Serum Copper to Zinc Ratio and Risk of Endometriosis: Insights from a Case-Control Study

Serum Copper to Zinc Ratio and Risk of Endometriosis: Insights from a Case-Control Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Serum Copper to Zinc Ratio and Risk of Endometriosis: Insights from a Case-Control Study Yanping Liu, Guihong Cheng, Hong Li, Qingxia Meng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4511841/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The significance of trace metal elements in the development of endometriosis has garnered increasing interest. We aimed to investigate the relationship between serum copper (Cu), zinc (Zn), iron (Fe), magnesium (Mg) levels, and the Cu/Zn ratio with the risk of endometriosis. This study involved 568 infertile patients diagnosed with endometriosis, compared to 819 infertile patients without endometriosis (Control group). Basic characteristics, hormonal parameters, and essential trace elements of the patients were measured and analyzed. The findings indicated a notable decrease in serum Zn levels in the endometriosis group compared to controls, alongside a significant increase in the Cu/Zn ratio (P < 0.001). Restricted cubic spline analysis (RCS) revealed a linear relationship between Zn levels and the Cu/Zn ratio with the risk of endometriosis. Moreover, Zn levels exhibited a negative correlation with endometriosis risk (P trend = 0.005), while the Cu/Zn ratio displayed a positive correlation with endometriosis risk, even after adjusting for age, body mass index (BMI), and baseline hormones (P trend < 0.001). Compared to the first quartile of Cu/Zn ratio after adjustment, the odds ratios (ORs) with 95% confidence intervals (CIs) for the second and fourth quartiles were 1.97 (1.37, 2.83) and 2.63 (1.80, 3.84), respectively. This study provided evidence of decreased serum Zn levels and increased Cu/Zn ratio being associated with an elevated risk of endometriosis among infertile patients. Endometriosis Copper Zinc Copper/zinc ratio Infertility Figures Figure 1 Introduction Endometriosis is a prevalent gynecological disorder which significantly impairs fertility among women of reproductive age. Common clinical manifestations of endometriosis include dysmenorrhea, irregular menstruation, dyspareunia, and infertility [ 1 ]. Nonetheless, a considerable number of patients are primarily diagnosed with endometriosis upon seeking medical assistance for infertility issues. Epidemiological studies indicate that the incidence of endometriosis among women experiencing infertility ranges from 30–50% [ 2 , 3 ]. Endometriosis exerts multifaceted effects on fertility, attributed to alterations in pelvic anatomy, compromised ovarian reserve, oocyte and embryo quality deterioration, and disrupted endometrial receptivity [ 4 , 5 ]. The pathological mechanisms of endometriosis involve various factors such as aberrant inflammatory response, hormonal imbalance, genetic predisposition, and immune dysregulation, yet remain elusive [ 6 ]. Trace metal elements play crucial roles in various biochemical processes in the human body, garnering increasing attention for their involvement in the pathogenesis of endometriosis. Hall et al. [ 7 ] performed a cross-sectional study utilizing NHANES 1999–2006 data, revealing a link between urinary cadmium concentrations and endometriosis prevalence in the US population. Likewise, Shen et al. found that concentrations of arsenic, cadmium, lead, and mercury in both serum and follicular fluid were positively correlated with an increased risk of endometriosis [ 8 ]. Additionally, Lai et al. [ 9 ] noted a correlation between decreased Zinc (Zn) levels and a higher risk of endometriosis in infertile women. Conversely, Su et al. [ 10 ] observed that elevated Zn levels in both blood and follicular fluid were linked to an increased risk of endometriosis. This inconsistency in research findings regarding the relationship between zinc levels and the risk of endometriosis may be attributed to differences in study design, sample size, characteristics, and analytical methods. Zn, an essential trace nutrient, acts as a crucial modulator of immune function, exhibiting potent antioxidant and anti-inflammatory properties vital for maintaining cellular redox homeostasis [ 11 ]. Zn deficiency compromises the activity of antioxidant enzymes, exacerbating oxidation stress (OS) conditions [ 12 ]. Conversely, copper (Cu) exhibits multifaceted involvement in OS. By catalyzing the Fenton reaction, Cu promotes the production of reactive oxygen species, which can subsequently induce lipid peroxidation, thereby amplifying OS responses [ 13 ]. Moreover, Cu participates in redox reactions, leading to the depletion of the antioxidant glutathione and disruption of cellular antioxidant defense mechanisms [ 14 ]. Both Cu and Zn serve as necessary enzyme cofactors in antioxidant defenses and neurotransmitter synthesis [ 15 ]. The intricate balance and levels of Cu and Zn within cells are pivotal for maintaining redox balance and regulating OS. The human body intricately manages and regulates the levels and proportions of trace elements crucial for blood circulation and cellular storage. When the system malfunctions, abnormalities in the levels or ratios of metal ions arise. In clinical settings, the Cu/Zn ratio holds more significance than the concentrations of these metals individually [ 16 , 17 ]. The potential significance of OS in the development of endometriosis is attracting attention [ 18 , 19 ]. Imbalances in the ratio