.74, 9.85)0.12
 Quartile 312.99 (4.73, 35.65)<0.00113.19 (3.63, 48.01)0.014.92 (1.44,16.82)0.01
 Quartile 421.17 (7.21, 62.17)<0.000120.59 (4.94, 85.88)0.0045.94 (1.94,18.17)0.004
P for trend<0.0001<0.0010.001

Abbreviations: BMI, body mass index; UA, uric acid; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; CTI, C-reactive protein-triglyceride glucose index; PIR, poverty-to-income ratio; DM, diabetes mellitus; CVD, cardiovascular disease; β, effect size for linear regression; CI, confidence interval; OR: odds ratio.

Note: Crude model: unadjusted; Model 1: adjusted for age, race, education, marital status, and PIR were adjusted; Model 2: Model 1+ LDL-c, HDL-c, UA, BMI, smoking, alcohol intake, DM, hypertension, CVD, and hyperlipidemia were adjusted.

Table 2
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The association between CTI and total testosterone and low testosterone level from NHANES 2015–2016 study, weighted.

ExposureCrude modelModel 1Model 2
Total testosterone (ng/dl), β (95%CI); P-value
CTI (Continuous)–84.1(–98.99, –69.21)<0.0001–82.74(–99.02, –66.46)<0.0001–44.6(–66.34, –22.87)<0.001
CTI quartile
 Quartile 1refrefref
 Quartile 2–102.81(–168.32, –37.30)0.01–102.6(–184.47, –20.72)0.03–44.62(–101.66, 12.41)0.12
 Quartile 3–182.07(–225.54, –138.60)<0.0001–179.86(–232.28, –127.43)<0.001–98.57(–145.38, –51.75)<0.001
 Quartile 4–212.15(–261.50, –162.81)<0.0001–206.94(–268.07, –145.81)<0.001–118.46(–170.99, –65.93)<0.001
P for trend<0.0001<0.0001<0.001
Low testosterone level, OR (95%CI); P-value
CTI (Continuous)2.70 (2.26, 3.24)<0.00012.69 (2.17, 3.34)<0.00011.84 (1.31, 2.57)0.002
CTI quartile
 Quartile 1refrefref
 Quartile 26.50 (2.05, 20.63)0.0046.30 (1.42, 27.94)0.032.70 (0.74, 9.85)0.12
 Quartile 312.99 (4.73, 35.65)<0.00113.19 (3.63, 48.01)0.014.92 (1.44,16.82)0.01
 Quartile 421.17 (7.21, 62.17)<0.000120.59 (4.94, 85.88)0.0045.94 (1.94,18.17)0.004
P for trend<0.0001<0.0010.001
ExposureCrude modelModel 1Model 2
Total testosterone (ng/dl), β (95%CI); P-value
CTI (Continuous)–84.1(–98.99, –69.21)<0.0001–82.74(–99.02, –66.46)<0.0001–44.6(–66.34, –22.87)<0.001
CTI quartile
 Quartile 1refrefref
 Quartile 2–102.81(–168.32, –37.30)0.01–102.6(–184.47, –20.72)0.03–44.62(–101.66, 12.41)0.12
 Quartile 3–182.07(–225.54, –138.60)<0.0001–179.86(–232.28, –127.43)<0.001–98.57(–145.38, –51.75)<0.001
 Quartile 4–212.15(–261.50, –162.81)<0.0001–206.94(–268.07, –145.81)<0.001–118.46(–170.99, –65.93)<0.001
P for trend<0.0001<0.0001<0.001
Low testosterone level, OR (95%CI); P-value
CTI (Continuous)2.70 (2.26, 3.24)<0.00012.69 (2.17, 3.34)<0.00011.84 (1.31, 2.57)0.002
CTI quartile
 Quartile 1refrefref
 Quartile 26.50 (2.05, 20.63)0.0046.30 (1.42, 27.94)0.032.70 (0.74, 9.85)0.12
 Quartile 312.99 (4.73, 35.65)<0.00113.19 (3.63, 48.01)0.014.92 (1.44,16.82)0.01
 Quartile 421.17 (7.21, 62.17)<0.000120.59 (4.94, 85.88)0.0045.94 (1.94,18.17)0.004
P for trend<0.0001<0.0010.001

Abbreviations: BMI, body mass index; UA, uric acid; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; CTI, C-reactive protein-triglyceride glucose index; PIR, poverty-to-income ratio; DM, diabetes mellitus; CVD, cardiovascular disease; β, effect size for linear regression; CI, confidence interval; OR: odds ratio.

