Abstract
Background
Metabolic syndrome (MetS) is common in aging men, but the age-specific relationship between the testosterone-to-estradiol (T/E2) ratio and metabolic abnormalities remains insufficiently characterized. This study evaluated age-stratified associations between the T/E2 ratio and MetS-related parameters in middle-aged and elderly Chinese men.
Methods
This retrospective cross-sectional study included 120 Chinese men aged 46–75 years. Participants were divided into three age groups: 46–55, 56–65, and 66–75 years. Serum testosterone, estradiol, sex hormone-binding globulin (SHBG), anthropometric indices, blood pressure, fasting blood glucose, and lipid profiles were assessed. MetS components were defined according to IDF-based criteria, and TyG index and TyG-BMI were calculated. Age-stratified Pearson correlation analyses were performed, with Spearman correlation and FDR adjustment used for sensitivity analyses.
Results
The T/E2 ratio decreased significantly across age groups, while SHBG increased and T/SHBG decreased with age. In the 46–55-year group, the T/E2 ratio was inversely correlated with fasting blood glucose, waist circumference, TyG-BMI, and total MetS points score. In the 66–75-year group, the main inverse association was observed between the T/E2 ratio and triglycerides. No consistent significant associations were observed in the 56–65-year group. Sensitivity analyses showed generally consistent directions for the main associations.
Conclusions
The T/E2 ratio shows age-related decline and age-specific associations with selected MetS-related parameters in middle-aged and elderly Chinese men. These findings suggest that the T/E2 ratio may reflect age-related metabolic heterogeneity, but prospective studies are needed to clarify its longitudinal and clinical relevance.
Keywords: testosterone-to-estradiol ratio, metabolic syndrome, sex hormone-binding globulin, TyG-BMI, age stratification, Chinese men
Introduction
MetS is characterized by a cluster of cardiometabolic risk factors, and it has emerged as a global health concern, with its prevalence showing a pronounced upward trend, especially in aging populations. In Chinese men, the incidence of MetS escalates significantly with age. Recent data indicates that men in the 66–75-year-old age group are more likely to develop MetS compared to those aged 46–55.1 This age-related increase in MetS aligns closely with the physiological decline in androgen levels.2 Testosterone (T) production typically decreases by 1–2% per year in men after the age of 40, accompanied by alterations in estrogen (E2) metabolism.3 Such concurrent rise in MetS and decline in androgens strongly implies an underlying connection between sex hormone balance and metabolic health.
Sex hormones play pivotal roles in regulating metabolic homeostasis,4 and testosterone promotes lipid oxidation and reduces visceral adiposity by enhancing lipoprotein lipase activity and increasing the synthesis of HDL-C.5,6 A meta-analysis by Zhang et al demonstrated that testosterone supplementation in hypogonadal men led to a significant reduction in triglyceride levels and an increase in HDL-C.7 On the other hand, estradiol modulates insulin sensitivity through estrogen receptor-mediated pathways,8 though excessive E2 may exacerbate insulin resistance in adipose tissue.9 The T/E2 ratio, rather than individual hormone levels, has emerged as a crucial regulatory marker of metabolic balance, reflecting the dynamic interplay between androgenic anabolic effects and estrogenic modulation.10 Preclinical studies have shown that a lower T/E2 ratio is associated with impaired glucose tolerance and dyslipidemia,11 while restoration of this ratio improves insulin sensitivity in animal models of androgen deficiency.12
Despite the clear biological plausibility of the T/E2 ratio in metabolic regulation, current research progress still seems to be hindered by significant gaps. Most existing studies have concentrated on overall T or E2 levels in relatively homogeneous age groups, overlooking the potentially diverse effects of sex hormone balance across different life stages. Moreover, there is a paucity of evidence from Asian populations, because a related systematic review included more than half of the studies conducted in Western cohorts,13 leaving a substantial knowledge gap regarding the applicability of these findings to Chinese men. This gap is particularly significant as age-related declines in the T/E2 ratio may follow distinct trajectories and have different metabolic consequences in East Asian populations, potentially due to genetic, lifestyle, or environmental differences.14
SHBG is also relevant because it influences circulating sex hormone availability and may affect the interpretation of total testosterone and estradiol measurements. In addition, the TyG index and TyG-BMI may provide additional information regarding combined glycemic, lipid, and adiposity-related metabolic burden. Considering these gaps, the present study aimed to characterize age-related differences in the T/E2 ratio, SHBG, and T/SHBG, and to evaluate age-stratified associations between the T/E2 ratio and MetS-related parameters, including waist circumference, fasting blood glucose, triglycerides, HDL-C, blood pressure, TyG index, TyG-BMI, and IDF-defined MetS components.