of Cu to Zn can lead to pathological conditions associated with OS [ 20 , 21 ]. Nevertheless, there is limited and contentious research concerning the association between serum Zn levels and the Cu/Zn ratio with endometriosis. In this context, we conducted a retrospective analysis of the distribution characteristics of Cu, Zn, iron (Fe), and magnesium (Mg) levels, as well as the ratio of Cu to Zn, among 1387 infertility patients. Additionally, we investigated the correlation between these elements and the risk of endometriosis. Subjects and Methods Subjects This case-control study was carried out at the Reproductive and Genetic Center of Suzhou Municipal Hospital (Suzhou, Jiangsu Province, China). Detailed clinical data were retrieved from the Clinical Reproductive Medical Management System. A total of 1387 infertile women underwent the first in vitro fertilization cycle from January 2018 to December 2022. Among them, 568 patients were diagnosed with endometriosis, while the control group comprised 819 patients with tubal or male factor infertility. Endometriosis diagnosis relied on a combination of patient-reported symptoms, physical examination findings, and imaging studies such as ultrasound or MRI, or confirmed through laparoscopic surgery. Exclusion criteria included various conditions such as polycystic ovary syndrome, thyroid disorders, chromosomal abnormalities, and prior ovarian surgeries. A history of smoking or long-term medication use will also be considered for exclusion. Hormone and trace metal elements Assays Serum samples collected during the early follicular phase (7.00–9.00 a.m.) were utilized to measure the baseline levels of sex hormones. Hormone levels, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), progesterone (P), prolactin (PRL), and anti-Müllerian hormone (AMH), were assessed using an automated electrochemiluminescence immunoassay system (Hitachi Model 7170, Japan). The concentrations of metal elements, including Cu, Zn, iron Fe, and Mg, were also assessed. In brief, specific assay kits for each element were utilized in accordance with the provided experimental protocols. The products/kits being utilized are described as follows: Quick Auto Neo Cu kit (SHINO-TEST CORPORATION, Japan), Quick Auto Neo Fe kit (SHINO-TEST COR-PORATION, Japan), Zn Assay Kit (Metallogenic Co., Ltd., Japan), and Mg-HR II Kit (FUJIFILM, Japan). Statistical Analyses The software package for social science statistics (SPSS, version 27) was utilized for conducting the statistical analysis. The normality of data distribution for continuous variables was assessed using the Shapiro-Wilk test. For data with a normal distribution, we presented mean values along with their standard deviations (SD) and compared them using the T-test. For data not following a normal distribution, we reported median values along with the 25th and 75th percentiles, and conducted comparisons using non-parametric tests (Mann-Whitney U test) for continuous variables between groups. Categorical data were expressed as proportions or percentages (%), with intergroup comparisons conducted using the chi-square test. RCS was employed to examine the linear correlation between trace metal levels and the risk of endometriosis. RCS was plotted using the rms package in R (version 4.2.1), with the 25th, 50th, 75th, and 95th percentiles chosen as fitting nodes for each parameter. Logistic regression was utilized to compute odds ratios (ORs) and 95% confidence intervals (CIs) in order to evaluate the correlation between levels of trace metals and the risk of endometriosis. Continuous variables were transformed into categorical variables based on quartiles, and P for trend tests were conducted [ 22 ]. A significance threshold of P < 0.05 was applied for determining statistical significance. Results Baseline Profile of Study Participants Out of 1387 patients experiencing infertility, 568 were diagnosed with endometriosis (Endometriosis group), while 819 were identified as the Control group, which included cases of tubal factor infertility or male factor infertility. Table 1 displays the clinical and biochemical profiles of the participants. No significant differences were observed between the two groups regarding mean age and duration of infertility (all p-values > 0.05). The mean body mass index (BMI) was significantly lower in the Endometriosis group (21.39 ± 2.74) compared to the control group (22.15 ± 3.06), with a p-value less than 0.001. There was a significant difference in the type of infertility, with 58.80% of individuals in the Endometriosis group experiencing primary infertility, compared to 41.50% in the control group (P < 0.001). In terms of baseline hormones, the Endometriosis group exhibited significantly higher levels of FSH (P = 0.003) and E2 (P = 0.013) compared to the control group. Conversely, the Endometriosis group exhibited a significantly lower median level of AMH compared to the control group [3.48 (2.27, 4.81) vs. 3.70 (2.43, 5.39), Endometriosis vs. control, µg/L; P = 0.032]. Levels of LH, P, PRL, and T did not exhibit significant differences between the two groups (all p-values > 0.05). Table 1 Baseline characteristics of Control and Endometriosis groups. Variables Control N = 819 Endometriosis N = 568 t/z/χ 2 P Age (years) 30.77 ± 3.52 30.79 ± 3.37 -0.068 0.946 Age strata (%) 1.388 0.239 ≤ 35 88.90 (728/819) 90.80 (516/819) > 35 11.10 (91/819) 9.20 (52/819) BMI (kg/m 2 ) 22.15 ± 3.06 21.39 ± 2.74 4.861 < 0.001 BMI strata (%) 12.676 0.002 24.9 17.46 (143/819) 10.92 (62/568) Type