Note: Crude model: unadjusted; Model 1: adjusted for age, race, education, marital status, and PIR were adjusted; Model 2: Model 1+ LDL-c, HDL-c, UA, BMI, smoking, alcohol intake, DM, hypertension, CVD, and hyperlipidemia were adjusted.

Graphics of smooth curve fittings between the CTI and total testosterone (A) and low testosterone level (B). The area between the upper and lower dashed lines is represented as 95% CI.
Figure 2

Graphics of smooth curve fittings between the CTI and total testosterone (A) and low testosterone level (B). The area between the upper and lower dashed lines is represented as 95% CI.

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Subgroup analyses

Table 3 lists the subgroup analyses according to age, BMI, smoking, DM, hypertension, and hyperlipidemia. The results of the subgroup analyses indicated a significant negative association between CTI and total testosterone, which was validated in most subgroups. Additionally, Table 3 also showed the relationship between CTI and the risk of low testosterone level, with a positive association remaining stable in most subgroups, such as those with BMI ≥ 30 kg/m2 (OR = 1.97, 95% CI: 1.30, 2.98, P = .004), now smoke (OR = 4.88, 95% CI: 2.60, 9.17, P < .0001), or without hypertension (OR = 1.82, 95% CI: 1.19, 2.79, P = .009). Notably, the study also found a significant interaction between hyperlipidemia and low testosterone level (P for interaction =.006), while no interactions were observed in other subgroups (P for interaction >.05). Additionally, we conducted subgroup analyses of the association between CTI quartiles and total testosterone as well as low testosterone level. The results were generally consistent with those in Table 3. Detailed results can be found in Tables S2 and S3.

Table 3
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Subgroup analysis of the association between CTI and total testosterone and low testosterone level.

SubgroupTotal testosteroneP for interactionLow testosterone levelP for interaction
 β (95%CI)P value OR (95%CI)P value 
Age group0.2790.955
 20–40y–31.61(–78.15, 14.93).1681.47 (0.72, 3.03).270
 40–60y–28.90(–63.91, 6.11).0991.68 (0.95, 2.97).073
 ≥60y–69.34(–113.14, –25.54).0042.07 (0.79, 5.44).128
BMI0.341
 <25 kg/m2–37.90(–74.01, –1.79).0413.46 (0.57, 21.05).164
 25–30 kg/m2–40.64(–85.89, 4.61).0751.23 (0.70, 2.19).449
 ≥30 kg/m2–45.22(–83.31, –7.12).0231.97 (1.30, 2.98).004
Smoke0.1080.545
 Never–29.97(–64.51, 4.58).0841.77 (1.14, 2.75).015
 Former–66.27(–109.97, –22.56).0061.18 (0.49, 2.84).688
 Now–59.39(–94.24, –24.55).0024.88 (2.60, 9.17)<.0001
DM0.390.626
 No–34.91(–63.25, –6.56).0191.32 (0.83, 2.09).224
 Borderline–45.63(–89.61, –1.66).0431.79 (0.48, 6.69).359
 Yes–46.67(–103.00, 9.66).0981.97 (0.99, 3.94).053
Hypertension0.2870.476
 No–25.29(–46.80, –3.78).0241.82 (1.19, 2.79).009
 Yes–64.94(–95.76, –34.13)<.0011.74 (1.00, 3.03).049
Hyperlipidemia0.6030.006
 No–27.21(–61.94, 7.51).1164.63 (1.95, 11.00).002
 Yes–48.93(–74.30, –23.57)<.0011.63 (1.05, 2.54).033
SubgroupTotal testosteroneP for interactionLow testosterone levelP for interaction
 β (95%CI)P value OR (95%CI)P value 
Age group0.2790.955
 20–40y–31.61(–78.15, 14.93).1681.47 (0.72, 3.03).270
 40–60y–28.90(–63.91, 6.11).0991.68 (0.95, 2.97).073
 ≥60y–69.34(–113.14, –25.54).0042.07 (0.79, 5.44).128
BMI0.341
 <25 kg/m2–37.90(–74.01, –1.79).0413.46 (0.57, 21.05).164
 25–30 kg/m2–40.64(–85.89, 4.61).0751.23 (0.70, 2.19).449
 ≥30 kg/m2–45.22(–83.31, –7.12).0231.97 (1.30, 2.98).004
Smoke0.1080.545
 Never–29.97(–64.51, 4.58).0841.77 (1.14, 2.75).015
 Former–66.27(–109.97, –22.56).0061.18 (0.49, 2.84).688
 Now–59.39(–94.24, –24.55).0024.88 (2.60, 9.17)<.0001
DM0.390.626
 No–34.91(–63.25, –6.56).0191.32 (0.83, 2.09).224
 Borderline–45.63(–89.61, –1.66).0431.79 (0.48, 6.69).359
 Yes–46.67(–103.00, 9.66).0981.97 (0.99, 3.94).053
Hypertension0.2870.476
 No–25.29(–46.80, –3.78).0241.82 (1.19, 2.79).009
 Yes–64.94(–95.76, –34.13)<.0011.74 (1.00, 3.03).049
Hyperlipidemia0.6030.006
 No–27.21(–61.94, 7.51).1164.63 (1.95, 11.00).002
 Yes–48.93(–74.30, –23.57)<.0011.63 (1.05, 2.54).033