Methods
Cohort Description
This retrospective cross-sectional study included 120 Chinese men aged 46–75 years who were evaluated at Harrison International Peace Hospital between 2018 and 2023. Participants were identified by consecutively screening the hospital electronic medical records during the study period. Participants were included if they had complete clinical and biochemical records for serum testosterone (T), estradiol (E2), SHBG, BMI, waist circumference (WC), fasting blood glucose (FBG), lipid profiles, and blood pressure (BP). Exclusion criteria comprised history of hormone therapy, malignant cancer, or severe organ dysfunction, such as liver or kidney failure. The study was approved by the Ethics Committee of Hengshui People’s Hospital (Ethical number: 2022-2-016) and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.
Age Stratification
Participants were stratified into three age groups at 10-year intervals: 46–55 years (n=48), 56–65 years (n=40), and 66–75 years (n=32).
Measurements
Serum testosterone (T, ng/dL) and estradiol (E2, pg/mL) were quantified using chemiluminescent immunoassays with a Cobas e411 analyzer (Roche Diagnostics, Rotkreuz, Zug, Switzerland). The T/E2 ratio was calculated as testosterone divided by estradiol.
SHBG was measured using the same biochemical platform, and T/SHBG was calculated as testosterone divided by SHBG. The TyG index was calculated as ln[TG (mg/dL) × FBG (mg/dL)/2], and TyG-BMI was calculated as TyG index multiplied by BMI. The number of abnormal MetS components was calculated by summing the five MetS components. The total MetS points score was used as an exploratory composite measure of metabolic burden.
FBG was measured using the glucose oxidase method, while TG and HDL-C were assessed by enzymatic colorimetry on a Hitachi 7600 analyzer (Tokyo, Japan). MetS components were defined as waist circumference ≥90 cm, TG ≥1.7 mmol/L, HDL-C <1.04 mmol/L, systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or use of blood pressure-lowering medication, and FBG ≥5.6 mmol/L or use of glucose-lowering medication. International Diabetes Federation (IDF)-defined MetS was defined as central obesity plus at least two other components.15
Statistical Analysis
Continuous variables were tested for normality using the Shapiro–Wilk test and for homogeneity of variance using Levene’s test. Normally distributed variables with homogeneous variances were compared using one-way analysis of variance (ANOVA), whereas non-normally distributed or heteroscedastic variables were compared using the Kruskal–Wallis test. Categorical variables were compared using chi-square tests.
Age-stratified Pearson correlation analyses were performed to evaluate associations between the T/E2 ratio and metabolic parameters. Spearman correlation analyses were used as sensitivity analyses. FDR adjustment was applied to assess the robustness of the main Pearson correlation findings. All statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). All statistical tests were two-sided, and p<0.05 was considered statistically significant.
Results
Baseline Characteristics
As shown in Table 1, a total of 120 Chinese men were included and stratified into three age groups: 46–55 years (n=48), 56–65 years (n=40), and 66–75 years (n=32). The T/E2 ratio decreased significantly across age groups, from 9.94 ± 2.83 in the 46–55-year group to 8.63 ± 2.84 in the 56–65-year group and 7.43 ± 1.95 in the 66–75-year group (p<0.001). Testosterone also decreased significantly with age, whereas SHBG increased and T/SHBG decreased across age groups. Estradiol showed a non-significant decreasing trend.
Table 1.