of infertility (%) 40.132 < 0.001 Primary 41.50 (340/819) 58.80 (334/568) Secondary 58.50 (479/819) 41.20 (234/568) Infertile Duration (years) 3 (2, 4) 3 (2, 4) -1.2 0.23 Baseline hormones FSH (mIU/mL) 7.56 ± 2.00 7.91 ± 2.33 -2.962 0.003 LH (mIU/mL) 4.83 ± 2.67 4.96 ± 4.29 -0.692 0.489 E2 (pg/mL) 38.0 (29.0, 51.0) 41.0 (30.0, 55.7) -2.49 0.013 P (ng/mL) 0.59 (0.42, 0.80) 0.60 (0.45, 0.79) -0.313 0.754 PRL (ng/mL) 15.27 (11.47, 20.68) 15.67 (11.82, 20.52) -0.621 0.535 T (ng/mL) 0.48 ± 0.19 0.47 ± 0.21 1.495 0.135 AMH (µg/L) 3.70 (2.43, 5.39) 3.48 (2.27, 4.81) -2.143 0.032 BMI, body mass index; FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estradiol; P, progesterone; PRL, prolactin; T, testosterone, AMH, anti-mullerian hormone. Distribution of serum metal element levels among study participants The distribution of serum metal element concentrations was presented in Table 2 . Specifically, the levels of serum Cu, Zn, Fe, and Mg are displayed as the minimum, 25th, 50th (median), 75th, and maximum values. The median Zn concentration showed a significant decrease in the endometriosis group when compared to the control group (14.6 vs. 15.1 µmol/L, Endometriosis vs. Control; P < 0.001). However, the levels of three other metallic elements—Cu (P = 0.226), Fe (P = 0.363), and Mg (P = 0.083)—exhibited comparable values across both groups. Of particular note, the endometriosis group exhibited a significantly higher Cu to Zn ratio compared to the control group (median of Cu/Zn %: 107.39 vs. 104.83, Endometriosis vs. Control; P < 0.001). Table 2 Distribution of serum metal element concentrations in Control and Endometriosis groups. Elements Control N = 819 Endometriosis N = 568 P Min P 25 P 50 P 75 Max Min P 25 P 50 P 75 Max Cu (µmol/L) 5.4 13.95 15.6 17.45 37 7.57 14.27 15.77 17.49 48.12 0.226 Zn (µmol/L) 8.9 13.6 15.1 16.8 26.5 5.6 13 14.6 16.5 27.1 < 0.001 Fe (µmol/L) 1.0 11.2 14.8 19.4 41.8 1.4 10.45 14.93 19.1 71.9 0.363 Mg (mmol/L) 0.69 0.86 0.91 0.95 1.27 0.71 0.87 0.92 0.97 1.21 0.083 Cu/Zn (%) 29.67 88.89 104.83 119.31 235.77 42.53 93.14 107.39 125.89 291.60 < 0.001 Min, Minimum; Max, Maximum; P 25 , 25th percentiles; P 50 , 50th percentiles; P 75 , 75th percentiles; Cu, copper; Zn, zinc; Fe, iron; Mg, magnesium. Correlation of serum metal levels and the risk of endometriosis To determine whether there was a linear correlation between serum metal levels and the risk of endometriosis, we conducted restricted cubic spline analyses (RCS) after controlling for confounding factors (age, BMI, and baseline hormone levels). As shown in Fig. 1 , Zn levels and the Cu/Zn % exhibited a linear relationship with the risk of endometriosis (Zn: P for nonlinearity = 0.154; Cu/Zn %: P for nonlinearity = 0.164). Moreover, Zn exhibited a negative association with the risk of endometriosis, whereas the Cu/Zn % demonstrated a positive association. Cu, Fe, and Mg levels showed a non-linear relationship with the risk of endometriosis. We further evaluated the ORs and 95% CIs for the association between serum metal element levels and the risk of endometriosis (Table 3 ). Initially, we categorized serum metal element levels into quartiles. Subsequently, we conducted an ordinal trend test using logistic regression models constructed with the median of serum metal element levels and Cu/Zn ratio quartiles. Cu, Fe, and Mg levels exhibited no notable correlation with the risk of endometriosis, whether in univariate or multivariate analysis (all P trend > 0.05). Conversely, serum Zn levels were inversely correlated with the risk of developing endometriosis (p trend value = 0.005). Compared to individuals in the fourth quartile of Zn, the ORs (95% CIs) for the first and second quartiles were 1.54 (1.13, 2.08) and 1.41 (1.04, 1.91), respectively, although no significance was observed after confounding for age, BMI, and baseline hormones (P trend = 0.065). Furthermore, the results showed a positive association between the Cu/Zn ratio and the risk of endometriosis (P trend < 0.001), which remained significantly positive after adjusting for age, BMI, and baseline hormones (P trend < 0.001). Compared to the first quartile of Cu/Zn ratio after adjustment, the ORs (95% CIs) for the second and fourth quartiles were 1.97 (1.37, 2.83) and 2.63 (1.80, 3.84), respectively. Table 3. Odds ratios (95% confidence intervals) for the association between serum trace metal concentrations and the risk of endometriosis. Elements Cases/Total (N) Median (range) Univariate Multivariate OR (95% CI) P OR (95% CI) P Cu (μmol/L) Q1 139/348 13.10 (5.40, 14.08) 1.00 (1.00, 1.00) Ref 1.00 (1.00, 1.00) Ref Q2 148/356 14.98 (14.09, 15.70) 1.19 (0.88, 1.62) 0.253 1.28 (0.89,1.83) 0.185 Q3 148/337 16.53 (15.73, 17.45) 1.31 (0.97, 1.78) 0.081 1.55 (1.07,2.26) 0.022 Q4 142/346 18.82 (17.47, 48.12) 1.17 (0.86, 1.58) 0.32 1.62 (1.10,2.39) 0.015 P for trend 0.371 0.058 Zn (μmol/L) Q1 164/352 12.30 (5.60, 13.30) 1.54 (1.13, 2.08) 0.006 1.59 (1.10, 2.29) 0.013 Q2 158/355 14.20 (13.40, 14.90) 1.41 (1.04, 1.91) 0.026 1.44 (0.999, 2.09) 0.051 Q3 121/335 15.70 (15.00, 16.60) 0.99 (0.73, 1.36) 0.976 1.19 (0.82, 1.73) 0.352 Q4 125/345 18.10 (16.60, 27.10) 1.00 (1.00, 1.00) Ref 1.00 (1.00, 1.00) Ref P for trend 0.005 0.065 Fe (μmol/L) Q1 156/348 8.30 (1.00, 10.90) 1.27 (0.94, 1.72) 0.125 1.27 (0.88, 1.83) 0.196 Q2 128/354 13.00 (11.00, 14.90) 0.88 (0.65, 1.20) 0.428 0.90 (0.62, 1.30) 0.568 Q3 150/342 17.00 (14.95, 19.30) 1.22 (0.90, 1.65) 0.203 1.35 (0.94, 1.95) 0.105 Q4 134/343 23.2 (19.30, 71.90) 1.00 (1.00, 1.00) Ref 1.00 (1.00, 1.00) Ref P for