Abbreviations: β, effect size for linear regression; CI, confidence interval; OR, odds ratio; BMI, body mass index; UA, uric acid; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; CTI, C-reactive protein-triglyceride glucose index; PIR, poverty-to-income ratio; DM, diabetes mellitus; CVD, cardiovascular disease.

Note: Crude model: unadjusted; Model 1: adjusted for age, race, education, marital status, and PIR were adjusted; Model 2: Model 1+ LDL-c, HDL-c, UA, BMI, smoking, alcohol intake, DM, hypertension, CVD, and hyperlipidemia were adjusted).

Table 3
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Subgroup analysis of the association between CTI and total testosterone and low testosterone level.

SubgroupTotal testosteroneP for interactionLow testosterone levelP for interaction
 β (95%CI)P value OR (95%CI)P value 
Age group0.2790.955
 20–40y–31.61(–78.15, 14.93).1681.47 (0.72, 3.03).270
 40–60y–28.90(–63.91, 6.11).0991.68 (0.95, 2.97).073
 ≥60y–69.34(–113.14, –25.54).0042.07 (0.79, 5.44).128
BMI0.341
 <25 kg/m2–37.90(–74.01, –1.79).0413.46 (0.57, 21.05).164
 25–30 kg/m2–40.64(–85.89, 4.61).0751.23 (0.70, 2.19).449
 ≥30 kg/m2–45.22(–83.31, –7.12).0231.97 (1.30, 2.98).004
Smoke0.1080.545
 Never–29.97(–64.51, 4.58).0841.77 (1.14, 2.75).015
 Former–66.27(–109.97, –22.56).0061.18 (0.49, 2.84).688
 Now–59.39(–94.24, –24.55).0024.88 (2.60, 9.17)<.0001
DM0.390.626
 No–34.91(–63.25, –6.56).0191.32 (0.83, 2.09).224
 Borderline–45.63(–89.61, –1.66).0431.79 (0.48, 6.69).359
 Yes–46.67(–103.00, 9.66).0981.97 (0.99, 3.94).053
Hypertension0.2870.476
 No–25.29(–46.80, –3.78).0241.82 (1.19, 2.79).009
 Yes–64.94(–95.76, –34.13)<.0011.74 (1.00, 3.03).049
Hyperlipidemia0.6030.006
 No–27.21(–61.94, 7.51).1164.63 (1.95, 11.00).002
 Yes–48.93(–74.30, –23.57)<.0011.63 (1.05, 2.54).033
SubgroupTotal testosteroneP for interactionLow testosterone levelP for interaction
 β (95%CI)P value OR (95%CI)P value 
Age group0.2790.955
 20–40y–31.61(–78.15, 14.93).1681.47 (0.72, 3.03).270
 40–60y–28.90(–63.91, 6.11).0991.68 (0.95, 2.97).073
 ≥60y–69.34(–113.14, –25.54).0042.07 (0.79, 5.44).128
BMI0.341
 <25 kg/m2–37.90(–74.01, –1.79).0413.46 (0.57, 21.05).164
 25–30 kg/m2–40.64(–85.89, 4.61).0751.23 (0.70, 2.19).449
 ≥30 kg/m2–45.22(–83.31, –7.12).0231.97 (1.30, 2.98).004
Smoke0.1080.545
 Never–29.97(–64.51, 4.58).0841.77 (1.14, 2.75).015
 Former–66.27(–109.97, –22.56).0061.18 (0.49, 2.84).688
 Now–59.39(–94.24, –24.55).0024.88 (2.60, 9.17)<.0001
DM0.390.626
 No–34.91(–63.25, –6.56).0191.32 (0.83, 2.09).224
 Borderline–45.63(–89.61, –1.66).0431.79 (0.48, 6.69).359
 Yes–46.67(–103.00, 9.66).0981.97 (0.99, 3.94).053
Hypertension0.2870.476
 No–25.29(–46.80, –3.78).0241.82 (1.19, 2.79).009
 Yes–64.94(–95.76, –34.13)<.0011.74 (1.00, 3.03).049
Hyperlipidemia0.6030.006
 No–27.21(–61.94, 7.51).1164.63 (1.95, 11.00).002
 Yes–48.93(–74.30, –23.57)<.0011.63 (1.05, 2.54).033

