Association between the C-reactive protein-triglyceride-glucose index and endometriosis: a cross-sectional study using data from the national health and nutrition examination survey, 1996-2006

Between 1999 and 2006, the NHANES included 6508 participants. Among them, 951 participants were excluded due to endometriosis, 3050 due to CTI, and 272 due to incomplete covariate data. Ultimately, data from 2235 participants were included in the final analysis. Based on the diagnosis of endometriosis, 175 (7.83%) participants comprised the endometriosis group while 2060 (92.17%) comprised the control group (Fig.  1 ). Participant characteristics are summarized in Table  1 . Participants with endometriosis were more likely to have used oral contraceptives for birth control and were more often non-Hispanic White than those without endometriosis. Moreover, patients with endometriosis exhibited higher rates of smoking and marriage, and were more likely to be obese. Notably, CRP, TyG, fasting TG, total cholesterol, and CTI were higher in patients with endometriosis than in those without (Table  1 ). Fig. 1 Flow chart of eligible participants selection Flow chart of eligible participants selection Table 1 Characteristics of participants Characteristics Overall ( N  = 2235) Non-endometriosis ( N  = 2060) Endometriosis ( N  = 175) P value Age (years) 0.095  ≤ 40 1455 (58.2%) 1368 (59.0%) 87 (51.3%)  > 40 780 (41.8%) 692 (41.0%) 88 (48.7%) Age at menarche (years) 0.387  < 12 509 (21.3%) 464 (20.8%) 45 (25.0%)  12–13 1187 (54.6%) 1089 (54.7%) 98 (53.9%)  ≥ 14 539 (24.2%) 507 (24.5%) 32 (21.1%) PIR 0.419   3.0 805 (43.9%) 725 (43.2%) 80 (50.1%) BMI (kg/m 2 ) 0.149  < 25 776 (42.0%) 720 (42.6%) 56 (36.5%)  ≥ 25 1459 (58.0%) 1340 (57.4%) 119 (63.5%) Smoked ≥ 100cigarettes 0.002  Yes 858 (43.1%) 768 (41.4%) 90 (57.6%)  No 1377 (56.9%) 1292 (58.6%) 85 (42.4%) Race/ethnicity 0.001  Mexican American 497 (7.4%) 488 (8.0%) 9 (1.4%)  Other Hispanic 96 (5.7%) 91 (6.1%) 5 (2.0%)  Non-Hispanic White 1088 (70.6%) 965 (69.0%) 123 (84.8%)  Non-Hispanic Black 457 (11.6%) 425 (12.1%) 32 (7.9%)  Other 97 (4.7%) 91 (4.8%) 6 (3.9%) Marital status 0.010  Married/Living with partner 1499 (68.3%) 1380 (67.3%) 119 (77.3%)  Never married 414 (14.6%) 391 (18.2%) 23 (7.3%)  Widowed/Divorced/Separated 322 (17.0%) 289 (14.5%) 33 (15.4%) Education level 0.112  High school and below 507 (15.8%) 486 (16.2%) 21 (11.5%)  Above high school 1728 (84.2%) 1574 (83.8%) 154 (88.5%) Hypertension 0.287  Yes 406 (18.9%) 358 (18.5%) 48 (21.9%)  No 1829 (81.1%) 1702 (81.5%) 127 (78.1%) Diabetes 0.436  Yes 97 (3.4%) 90 (3.5%) 7 (2.6%)  No 2138 (96.6%) 1970 (96.5%) 168 (97.4%) Alcohol intake 0.850  Yes 1376 (68.2%) 1257 (68.1%) 119 (69.1%)  No 859 (31.8%) 803 (31.9%) 56 (30.9%) Oral contraceptive 0.020  Yes 1742 (80.8%) 1586 (79.9%) 156 (89.3%)  No 493 (19.2%) 474 (20.1%) 19 (10.7%) Infertility 0.160  Yes 311 (17.1%) 286 (12.0%) %) 25 (17.7%)  No 1924 (82.9%) 1774 (88.0%) 150 (82.3%) CRP (mg/dL) 0.47 (0.73) 0.46 (0.74) 0.57 (0.67) 0.041 Fasting triglyceride (mg/dL) 121.62 (99.40) 117.20 (81.42) 160.52 (192.34) 0.007 Fasting glucose, mg/dl 94.32 (20.48) 94.29 (20.45) 94.56 (20.84) 0.857 TyG 8.48 (0.58) 8.45 (0.56) 8.68 (0.68) < 0.001 Total cholesterol (mg/dL) 195.51 (40.22) 194.35 (39.89) 205.78 (41.79) 0.001 CTI 7.83 (0.95) 7.79 (0.94) 8.20 (0.98) < 0.001 Values are mean±SD or number (%). P<0.05 was deemed significant. BMI body mass index, CRP C-reactive protein, TyG triglyceride glucose index, CTI C-reactive protein-triglyceride glucose index, PIR poverty income ratio Characteristics of participants 286 (12.0%) %) Values are mean±SD or number (%). P<0.05 was deemed significant. BMI body mass index, CRP C-reactive protein, TyG triglyceride glucose index, CTI C-reactive protein-triglyceride glucose index, PIR poverty income ratio