trend 0.066 0.091 Mg (mmol/L) Q1 138/361 0.83 (0.69, 0.86) 1.00 (1.00, 1.00) Ref 1.00 (1.00, 1.00) Ref Q2 141/360 0.89 (0.87, 0.91) 1.04 (0.77, 1.40) 0.796 1.20 (0.83, 1.73) 0.328 Q3 144/346 0.94 (0.92, 0.96) 1.15 (0.85, 1.56 0.357 1.26 (0.88, 1.81) 0.215 Q4 145/320 1.00 (0.97, 1.27) 1.34 (0.99, 1.82) 0.061 1.55 (1.06,2.26) 0.024 P for trend 0.245 0.159 Cu/Zn (%) Q1 117/347 80.95 (29.67, 90.55) 1.00 (1.00, 1.00) Ref 1.00 (1.00, 1.00) Ref Q2 158/347 98.28 (90.59, 105.66) 1.64 (1.21, 2.23) 0.002 1.97 (1.37, 2.83) <0.001 Q3 123/347 112.38 (105.67, 122.10) 1.08 (0.79, 1.48) 0.632 1.22 (0.83, 1.79) 0.321 Q4 170/346 138.85 (122.14, 291.60) 1.90 (1.40, 2.58) <0.001 2.63 (1.80, 3.84) <0.001 P for trend <0.001 <0.001 Based on the distribution characteristics, the levels of serum metal elements and the copper-to-zinc ratio were divided into four quartiles, represented as Q1, Q2, Q3, and Q4. Univariate, unadjusted for confounders; Multivariate, adjusted for age, BMI, and baseline hormones (FSH, LH, E2, P, PRL, T, AMH). Discussion This study aimed to explore the association between Cu, Zn, Fe, Mg, and the Cu/Zn ratio with the risk of endometriosis. We examined 819 participants with tubal or male factor infertility, as well as 568 individuals diagnosed with endometriosis. Our results revealed indicated a significant decrease in serum Zn levels and a notable elevation in the Cu/Zn ratio in individuals with endometriosis compared to the individuals without endometriosis. Logistic regression analysis showed a significant positive association between the Cu/Zn ratio and the risk of endometriosis. Endometriosis is a prevalent and intricate syndrome, with its pathogenesis remaining largely elusive. Among the numerous candidate factors in pathophysiology, oxidative stress is purported to exert a significant influence [ 18 , 23 ]. Reports suggest that individuals with endometriosis may exhibit elevated oxidative stress parameters, accompanied by a notable decrease in plasma superoxide dismutase 1 (SOD1) levels and an increase in lipid peroxidation enzymes [ 24 , 25 ]. Extensive literature substantiates the involvement of trace elements in oxidative stress pathways [ 26 , 27 ]. In recent years, there has been a growing focus on the association between imbalances in trace element homeostasis and the risk of endometriosis. Cu ranks as the third most prevalent trace metal in the human body, serving as a crucial cofactor for numerous key enzymes essential in various cellular processes and metabolic functions [ 28 ]. It can act both as an antioxidant, reducing oxidative damage, and as a pro-oxidant, leading to OS and disease progression, such as Alzheimer's disease [ 29 ]. Certain studies have observed higher levels of Cu in the serum of individuals with endometriosis compared to healthy women [ 30 – 32 ]. This implies that elevated serum Cu levels might be linked to an increased risk of endometriosis, although the specific mechanisms require further investigation. In our study, while the serum Cu concentrations in the endometriosis group exhibited a slight increase compared to those in the control group, no significant statistical disparity was detected (median of Cu: 15.77 vs. 15.6, Endometriosis vs. Control). The latest case-control study, involving 451 blood samples, reported findings consistent with ours [ 10 ]. It's important to note that in both our study and the aforementioned case-control study [ 10 ], the control group consisted of infertility patients rather than healthy women. This difference in control group selection could have contributed to the absence of statistically significant differences in serum Cu levels, warranting further investigation. Zn is an indispensable micronutrient essential for various physiological functions in the human body, encompassing enzymatic reactions, DNA synthesis, immune responses, wound healing, as well as growth and development processes. [ 11 ]. As a cofactor for numerous enzymes, Zn plays a crucial role in preserving the structural integrity of proteins and cell membranes [ 33 ]. Furthermore, Zn assumes a critical role in modulating oxidative-reductive balance, exerting antioxidant effects, and shielding cells from oxidative damage, often in conjunction with other antioxidants like vitamin E [ 34 ]. Zinc levels impact the activity of various antioxidant enzymes, such as Cu/Zn superoxide dismutase, which contributes to preventing DNA damage [ 35 ]. Multiple clinical observations have indicated decreased serum Zn concentrations in individuals afflicted with endometriosis [ 9 , 36 ]. Messalli et al. compared serum Zn levels between 42 patients with endometriosis and 44 healthy patients. They noted a significant difference, with serum zinc concentration being lower in the endometriosis group (1294 +/- 62.22 microg/l) [ 36 ]. In a cross-sectional study, Lai et al. likewise found markedly lower median blood Zn concentrations in infertile women with endometriosis compared to those without the condition (11.62 vs. 4.47 mg/L) [ 9 ]. However, a case-control study by Su et al. yielded opposite results, showing that women with endometriosis had significantly higher median Zn levels (8666.14 µg/L vs. 4847.88 µg/L) [ 10 ]. In this study, we observed that the zinc concentration in the serum was significantly lower in the Endometriosis group compared to the Control group (14.6 vs. 15.1 µmol/L). Furthermore, serum Zn levels exhibited a negative correlation with the risk of endometriosis, although no significance was observed after adjusting for age, BMI, and