Abbreviations: β, effect size for linear regression; CI, confidence interval; OR, odds ratio; BMI, body mass index; UA, uric acid; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; CTI, C-reactive protein-triglyceride glucose index; PIR, poverty-to-income ratio; DM, diabetes mellitus; CVD, cardiovascular disease.

Note: Crude model: unadjusted; Model 1: adjusted for age, race, education, marital status, and PIR were adjusted; Model 2: Model 1+ LDL-c, HDL-c, UA, BMI, smoking, alcohol intake, DM, hypertension, CVD, and hyperlipidemia were adjusted).

Receiver operating characteristic analyses

As shown in Fig. 3 and Table 4, the ROC analysis indicated that the AUCs (95% CI) for CTI, TyG, CRP, and VAI were 0.7357 (0.6975, 0.7739), 0.6805 (0.6383, 0.7227), 0.6853 (0.6439, 0.7268), and 0.6819 (0.6404, 0.7235), respectively. Compared to TyG, CRP, and VAI, CTI performed better in predicting low testosterone level. These results suggest that CTI might be superior to TyG, CRP, and VAI in predicting the occurrence of low testosterone level in adult men in the US.

ROC curve analysis for different indicators in predicting low testosterone level.
Figure 3

ROC curve analysis for different indicators in predicting low testosterone level.

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Table 4
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Comparison of predictability among different indicators for low testosterone level.

IndicatorsAUC95% CI low95% CI upperCut-offSpecificitySensitivity
CTI0.73570.69750.77399.00220.63570.7249
TyGa0.68050.63830.72278.75510.64730.6243
CRPa0.68530.64390.72682.45000.69090.6085
VAIa0.68190.64040.72351.11290.51810.7725
IndicatorsAUC95% CI low95% CI upperCut-offSpecificitySensitivity
CTI0.73570.69750.77399.00220.63570.7249
TyGa0.68050.63830.72278.75510.64730.6243
CRPa0.68530.64390.72682.45000.69090.6085
VAIa0.68190.64040.72351.11290.51810.7725

Abbreviations: AUC, area under the curve; CI, confidence interval; CTI, C-reactive protein-triglyceride glucose index; TyG, triglyceride-glucose; CRP, C-reactive protein; VAI: visceral adiposity index.

a

Statistically significant difference in AUC when comparing to CTI (Z test).

Table 4
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Comparison of predictability among different indicators for low testosterone level.

IndicatorsAUC95% CI low95% CI upperCut-offSpecificitySensitivity
CTI0.73570.69750.77399.00220.63570.7249
TyGa0.68050.63830.72278.75510.64730.6243
CRPa0.68530.64390.72682.45000.69090.6085
VAIa0.68190.64040.72351.11290.51810.7725
IndicatorsAUC95% CI low95% CI upperCut-offSpecificitySensitivity
CTI0.73570.69750.77399.00220.63570.7249
TyGa0.68050.63830.72278.75510.64730.6243
CRPa0.68530.64390.72682.45000.69090.6085
VAIa0.68190.64040.72351.11290.51810.7725

Abbreviations: AUC, area under the curve; CI, confidence interval; CTI, C-reactive protein-triglyceride glucose index; TyG, triglyceride-glucose; CRP, C-reactive protein; VAI: visceral adiposity index.

a

Statistically significant difference in AUC when comparing to CTI (Z test).