NHANES, a nationally representative study approved by the Research Ethics Review Board of the National Center for Health Statistics (NCHS), was conducted by the Centers for Disease Control and Prevention. Informed consent was obtained from all participants at the time of enrollment. Data were sourced from 41,474 individuals in 4 consecutive two-year NHANES cycles (1999–2000, 2001–2002, 2003–2004, 2005–2006). Ultimately, data from 2235 female participants 20–50 years of age were included. Inclusion criteria were as follows: female sex; age 20–50 years; and available data regarding endometriosis diagnosis and relevant variables, including the CTI and other covariates. Individuals without complete data regarding endometriosis, CTI, or covariates such as body mass index (BMI), smoking status, or other relevant factors, were excluded. Additionally, individuals < 20 years of age and those with incomplete clinical data were also excluded. Participants who fulfilled the inclusion criteria were assigned to the endometriosis or control group according to their diagnosis. A questionnaire-based survey asking, “Has a doctor or other health professional ever told you that you had endometriosis (age at interview, 20–54 years)?” was collected to diagnose endometriosis. Participants who responded affirmatively were allocated the endometriosis group; otherwise, they were allocated to the control group. Although relying on questionnaire responses to determine the primary study outcome may introduce some degree of uncertainty, the lack of direct diagnostic methods, such as laparoscopy or pathological confirmation, in the NHANES dataset complicated the precise identification of endometriosis cases. However, previous studies have demonstrated the feasibility and acceptance of using questionnaires to identify the presence of endometriosis among NHANES participants [ 15 – 18 ]. The CTI [ 7 ] was calculated as follows: CTI = 0.412 × ln (CRP) + TyG (TyG = ln [fasting triglyceride (TG) (mg/dL) × fasting glucose (FPG) (mg/dL)/2]) [ 19 ]. Blood samples were collected in the morning after an 8.5 h fast and processed in NCHS-certified laboratories. Serum TG levels were assessed using chemistry analyzers (Modular P and Cobas 6000, Roche Diagnostics, Basel, Switzerland), whereas FPG levels were assessed using the oxygen rate method on a laboratory analyzer (DxC800, Beckman-Coulter Diagnostics, Brea, CA, USA) [ 20 , 21 ]. CRP levels were determined using latex-enhanced nephelometry (CSL Behring, King of Prussia, PA, USA) [ 22 ]. Additional details regarding the laboratory procedures are available on the official NHANES website. An elevated CTI usually suggests a more severe level of inflammation and IR [ 19 ]. Covariates included age, age at menarche (years), poverty income ratio (PIR), and BMI, smoked ≥ 100 cigarettes, race/ethnicity, marital status, education level, hypertension, diabetes, alcohol intake, oral contraceptive use, infertility, CRP (mg/dL), fasting TG (mg/dL), FPG (mg/dl), TG glucose index (TyG), total cholesterol (mg/dL), and CTI. Age was categorized into 2 groups according to clinical relevance (≤ 40 and > 40 years); BMI was classified as normal (< 25 kg/m 2 ) or overweight (≥ 25 kg/m 2 ), based on clinical significance; and smoking status was categorized as having smoked at least 100 cigarettes in one’s lifetime (yes, no). There were 3 levels for PIR: < 1.3; 1.5–3.0; and ≥ 3.0. To assess differences between the 2 groups, the Student’s t -test was used for continuous variables. This test helps determine whether there are statistically significant differences in the means between the 2 groups. For categorical variables, the chi-squared test was used to evaluate whether there was a significant association between categorical outcomes across groups. By selecting the appropriate statistical method(s), the analysis ensured robust data evaluation. Logistic regression models were constructed to assess the relationship