baseline hormones. Overall, there are inconsistencies in Zn concentrations in the blood of patients with endometriosis, but the abnormal activity of Zn correlates with the condition, suggesting Zn's involvement in the multifaceted pathogenesis of the disease. The human body employs a sophisticated mechanism to regulate trace metal elements, and one common imbalance observed is elevated Cu levels alongside reduced Zn levels. Indeed, in clinical settings, the Cu/Zn ratio often holds greater significance than independent concentrations [ 16 , 17 ]. Recent studies have revealed complex interactions involving the serum Cu/Zn ratio across various diseases. In breast cancer patients, a higher Cu/Zn ratio was found to be correlated with lower overall survival rates following diagnosis, indicating its potential as an independent predictive marker [ 37 ]. Similarly, in chronic obstructive pulmonary disease (COPD), elevated serum Cu/Zn ratios were linearly associated with an increased risk of COPD in men [ 38 ]. Additionally, the serum Cu/Zn ratio has shown promise as a diagnostic marker for ectopic pregnancy, with higher ratios associated with the condition [ 39 ]. Moreover, during pregnancy, a higher plasma Cu/Zn ratio has been independently linked to pregnancy-specific psychological distress symptoms, suggesting a potential role for micronutrients as novel biomarkers for perinatal mood disorders [ 40 ]. Overall, a common feature across these diseases is an increase in the Cu/Zn ratio attributed to either decreased serum Zn or increased serum Cu. In this context, the plasma Cu/Zn ratio may represent downstream outcomes of a series of complex mechanisms. These findings suggest that the Cu/Zn ratio may serve as a valuable tool in clinical research as a prognostic and predictive factor for various pathological and pre-pathological states. However, the serum Cu/Zn ratio is rarely mentioned in endometriosis. Our results revealed that the endometriosis group exhibited a higher Cu/Zn ratio compared to the control group. RSC indicates that an increased Cu/Zn ratio is linearly associated with a higher risk of endometriosis. Further logistic regression analysis confirmed a positive correlation between the Cu/Zn ratio and the risk of endometriosis. We also analyzed two other trace elements, Fe and Mg. There were no significant differences in the distribution of Fe and Mg between the endometriosis and control groups. Additionally, no significant correlations were found between Fe and Mg levels and the risk of endometriosis. Overall, among the four trace elements examined in this study, Cu showed a slight increase in endometriosis patients, while Zn levels were significantly lower. Fe and Mg did not show notable differences. Importantly, our findings highlight the predictive value of the Cu/Zn ratio in assessing the risk of endometriosis. This study included a substantial number of participants, enhancing the reliability and generalizability of the findings. To our knowledge, this is the first study to evaluate the relationship between the Cu/Zn ratio and the risk of endometriosis, adding a new dimension to the understanding of endometriosis. These findings offer practical insights that could influence future diagnostic and therapeutic strategies. However, several limitations need to be noted. Firstly, it was a single-center retrospective analysis, thus inherently constituting bias and confounding factors despite our adjustments for potential confounders. Secondly, we selectively studied basic trace elements in serum, while the levels in follicular fluid, urine, and endometrial tissue were also worth investigating, as this would have provided a more comprehensive understanding. Lastly, unfortunately, we did not measure oxidative stress markers, which would have facilitated serum Cu/Zn correlation analysis, potentially limiting interpretation and inference. Therefore, future research will necessitate multicenter, multi-tissue, multi-parameter, and more comprehensive studies. Conclusion Our study revealed an association between decreased serum Zn levels and increased Cu/Zn ratio with the risk of endometriosis, emphasizing the predictive potential of the Cu/Zn ratio. The study provided valuable real-world data on the role of trace metal elements in the pathogenesis of endometriosis. Considering the limitations of this study, further multicenter prospective research incorporating additional tissues such as follicular fluid, urine, and endometrial tissue, as well as more parameters including oxidative stress-related markers, is necessary. Moreover, investigating the causal relationships and biological mechanisms involved is warranted. Declarations Author Contributions: Conceptualization: Y. L., H. L. and Q. M.; Methodology, Y. L. and G. C.; Software: Y. L.; Validation: Y. L. and G. C.; Writing—original draft preparation, Y. L.; Writing—review and editing: H. L. and Q. M.; Supervision: H. L. and Q. M.; All authors read and approved the final manuscript. Funding: This research was funded by The National Key Research and Development Program of China (2022YFC2702901) and Gusu Health Talents Project (GSWS2023012 and GSWS2023111). Data availability : Data is available upon request. Conflicts of Interest: The authors declare no conflict of interest. Ethical approval : The research involving human participants received ethical approval from the Reproductive Medicine Ethics Committee of Suzhou Municipal Hospital. Informed c onsent: The participants consented in writing to take part in the study. References Giudice LC, Kao LC (2004) Endometriosis. 