Baseline Characteristics of the Study Cohort by Age Group
| Variable | 46–55 Years (n=48) | 56–65 Years (n=40) | 66–75 Years (n=32) | p value |
|---|---|---|---|---|
| Age (years) | 50.62 ± 3.10 | 60.83 ± 2.82 | 71.22 ± 2.89 | <0.001 |
| BMI (kg/m2) | 26.80 ± 2.32 | 26.48 ± 2.13 | 26.00 ± 1.51 | 0.239 |
| Waist circumference (cm) | 93.88 ± 7.39 | 95.10 ± 5.46 | 93.78 ± 4.38 | 0.584 |
| Fasting blood glucose (mmol/L) | 6.25 ± 1.61 | 6.64 ± 1.66 | 6.66 ± 1.25 | 0.139 |
| Systolic blood pressure (mmHg) | 124.29 ± 10.35 | 125.70 ± 7.07 | 124.81 ± 8.16 | 0.321 |
| Diastolic blood pressure (mmHg) | 85.85 ± 8.01 | 85.70 ± 5.41 | 86.38 ± 3.82 | 0.739 |
| Triglycerides (mmol/L) | 3.33 ± 1.50 | 2.53 ± 1.28 | 2.37 ± 0.97 | 0.009 |
| HDL-C (mmol/L) | 1.06 ± 0.19 | 1.08 ± 0.23 | 1.07 ± 0.18 | 0.702 |
| Testosterone (ng/dL) | 306.33 ± 86.20 | 257.55 ± 88.26 | 218.06 ± 74.29 | <0.001 |
| Estradiol (pg/mL) | 33.57 ± 8.63 | 30.21 ± 5.28 | 29.30 ± 5.17 | 0.075 |
| T/E2 ratio | 9.94 ± 2.83 | 8.63 ± 2.84 | 7.43 ± 1.95 | <0.001 |
| SHBG (nmol/L) | 34.21 ± 7.40 | 38.31 ± 5.22 | 42.71 ± 3.00 | <0.001 |
| T/SHBG | 9.53 ± 3.87 | 6.83 ± 2.49 | 5.12 ± 1.75 | <0.001 |
| TyG index | 9.56 ± 0.56 | 9.36 ± 0.57 | 9.34 ± 0.48 | 0.071 |
| TyG-BMI | 256.81 ± 31.73 | 248.38 ± 29.68 | 242.81 ± 17.47 | 0.177 |
| No. of abnormal MetS components | 2.92 ± 1.01 | 3.25 ± 1.17 | 3.31 ± 1.18 | 0.334 |
| Total MetS points score | 11.65 ± 3.61 | 14.53 ± 2.96 | 16.75 ± 2.40 | <0.001 |
| WC ≥90 cm, n (%) | 35 (72.9%) | 34 (85.0%) | 28 (87.5%) | 0.191 |
| TG ≥1.7 mmol/L, n (%) | 37 (77.1%) | 23 (57.5%) | 20 (62.5%) | 0.128 |
| Reduced HDL-C, n (%) | 20 (41.7%) | 14 (35.0%) | 13 (40.6%) | 0.800 |
| Elevated BP, n (%) | 23 (47.9%) | 30 (75.0%) | 21 (65.6%) | 0.029 |
| Elevated FBG, n (%) | 25 (52.1%) | 29 (72.5%) | 24 (75.0%) | 0.052 |
| IDF-defined MetS, n (%) | 25 (52.1%) | 23 (57.5%) | 21 (65.6%) | 0.487 |
Notes: Data are presented as mean ± SD or n (%). P values were calculated using one-way ANOVA or Kruskal–Wallis tests for continuous variables and chi-square tests for categorical variables. MetS components were defined as WC ≥90 cm, TG ≥1.7 mmol/L, HDL-C <1.04 mmol/L, SBP ≥130 mmHg or DBP ≥85 mmHg/use of BP-lowering medication, and FBG ≥5.6 mmol/L/use of glucose-lowering medication. IDF-defined MetS was defined as central obesity plus at least two other components. TyG = ln[TG (mg/dL) × FBG (mg/dL)/2]; TyG-BMI = TyG × BMI.
Among metabolic parameters, triglyceride levels differed significantly among age groups, and total MetS points score increased across age groups. The proportion of participants with elevated BP also differed significantly among the three groups. BMI, waist circumference, fasting blood glucose, systolic blood pressure, diastolic blood pressure, HDL-C, TyG index, TyG-BMI, number of abnormal MetS components, and IDF-defined MetS did not differ significantly among the three age groups. The distribution of the T/E2 ratio by age group is shown in Figure 1.
Figure 1.
Distribution of the T/E2 ratio by age group.
Association Analysis Between T/E2 and the MetS Components
Age-stratified Pearson correlation analyses are shown in Table 2 and visualized in Figure 2. In the 46–55-year group, the T/E2 ratio showed moderate inverse correlations with fasting blood glucose (r=−0.435, p=0.002), waist circumference (r=−0.499, p<0.001), TyG-BMI (r=−0.432, p=0.002), and total MetS points score (r=−0.497, p<0.001). A weaker inverse correlation was also observed with diastolic blood pressure (r=−0.309, p=0.033). No significant association was observed between the T/E2 ratio and HDL-C or triglycerides in this age group.
Table 2.