between CTI and endometriosis. Three models were constructed: Model 1 (unadjusted); Model 2 (adjusted for age and ethnicity); and Model 3 (additionally adjusted for PIR, BMI, education level, marital status, smoking habits, hypertension, diabetes, drinking status, age at menarche, total cholesterol, and use of oral contraceptives). The relationship between an increase in CTI of 1 mg/dL and endometriosis was determined. In addition, stratified analyses were performed according to participant age, BMI, age at menarche, smoking, drinking and marital status, and use of oral contraceptives. Prevalence was calculated as odds ratio (OR) and corresponding 95% confidence interval (CI). To flexibly model the association between CTI and the prevalence of endometriosis, restricted cubic splines with three knots was used. Statistical analysis was performed using R version 4.2 (R Foundation for Statistical Computing, Vienna, Austria) and EmpowerStats version 5.0 ( http://www.empowerstats.net ). Differences with P  < 0.05 were considered to be statistically significant.

Endometriosis is a common, chronic, inflammatory, and benign gynecological disorder characterized by the growth of endometrioid tissue outside the uterine cavity, with a prevalence of approximately 10% in women of childbearing age [ 1 – 3 ]]. The standard method for diagnosing endometriosis is laparoscopy-guided biopsy [ 4 , 5 ]], which often leads to significant delays in diagnosis, typically ranging from to 6–11 years [ 6 ]]. The development of innovative diagnostic methods and predictive biomarkers is essential for improving diagnostic accuracy and sensitivity and, ultimately, enhancing patient quality of life. The C-reactive protein (CRP)–triglyceride (TG)–glucose index (CTI) is gaining recognition as a new metric for thorough evaluation of the severity of inflammation and insulin resistance (IR). The CTI was calculated using the following formula: 0.412 × ln(CRP) + ln[TG (mg/dL) × fasting plasma glucose [FPG] (mg/dL)/2]. A novel metric, termed the “CTI”, provides a comprehensive assessment of both inflammatory status and IR [ 7 ]. The CTI is the sole metric that combines the intensity of inflammation and IR, and has been recognized to be valuable in predicting survival rates in the Chinese cancer population [ 7 ]. Additionally, the CTI is a straightforward and rapid indicator that incurs no additional costs beyond standard laboratory investigations. Consequently, in the general population, there is no further f [ 8 ]inancial burden on patients or the healthcare system. Elevated CRP levels indicate a systemic inflammatory response [ 9 ]. Endometriosis is a complex chronic inflammatory disease [ 10 ]. The classification of endometriosis as an inflammatory disorder is supported by various lines of evidence, including alterations in the peritoneal environment of affected women, the recruitment of numerous immune cells to endometriotic lesions, and the abnormal production of pro-inflammatory cytokines and regulatory proteins [ 11 ]. Elevated levels of pro-inflammatory markers, such as CRP, have been consistently observed in women diagnosed with endometriosis. These inflammatory responses are believed to promote lesion survival, vascularization, and cell proliferation, exacerbating the disease [ 12 ]. Recent studies have suggested a link between IR and inflammatory pathways in endometriosis, highlighting the multifaceted role of inflammation in disease development [ 8 , 13 , 14 ]. Considering these perspectives, it is important to investigate the potential link between CTI and the risk for developing endometriosis. As such, our aim was to explore the relationship between the CTI and endometriosis by analyzing data from the National Health and Nutrition Examination Survey (NHANES, 1999–2006), with the intention of offering compelling evidence supporting this association.