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J trace Elem Med biology: organ Soc Minerals Trace Elem 71:126944. https://doi.org/10.1016/j.jtemb.2022.126944 Mravunac M, Szymlek-Gay EA, Daly RM, Roberts BR, Formica M, Gianoudis J, O'Connell SL, Nowson CA, Cardoso BR (2019) Greater Circulating Copper Concentrations and Copper/Zinc Ratios are Associated with Lower Psychological Distress, But Not Cognitive Performance, in a Sample of Australian Older Adults. Nutrients. 11https://doi.org/10.3390/nu11102503 Ansariniya H, Yavari A, Javaheri A, Zare F (2022) Oxidative stress-related effects on various aspects of endometriosis. Am J Reprod Immunol 88:e13593. https://doi.org/10.1111/aji.13593 Van Langendonckt A, Casanas-Roux F, Donnez J (2002) Oxidative stress and peritoneal endometriosis. Fertil Steril 77:861–870. https://doi.org/10.1016/s0015-0282(02)02959-x Bahi GA, Boyvin L, Meite S, M'Boh GM, Yeo K, N'Guessan KR, Bidie AD, Djaman AJ (2017) Assessments of serum copper and zinc concentration, and the Cu/Zn ratio determination in patients with multidrug resistant pulmonary tuberculosis (MDR-TB) in Cote d'Ivoire. BMC Infect Dis 17:257. https://doi.org/10.1186/s12879-017-2343-7 Ozturk P, Belge Kurutas E, Ataseven A (2013) Copper/zinc and copper/selenium ratios, and oxidative stress as biochemical markers in recurrent aphthous stomatitis. J trace Elem Med biology: organ Soc Minerals Trace Elem 27:312–316. https://doi.org/10.1016/j.jtemb.2013.04.002 Li D, Jiang T, Wang X, Yin T, Shen L, Zhang Z, Zou W, Liu Y, Zong K, Liang D, Cao Y, Xu X, Liang C, Ji D (2023) Serum Essential Trace Element Status in Women and the Risk of Endometrial Diseases: a Case-Control Study: Serum Essential Trace Element Status in Women and the Risk of Endometrial Diseases: a Case-Control Study. Biol Trace Elem Res 201:2151–2161. https://doi.org/10.1007/s12011-022-03328-x Chen C, Zhou Y, Hu C, Wang Y, Yan Z, Li Z, Wu R (2019) Mitochondria and oxidative stress in ovarian endometriosis. Free Radic Biol Med 136:22–34. https://doi.org/10.1016/j.freeradbiomed.2019.03.027 Donabela FC, Meola J, Padovan CC, de Paz CC, Navarro PA (2015) Higher SOD1 Gene Expression in Cumulus Cells From Infertile Women With Moderate and Severe Endometriosis. Reproductive Sci 22:1452–1460. https://doi.org/10.1177/1933719115585146 Prieto L, Quesada JF, Cambero O, Pacheco A, Pellicer A, Codoceo R, Garcia-Velasco JA (2012) Analysis of follicular fluid and serum markers of oxidative stress in women with infertility related to endometriosis. Fertil Steril 98:126–130. https://doi.org/10.1016/j.fertnstert.2012.03.052 Oteiza PI (2012) Zinc and the modulation of redox homeostasis. Free Radic Biol Med 53:1748–1759. https://doi.org/10.1016/j.freeradbiomed.2012.08.568 Wandt VK, Winkelbeiner N, Bornhorst J, Witt B, Raschke S, Simon L, Ebert F, Kipp AP, Schwerdtle T (2021) A matter of concern - Trace element dyshomeostasis and genomic stability in neurons. Redox Biol 41:101877. https://doi.org/10.1016/j.redox.2021.101877 Bost M, Houdart S, Oberli M, Kalonji E, Huneau JF, Margaritis I (2016) Dietary copper and human health: Current evidence and unresolved issues. J trace Elem Med biology: organ Soc Minerals Trace Elem 35:107–115. https://doi.org/10.1016/j.jtemb.2016.02.006 Sensi SL, Granzotto A, Siotto M, Squitti R (2018) Copper and Zinc Dysregulation in Alzheimer's Disease. Trends Pharmacol Sci 39:1049–1063. https://doi.org/10.1016/j.tips.2018.10.001 Lin Y, Yuan M, Wang G (2024) Copper homeostasis and cuproptosis in gynecological disorders: Pathogenic insights and therapeutic implications. J trace Elem Med biology: organ Soc Minerals Trace Elem 84:127436. https://doi.org/10.1016/j.jtemb.2024.127436 Pollack AZ, Louis GM, Chen Z, Peterson CM, Sundaram R, Croughan MS, Sun L, Hediger ML, Stanford JB, Varner MW, Palmer CD, Steuerwald AJ, Parsons PJ (2013) Trace elements and endometriosis: the ENDO study. Reprod Toxicol 42:41–48. https://doi.org/10.1016/j.reprotox.2013.05.009 Turgut A, Ozler A, Goruk NY, Tunc SY, Evliyaoglu O, Gul T (2013) Copper, ceruloplasmin and oxidative stress in patients with advanced-stage endometriosis. Eur Rev Med Pharmacol Sci 17:1472–1478 Weiss A, Murdoch CC, Edmonds KA, Jordan MR, Monteith AJ, Perera YR, Rodriguez Nassif AM, Petoletti AM, Beavers WN, Munneke MJ, Drury SL, Krystofiak ES, Thalluri K, Wu H, Kruse ARS, DiMarchi RD, Caprioli RM, Spraggins JM, Chazin WJ, Giedroc DP, Skaar EP (2022) Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis. Cell 185:2148–2163e2127. https://doi.org/10.1016/j.cell.2022.04.011 Faure P (2003) Protective effects of antioxidant micronutrients (vitamin E, zinc and selenium) in type 2 diabetes mellitus. Clin Chem Lab Med 41:995–998. https://doi.org/10.1515/CCLM.2003.152 Jomova K, Makova M, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Rhodes CJ, Valko M (2022) Essential metals in health and disease. Chemico-Biol Interact 367:110173. https://doi.org/10.1016/j.cbi.2022.110173 Messalli EM, Schettino MT, Mainini G, Ercolano S, Fuschillo G, Falcone F, Esposito E, Di Donna MC, De Franciscis P, Torella M (2014) The possible role of zinc in the etiopathogenesis of endometriosis. Clin Exp Obstet Gynecol 41:541–546 Bengtsson Y, Demircan K, Vallon-Christersson J, Malmberg M, Saal LH, Ryden L, Borg A, Schomburg L, Sandsveden M, Manjer J (2023) Serum copper, zinc and copper/zinc ratio in relation to survival after breast cancer diagnosis: A prospective multicenter cohort study. Redox Biol 63:102728. https://doi.org/10.1016/j.redox.2023.102728 Kunutsor