Age-Stratified Pearson Correlations Between T/E2 Ratio and Metabolic Parameters
| Variable Correlated with T/E2 Ratio | 46–55 Years (n=48) | 56–65 Years (n=40) | 66–75 Years (n=32) |
|---|---|---|---|
| HDL-C (mmol/L) | −0.245 (0.094) | 0.082 (0.616) | 0.057 (0.757) |
| Triglycerides (mmol/L) | −0.087 (0.558) | −0.126 (0.440) | −0.475 (0.006) |
| Fasting blood glucose (mmol/L) | −0.435 (0.002) | −0.115 (0.479) | 0.221 (0.223) |
| Waist circumference (cm) | −0.499 (<0.001) | 0.047 (0.774) | −0.337 (0.060) |
| Diastolic blood pressure (mmHg) | −0.309 (0.033) | −0.110 (0.501) | −0.229 (0.208) |
| Systolic blood pressure (mmHg) | −0.193 (0.188) | −0.041 (0.803) | −0.048 (0.793) |
| TyG index | −0.282 (0.053) | −0.152 (0.350) | −0.251 (0.166) |
| TyG-BMI | −0.432 (0.002) | −0.234 (0.147) | −0.306 (0.089) |
| No. of abnormal MetS components | −0.225 (0.124) | −0.285 (0.074) | −0.228 (0.210) |
| Total MetS points score | −0.497 (<0.001) | −0.256 (0.111) | −0.220 (0.227) |
Notes: Values are Pearson r coefficients with two-sided p values in parentheses.
Figure 2.
Heatmap of Pearson correlations between the T/E2 ratio and metabolic parameters by age group. Pearson r values are shown in each cell.
In the 56–65-year group, no significant correlations were observed between the T/E2 ratio and the assessed metabolic parameters. In the 66–75-year group, the T/E2 ratio was inversely correlated with triglycerides (r=−0.475, p=0.006). The inverse association with waist circumference was borderline but did not reach conventional statistical significance (r=−0.337, p=0.060).
Robustness Analysis
Key associations are summarized in Table 3. Spearman correlation analyses showed generally consistent directions for the main associations, particularly in the 46–55-year group. After FDR adjustment, the associations of the T/E2 ratio with fasting blood glucose, waist circumference, TyG-BMI, and total MetS points score in the 46–55-year group remained statistically significant. The association between the T/E2 ratio and triglycerides in the 66–75-year group also remained significant after FDR adjustment. Complete Spearman correlation results and FDR-adjusted Pearson results are provided in Tables S1 and S2, respectively.
Table 3.
Key Associations Between T/E2 Ratio and Metabolic Parameters
| Age Group | Variable | Pearson r (p) | Spearman ρ | FDR-Adjusted p value |
|---|---|---|---|---|
| 46–55 years (n=48) | Fasting blood glucose (mmol/L) | −0.435 (0.002) | −0.426 (0.003) | 0.016 |
| 46–55 years (n=48) | Waist circumference (cm) | −0.499 (<0.001) | −0.467 (<0.001) | 0.005 |
| 46–55 years (n=48) | TyG-BMI | −0.432 (0.002) | −0.409 (0.004) | 0.016 |
| 46–55 years (n=48) | Total MetS points score | −0.497 (<0.001) | −0.426 (0.003) | 0.005 |
| 66–75 years (n=32) | Triglycerides (mmol/L) | −0.475 (0.006) | −0.341 (0.056) | 0.036 |
Notes: Values are correlation coefficients with two-sided p values in parentheses; FDR-adjusted p values are shown in the final column.
Discussion
This study evaluated age-specific associations between the T/E2 ratio and MetS-related parameters in middle-aged and elderly Chinese men. The main findings were as follows. First, the T/E2 ratio declined with age, accompanied by a decrease in testosterone, an increase in SHBG, and a decrease in T/SHBG. Second, the association between the T/E2 ratio and metabolic parameters differed by age group. The most consistent associations were observed in the 46–55-year group, particularly for fasting blood glucose, waist circumference, TyG-BMI, and total MetS points score. Third, in the 66–75-year group, the main association was observed between the T/E2 ratio and triglycerides.
The age-related decline in the T/E2 ratio was largely consistent with the decline in testosterone and the increase in SHBG. Testosterone levels are known to decline with aging, and this decline may be related to changes in testicular function, hypothalamic-pituitary regulation, and comorbid metabolic status.16–18 In the present study, estradiol showed only a non-significant decreasing trend, whereas the changes in testosterone, SHBG, and T/SHBG were more evident. Although aromatase activity may increase with age or adiposity, circulating estradiol levels in older men are influenced by multiple factors, including androgen substrate availability, adiposity, SHBG, and overall metabolic status. Therefore, the observed decline in the T/E2 ratio should be interpreted as a net change in sex hormone balance rather than direct evidence of altered aromatase activity. These observations are also consistent with previous work describing age-related changes in testosterone, estradiol, and related outcomes in older men.19,20
The most consistent metabolic associations were observed in the 46–55-year group. In this group, a lower T/E2 ratio was associated with higher fasting blood glucose, larger waist circumference, higher TyG-BMI, and higher total MetS points score. These findings are biologically plausible because abdominal adiposity, glycemic dysregulation, and sex hormone balance may interact during the transition from middle age to older age. Previous studies have reported associations between testosterone-related indices and MetS components, including obesity, dyslipidemia, and insulin resistance.21–24
In the 66–75-year group, the main association was observed between the T/E2 ratio and triglycerides. This pattern suggests that lipid-related metabolic abnormalities may remain linked to sex hormone balance in older men, although the overall correlation structure differed from that observed in the 46–55-year group. The lack of consistent associations in the 56–65-year group also indicates that the relationship between sex hormone balance and metabolic parameters may not follow a simple linear pattern across age.