Results of the present study revealed a strong positive association between the CTI and endometriosis. Therefore, actively managing blood glucose levels and minimizing inflammatory responses may aid in decreasing the prevalence of endometriosis; however, additional foundational research is necessary to investigate the possible relationships between them.

This cross-sectional study, involving data from 2235 representative participants, found positive associations between the CTI and endometriosis, with a threshold concentration of approximately 8.053 mg/dL. Our results indicate that individuals with endometriosis were generally older and primarily non-Hispanic White. The diagnosis of endometriosis is frequently delayed, typically occurring 6–11 years after the initial symptoms appear, which likely accounts for the older age of these patients [ 6 ]. The increased incidence among White individuals may be associated with greater racial susceptibility. Additionally, we found that individuals with obesity or those with a history of smoking were more likely to develop endometriosis. This may be due to the inflammatory response triggered by smoking [ 23 , 24 ], whereas higher estrogen levels in patients with obesity could promote the development of endometriosis [ 25 ]. Endometriosis is a chronic condition, prevalent among women of reproductive age, that affects approximately 10% of this population [ 2 , 3 , 26 ]. There are several hypotheses regarding the pathogenesis of endometriosis, with the leading being that ectopic endometrial-like glands and stroma may arise from metaplasia of local tissue or from the transplanted ectopic endometrium [ 27 , 28 ]. This finding implies that normal endometrial cells may undergo changes in other parts of the body, resulting in the formation of new pathological tissue(s). Furthermore, elevated levels of local estrogen are believed to play a crucial role in this process because they not only aid in the survival and implantation of ectopic endometriotic lesions, but also promote their proliferation [ 3 , 25 ]. However, its exact pathophysiology remains unclear. Recent studies have highlighted the potential contributions of inflammation and oxidative stress in this context [ 29 – 33 ]. A cohort study from Japan also suggested that consuming a diverse range of anti-inflammatory foods, such as vegetables, may ultimately affect perinatal mortality and morbidity in patients with endometriosis [ 34 , 35 ]. A recent cross-sectional analysis revealed that the dietary inflammatory index is positively associated with the prevalence of endometriosis [ 34 , 36 ]. The inflammatory nature of endometriosis is well-established [ 37 , 38 ]. Considering the central role of inflammation in the pathogenesis of endometriosis, addressing inflammatory dysfunction has emerged as a promising strategy for developing new treatments [ 17 , 39 ]. This approach provides an avenue for exploring innovative options for prevention and management of this disease. The results of our investigation are consistent with those of earlier studies reporting the significant association between inflammation and endometriosis [ 40 ]. Similarly, several studies have shown that chronic inflammation plays a crucial role in the pathogenesis of endometriosis [ 17 , 35 ]. For example, research using the Dietary Inflammatory Index revealed a positive association between pro-inflammatory diets and the prevalence of endometriosis [ 18 , 41 ]. Similar to our findings, higher levels of inflammatory indicators, such as CRP and the TyG index, are significantly associated with endometriosis [ 42 – 45 ]. This similarity emphasizes the role of systemic inflammation in the progression of endometriosis, and supports the hypothesis that inflammatory processes are central to disease development [ 43 , 46 ]. Furthermore, the roles of demographic and lifestyle factors, including smoking and BMI [ 47 , 48 ], were more prominently analyzed in our study, revealing that these factors may modulate the relationship between inflammation and endometriosis. This provides a more nuanced understanding of how lifestyle and metabolic factors interact with inflammatory processes to influence the risk for endometriosis. The key strength of this study is its foundation in a weighted and representative population with a substantial sample size. It should be emphasized that we also performed restricted cubic splines analysis. Nevertheless, this study had several limitations, the first of which was its cross-sectional design, making it difficult to determine causation between CTI and endometriosis. Second, because participants < 20 years of age were excluded, these findings may not be generalizable to younger patients. Third, because most of the data were gathered through self-report questionnaires or interviews, the control group may have unintentionally included individuals with undiagnosed endometriosis, potentially resulting in recall and reporting bias. Finally, due to limitations of the database, we could not incorporate data regrading all covariates related to endometriosis and inflammation levels to ensure a sufficiently large sample size. Therefore, future research should involve a more diverse population and consider additional potential covariates to clarify the causal association between the CTI and endometriosis.