Discussion

This cross-sectional study, based on the nationally representative 2015–2016 NHANES, assessed the association between CTI (a novel marker of inflammation and IR) and low testosterone level. Our results found that adult males with higher CTI had lower total testosterone levels and a higher risk of low testosterone level. When we divided CTI into quartiles, the results remained stable. Subgroup analyses further evaluated the reliability of the results. Additionally, the predictive ability of CTI for low testosterone level was superior to that of TyG, CRP, and VAI.

This is the first study to provide evidence of the association between CTI and low testosterone level, potentially offering new insights for men's health management. Testosterone, as a fundamental sex steroid, has various important physiological functions, such as regulating male reproduction and sexual capability (erectile function, libido), cognitive ability, and cardiovascular health.1-3 Testosterone deficiency in men may be associated with obesity, metabolic complications, and an increased risk of mortality from various diseases.29 Therefore, it is essential to identify the risk factors for testosterone deficiency in men.

Previous studies have indicated that IR in men is closely associated with testosterone deficiency.11-13 Therefore, scholars have developed many new IR indicators to assess testosterone deficiency in men. Homeostatic Model Assessment (HOMA-IR) method uses insulin and glucose levels to determine IR and is an alternative to the gold standard glucose clamp.30 However, insulin testing is difficult to popularize, which limits the use of HOMA-IR methods.31 Subsequently, the TyG index was developed to assess IR.32,33 Compared to HOMA-IR, the TyG index not only considers the abnormalities in glucose metabolism under IR conditions but also integrates the defects in fatty acid metabolism around the body.34 Currently, the TyG index has become an alternative to HOMA-IR and is used in various clinical practices. Studies have shown that the predictive value of the TyG index may be superior to HOMA-IR in certain diseases, such as arterial stiffness in patients with type 2 diabetes, early chronic kidney disease, and metabolic syndrome.35-37 Additionally, for andrological diseases, the TyG index is significantly associated with ED, adverse prognostic factors after radical prostatectomy, and sperm parameters in male infertility patients, demonstrating good predictive value.38-40 There are certain discrepancies in the studies concerning the association between the TyG index and testosterone deficiency. A study involving 4299 Chinese men indicated that the TyG index has a stronger predictive ability for hypogonadism compared to HOMA-IR.41 Conversely, a study by Liu et al. based on NHANES data showed that the TyG index is less effective than HOMA-IR in predicting the occurrence of testosterone deficiency.27 They explained that these differences might be due to variations in study populations, laboratory procedures, and the history of medication use. However, these studies all indicated that the TyG index is a good predictor of testosterone deficiency.

Our study showed that CTI has a better ability to predict low testosterone level compared to the TyG index, CRP, and VAI. CTI is a novel indicator that integrates CRP with the TyG index, providing a comprehensive assessment of inflammation and the severity of IR. It has been shown to have potential value in predicting the survival rates of cancer patients.25,26 The association between CTI and low testosterone level may be related to inflammation and IR. Obesity may increase inflammatory factors, IL-6, IL-8, and IL-1β, thereby increasing IR.42,43 In IR, various cytokines and inflammatory mediators, particularly CRP, TNF-), MCP-1, and IL, are upregulated.15,17 The underlying mechanism linking inflammation and IR may involve the activation of the IKKβ/NF-κB and JNK pathways. These pathways can be activated by various stimuli, which in turn increase the expression of inflammatory factors involved in IR. The JNK pathway can also impair insulin signaling through serine phosphorylation of insulin receptor substrate-1 (IRS-1).44 Therefore, there may be a vicious cycle between inflammation and IR, and a comprehensive assessment of both inflammation and IR may better reflect t low testosterone level. A recent cross-sectional study showed that CRP levels are negatively correlated with testosterone levels and SHBG levels, and this association remained stable even after adjusting for confounding factors and IL-6.45 As described above, the TyG index is currently a good indicator for assessing IR. CTI organically combines CRP with the TyG index, which may explain why CTI is superior to the TyG index in predicting low testosterone level. While both IR and systemic inflammation are well-established independent contributors to testosterone deficiency, our study introduces a novel integrative index (CTI) that captures both mechanisms within a single parameter. This approach aligns with the growing emphasis on composite metabolic and inflammatory markers for disease prediction. Compared to traditional individual indicators such as the TyG index, CRP, and VAI, CTI provides a holistic assessment of metabolic-inflammatory status, potentially allowing for earlier identification of at-risk individuals before overt testosterone deficiency manifests. Although the improvement in predictive performance over existing markers may seem modest, even small gains in diagnostic efficiency could be clinically meaningful in large-scale screening efforts. Future prospective studies should explore its real-world applicability in clinical decision-making and risk stratification for hypogonadism.