The inclusion of SHBG and T/SHBG provides additional context for interpreting total testosterone and estradiol. SHBG can influence circulating sex hormone availability and may be related to metabolic dysfunction. The inverse association between the T/E2 ratio and TyG-BMI in the 46–55-year group further supports a link between sex hormone balance and combined glycemic-adiposity-related metabolic burden. Metabolic indices incorporating triglycerides, glucose, and adiposity may help characterize metabolic risk beyond BMI alone.23,24 This is also consistent with previous work suggesting that visceral adiposity-related indices may be clinically relevant in male metabolic and reproductive health.25
HDL-C was not significantly associated with the T/E2 ratio in the revised age-stratified analyses. Therefore, HDL-C was not interpreted as a major supportive finding. This result suggests that the relationship between sex hormone balance and lipid metabolism in this cohort may be more apparent for triglycerides than for HDL-C.
This study has several limitations. First, the retrospective cross-sectional design precludes causal or temporal inference. Therefore, the observed associations should not be interpreted as evidence that changes in the T/E2 ratio cause metabolic abnormalities. Second, this was a single-center study with a modest sample size, and the subgroup sample size was limited after age stratification. Third, multiple correlation analyses were performed; although sensitivity analyses using Spearman correlation and FDR adjustment supported the main findings, the results should still be considered exploratory. Fourth, HbA1c, insulin, and HOMA-IR were not available, which limited the evaluation of insulin resistance. Fifth, residual confounding by diet, physical activity, medication use, and comorbidities cannot be excluded. Prospective studies with larger samples and repeated hormone and metabolic measurements are needed to clarify the longitudinal significance of the T/E2 ratio in male metabolic health.
Conclusions
In middle-aged and elderly Chinese men, the T/E2 ratio declined with age, accompanied by increased SHBG and decreased T/SHBG. The association between the T/E2 ratio and MetS-related parameters appeared age-specific. The most consistent associations were observed in the 46–55-year group, particularly for fasting blood glucose, waist circumference, TyG-BMI, and total MetS points score, whereas the main association in the 66–75-year group was observed for triglycerides. These findings suggest that the T/E2 ratio may reflect age-related metabolic heterogeneity, but prospective studies are needed to clarify its longitudinal and clinical significance.
Funding Statement
This work was supported by the The 2023 Medical Science Research Project Plan of Hebei Province under Grant 20232180.
Abbreviations
BMI, Body Mass Index; BP, Blood Pressure; DBP, Diastolic Blood Pressure; E2, Estradiol; FBG, Fasting Blood Glucose; FDR, False Discovery Rate; HDL-C, High-Density Lipoprotein Cholesterol; IDF, International Diabetes Federation; MetS, Metabolic Syndrome; SBP, Systolic Blood Pressure; SHBG, Sex Hormone-Binding Globulin; T, Testosterone; T/E2 ratio, Testosterone-to-Estradiol Ratio; TG, Triglycerides; TyG, Triglyceride-Glucose Index; TyG-BMI, Triglyceride-Glucose Index Multiplied by Body Mass Index; WC, Waist Circumference.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Clearance
This study was approved by the Ethics Committee of Hengshui People’s Hospital (Ethical number: 2022-2-016) and was conducted in accordance with the Declaration of Helsinki.
Informed Consent Statement
Written informed consent was obtained from all participants.
Author Contributions
Gang Ma: Conceptualization, Investigation, Methodology, Supervision, Validation, Writing – original draft, Writing – review & editing.
Xiaodong Chen: Conceptualization, Data curation, Methodology, Software, Writing – original draft, Writing – review & editing.
Yanmei Miao: Formal analysis, Project administration, Visualization, Writing – review & editing.
Xuexia Ji: Formal analysis, Project administration, Visualization, Writing – review & editing.
Zhicheng Qiao: Formal analysis, Project administration, Visualization, Writing – review & editing.
All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Gang Ma is the lead author.
Disclosure
The authors report there are no competing interests to declare.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.