Results reflecting the association between the CTI and endometriosis, analyzed using the 3 different models, are summarized in Table  2 . In all models, a continuous increase in CTI was significantly associated with an elevated prevalence of endometriosis. Specifically, in the unadjusted model (i.e., Model 1), the OR for continuous CTI was 1.563 (95% CI 1.295–1.885; p  < 0.001), whereas in the model adjusted for age and ethnicity (i.e., Model 2), the OR increased slightly to 1.609 (95% CI 1.334–1.941; p  < 0.001). After further adjustment for various factors, including BMI, PIR, education level, and lifestyle habits (i.e., Model 3), the OR remained significant (1.565 [95% CI 1.246–1.966]; p  < 0.001), indicating a consistent relationship between higher CTI and the risk for endometriosis. When stratified according to quartiles, the highest CTI quartile (Q4) was associated with significantly increased odds of endometriosis across all models, with ORs of 3.430 (95% CI 1.589–7.402; p  = 0.002) in Model 1, 3.615 (95% CI 1.667–7.839; p  = 0.002) in Model 2, and 3.029 (95% CI 1.306–7.025; p  = 0.011) in Model 3. These results suggest that an elevated CTI is strongly associated with an increased risk for endometriosis even after controlling for multiple demographic and clinical factors. Table 2 Association between CTI and endometriosis Exposures OR (95% CI) P Model 1 Model 2 Model 3 CTI (continuous) 1.563 (1.295–1.885) <0.001 1.609 (1.334–1.941) <0.001 1.565 (1.246–1.966) <0.001 CTI (Quartiles)  Q1 Reference Reference Reference  Q2 2.105 (0.965–4.593) 0.061 2.153 (0.976–4.747) 0.057 2.000 (0.901–4.442) 0.087  Q3 1.838 (0.850–3.976) 0.120 1.976 (0.895–4.363) 0.090 1.695 (0.777–3.698) 0.179  Q4 3.430 (1.589–7.402) 0.002 3.615 (1.667–7.839) 0.002 3.029 (1.306–7.025) 0.011 P for trend 0.005 0.003 0.051 Model 1: unadjusted model Model 2: adjusted for age, ethnicity Model 3: further adjusted for PIR, BMI, education level, marital status, smoking habits, hypertension, diabetes, drinking status, age at menarche, total cholesterol, and the use of contraceptive pills Association between CTI and endometriosis Model 1: unadjusted model Model 2: adjusted for age, ethnicity Model 3: further adjusted for PIR, BMI, education level, marital status, smoking habits, hypertension, diabetes, drinking status, age at menarche, total cholesterol, and the use of contraceptive pills Relationships between the predicted values were visualized by plotting restricted cubic splines (Fig.  2 ). A nonlinear positive relationship between CTI and the prevalence of endometriosis was observed (nonlinearity, p  = 0.603), with a breakpoint identified at 8.053. Fig. 2 Restricted cubic splines for associations between CTI and endometriosis Restricted cubic splines for associations between CTI and endometriosis The results of the stratified assessment according to age, age at menarche, BMI, smoking, drinking, marital status, and oral contraceptive use are presented in Fig.  3 . Individuals > 40 years of age, a BMI ≥ 25 kg/m 2 , smoked ≥ 100 cigarettes, married or living with a partner, and oral contraceptive use exhibited more vulnerability. Following the stratification of analyses based on alcohol consumption habits, comparable results were found regarding positive associations between the CTI and the prevalence of endometriosis. Fig. 3 Subgroup analysis of the association between the remnant CTI and endometriosis Subgroup analysis of the association between the remnant CTI and endometriosis Furthermore, a higher endometriosis prevalence was observed among those with CTI in > 40 years of age (OR 1.57 [95% CI 1.16–2.13]), BMI ≥ 25 kg/m 2 (OR 1.38 [95% CI 1.06–1.80]), smoking ≥ 100 cigarettes (OR 1.43 [95% CI 1.06–1.96]), being married or living with a partner (OR 1.41 [95% CI 1.09–1.85]) and oral contraceptive use (OR 1.35 95% CI 1.07–1.69]).