Although our study is limited by sample size, restricting our ability to validate CTI in specific low-risk subpopulations, our subgroup analysis provides important insights. Notably, we observed a significant association between higher CTI levels and increased risk of low testosterone in individuals without hypertension, suggesting that CTI may be a relevant marker even in those without traditional metabolic risk factors. This finding highlights the potential for CTI to be applied in broader clinical settings, warranting further investigation in larger and more diverse cohorts to confirm its predictive utility across different subpopulations. CTI is also low-cost and may become a simple indicator for early risk assessment of low testosterone level in adult men in the future.

Our study still has some limitations. Firstly, as a cross-sectional study, it cannot assess causality. Secondly, due to data limitations, we were unable to assess symptoms and/or signs after testosterone deficiency and could only define total testosterone levels below 300 ng/dl as low testosterone level. Additionally, some participants were excluded because they did not have available CTI data, which may lead to selection bias. Finally, even though we adjusted for many confounding factors, there may still be potential confounders that were not accounted for, such as the history of using certain medications.

Conclusion

This study showed adult males with higher CTI may have a higher risk of reduced testosterone levels or low testosterone level. Additionally, CTI has a better predictive ability for low testosterone level compared to the TyG index, CRP, and VAI, suggesting that CTI could become a simple indicator for early risk assessment of low testosterone level in adult men. More well-designed prospective studies are needed in the future to further validate this relationship.

Acknowledgments

We gratefully acknowledge the dedicated efforts of the NHANES staff and the invaluable participation of all study subjects.

Author contributions

Conceptualization: Bo Zhang, Yi Gu, Yiming Chen, and Xingliang Feng; Data curation: Bo Zhang, Yi Gu, Wei Xia, and Naiyuan Shao; Formal analysis: Bo Zhang, Yiming Chen, Wei Xia, Qianfeng Zhuang, and Xingliang Feng; Investigation: Bo Zhang, Yi Gu Yiming Chen, Wei Xia, and Xingliang Feng; Methodology: Bo Zhang, Yiming Chen, and Xingliang Feng; Writing—original draft: Bo Zhang, Yi Gu, and Yiming Chen; Writing—review & editing: Naiyuan Shao, Qianfeng Zhuang, and Xingliang Feng; Funding acquisition: Naiyuan Shao, Qianfeng Zhuang, and Xingliang Feng; All authors contributed to the article and approved the submitted version.

Bo Zhang and Yi Gu contributed equally to this work.

Funding

This work was supported by grants from the Nanjing Medical University Changzhou Medical Center Project (CMCB202312), the Changzhou Municipal Health Commission Major Projects (ZD202306 and ZD202332), the Changzhou Sci&Tech Program (CJ20245011), the Youth science and technology talent lifting project program from Jiangsu Province and the Top Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project (2024CZBJ006).

Conflicts of interest

The authors declare that they have no conflicts of interest relevant to this study.

Data availability

The datasets generated and/or analyzed during the current study are publicly available in the National Health and Nutrition Examination Survey (NHANES) repository, accessible at https://www.cdc.gov/nchs/nhanes/. All results supporting this research are fully presented in the figures and tables within this manuscript. Additional detailed data and processing code are available upon reasonable request from the corresponding author.

Ethical statement

All studies involving human subjects in the NHANES research were conducted in strict accordance with the Declaration of Helsinki. The NHANES protocol was reviewed and approved by the National Center for Health Statistics Research Ethics Review Board (Protocol No. #2011-17). Written informed consent was obtained from all participants prior to their participation in the survey.

Ethical approval and informed consent

The NHANES protocol was reviewed and approved by the National Center for Health Statistics (NCHS) Ethics Review Board (NCHS IRB/ERB Protocol No. #2011-17). This protocol involved human research, and written informed consent was obtained from all participants prior to inclusion in the study, in accordance with the Declaration of Helsinki.

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© The Author(s) 2025. Published by Oxford University Press on behalf of The International Society for Sexual Medicine.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
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