SK, Voutilainen A, Laukkanen JA (2023) Serum Copper-to-Zinc Ratio and Risk of Chronic Obstructive Pulmonary Disease: A Cohort Study. Lung 201:79–84. https://doi.org/10.1007/s00408-022-00591-6 Tok A, Ozer A, Baylan FA, Kurutas EB (2021) Copper/Zinc Ratio Can Be a Marker to Diagnose Ectopic Pregnancy and Is Associated with the Oxidative Stress Status of Ectopic Pregnancy Cases. Biol Trace Elem Res 199:2096–2103. https://doi.org/10.1007/s12011-020-02327-0 Hulsbosch LP, Boekhorst M, Gigase FAJ, Broeren MAC, Krabbe JG, Maret W, Pop VJM (2023) The first trimester plasma copper-zinc ratio is independently related to pregnancy-specific psychological distress symptoms throughout pregnancy. Nutrition 109:111938. https://doi.org/10.1016/j.nut.2022.111938 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4511841","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":312275016,"identity":"044ac2f0-497f-4f64-bb3c-6b9cf3850c2b","order_by":0,"name":"Yanping Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIie2RsQrCMBRFX4nEJZo1peo3ZKqUDv2VgoNLB8F/qIvd/QgXl+pYyVpxVejglEmhk9BBsEbBLe0omLPkBt7hPngABsMP0kfvlwCgDJjKoV7BXwWHLZVvJPwTmpQucVm1KwZjur5fvEgA7UYcqp1uMeLaSS6Jt7ptuZ0KsJdXbiW5XmG9WBB+OqTspfBTxJEVN7Q8lJJLpQRtFEe1HJf43cIaFTz3h7GsW7BbK1PCcjnbJxqFUrE53+Ii4EchHTv1R3Qx2VwqjVLTqQ+YAbAQEFM3VV8tqFQzNAOrbBg1GAyG/+QJEnhKG36sE8IAAAAASUVORK5CYII=","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School of Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yanping","middleName":"","lastName":"Liu","suffix":""},{"id":312275017,"identity":"fd117fb2-0bbc-45f3-aeed-2fef6b884a17","order_by":1,"name":"Guihong Cheng","email":"","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guihong","middleName":"","lastName":"Cheng","suffix":""},{"id":312275018,"identity":"54091910-2f77-4453-841a-fde43ca02c46","order_by":2,"name":"Hong Li","email":"","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Li","suffix":""},{"id":312275019,"identity":"5a90a15a-7409-445d-a9d6-adebd7b33a25","order_by":3,"name":"Qingxia Meng","email":"","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qingxia","middleName":"","lastName":"Meng","suffix":""}],"badges":[],"createdAt":"2024-06-01 04:23:21","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4511841/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4511841/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58751273,"identity":"10f7b47e-605a-47d1-af99-cd431b836d2c","added_by":"auto","created_at":"2024-06-20 16:08:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54007,"visible":true,"origin":"","legend":"\u003cp\u003eRestricted cubic spline curves depicting the odds ratios of endometriosis risk in relation to serum metal levels and copper/zinc (%). A) Copper and endometriosis; B) Zinc and endometriosis; C) Iron and endometriosis; D) Magnesium and endometriosis; E) Copper/Zinc ratio and endometriosis. The solid red line represents the odds ratio, while the red shaded area indicates the 95% confidence interval. The distribution percentiles for increasing weights are at the 25th, 50th, and 75th percentiles. The model is adjusted for age, body mass index, and baseline hormones. Cu: copper; Zn: zinc; Fe: iron; P: phosphorus; Mg: magnesium.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4511841/v1/d435a303dfe250479aab924d.png"},{"id":61452705,"identity":"0ae6b114-4d7e-4ab7-8d94-006378236236","added_by":"auto","created_at":"2024-07-31 02:26:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":726572,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4511841/v1/975b0381-b474-4a2f-bb44-f8c23b6fa13f.pdf"},{"id":58751272,"identity":"63cde704-0196-4af5-88c2-bd29879f666e","added_by":"auto","created_at":"2024-06-20 16:08:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":325458,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.docx","url":"https://assets-eu.researchsquare.com/files/rs-4511841/v1/2bd547d7c8512abf7b2dc272.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Serum Copper to Zinc Ratio and Risk of Endometriosis: Insights from a Case-Control Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a prevalent gynecological disorder which significantly impairs fertility among women of reproductive age. Common clinical manifestations of endometriosis include dysmenorrhea, irregular menstruation, dyspareunia, and infertility [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Nonetheless, a considerable number of patients are primarily diagnosed with endometriosis upon seeking medical assistance for infertility issues. Epidemiological studies indicate that the incidence of endometriosis among women experiencing infertility ranges from 30\u0026ndash;50% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Endometriosis exerts multifaceted effects on fertility, attributed to alterations in pelvic anatomy, compromised ovarian reserve, oocyte and embryo quality deterioration, and disrupted endometrial receptivity [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The pathological mechanisms of endometriosis involve various factors such as aberrant inflammatory response, hormonal imbalance, genetic predisposition, and immune dysregulation, yet remain elusive [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTrace metal elements play crucial roles in various biochemical processes in the human body, garnering increasing attention for their involvement in the pathogenesis of endometriosis. Hall et al. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] performed a cross-sectional study utilizing NHANES 1999\u0026ndash;2006 data, revealing a link between urinary cadmium concentrations and endometriosis prevalence in the US population. Likewise, Shen et al. found that concentrations of arsenic, cadmium, lead, and mercury in both serum and follicular fluid were positively correlated with an increased risk of endometriosis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, Lai et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] noted a correlation between decreased Zinc (Zn) levels and a higher risk of endometriosis in infertile women. Conversely, Su et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] observed that elevated Zn levels in both blood and follicular fluid were linked to an increased risk of endometriosis. This inconsistency in research findings regarding the relationship between zinc levels and the risk of endometriosis may be attributed to differences in study design, sample size, characteristics, and analytical methods.\u003c/p\u003e \u003cp\u003eZn, an essential trace nutrient, acts as a crucial modulator of immune function, exhibiting potent antioxidant and anti-inflammatory properties vital for maintaining cellular redox homeostasis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Zn deficiency compromises the activity of antioxidant enzymes, exacerbating oxidation stress (OS) conditions [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Conversely, copper (Cu) exhibits multifaceted involvement in OS. By catalyzing the Fenton reaction, Cu promotes the production of reactive oxygen species, which can subsequently induce lipid peroxidation, thereby amplifying OS responses [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Moreover, Cu participates in redox reactions, leading to the depletion of the antioxidant glutathione and disruption of cellular antioxidant defense mechanisms [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Both Cu and Zn serve as necessary enzyme cofactors in antioxidant defenses and neurotransmitter synthesis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The intricate balance and levels of Cu and Zn within cells are pivotal for maintaining redox balance and regulating OS. The human body intricately manages and regulates the levels and proportions of trace elements crucial for blood circulation and cellular storage. When the system malfunctions, abnormalities in the levels or ratios of metal ions arise. In clinical settings, the Cu/Zn ratio holds more significance than the concentrations of these metals individually [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The potential significance of OS in the development of endometriosis is attracting attention [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Imbalances in the ratio of Cu to Zn can lead to pathological conditions associated with OS [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Nevertheless, there is limited and contentious research concerning the association between serum Zn levels and the Cu/Zn ratio with endometriosis.\u003c/p\u003e \u003cp\u003eIn this context, we conducted a retrospective analysis of the distribution characteristics of Cu, Zn, iron (Fe), and magnesium (Mg) levels, as well as the ratio of Cu to Zn, among 1387 infertility patients. Additionally, we investigated the correlation between these elements and the risk of endometriosis.\u003c/p\u003e"},{"header":"Subjects and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003eThis case-control study was carried out at the Reproductive and Genetic Center of Suzhou Municipal Hospital (Suzhou, Jiangsu Province, China). Detailed clinical data were retrieved from the Clinical Reproductive Medical Management System. A total of 1387 infertile women underwent the first in vitro fertilization cycle from January 2018 to December 2022. Among them, 568 patients were diagnosed with endometriosis, while the control group comprised 819 patients with tubal or male factor infertility. Endometriosis diagnosis relied on a combination of patient-reported symptoms, physical examination findings, and imaging studies such as ultrasound or MRI, or confirmed through laparoscopic surgery. Exclusion criteria included various conditions such as polycystic ovary syndrome, thyroid disorders, chromosomal abnormalities, and prior ovarian surgeries. A history of smoking or long-term medication use will also be considered for exclusion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eHormone and trace metal elements Assays\u003c/h2\u003e \u003cp\u003eSerum samples collected during the early follicular phase (7.00\u0026ndash;9.00 a.m.) were utilized to measure the baseline levels of sex hormones. Hormone levels, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), progesterone (P), prolactin (PRL), and anti-M\u0026uuml;llerian hormone (AMH), were assessed using an automated electrochemiluminescence immunoassay system (Hitachi Model 7170, Japan). The concentrations of metal elements, including Cu, Zn, iron Fe, and Mg, were also assessed. In brief, specific assay kits for each element were utilized in accordance with the provided experimental protocols. The products/kits being utilized are described as follows: Quick Auto Neo Cu kit (SHINO-TEST CORPORATION, Japan), Quick Auto Neo Fe kit (SHINO-TEST COR-PORATION, Japan), Zn Assay Kit (Metallogenic Co., Ltd., Japan), and Mg-HR II Kit (FUJIFILM, Japan).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eThe software package for social science statistics (SPSS, version 27) was utilized for conducting the statistical analysis. The normality of data distribution for continuous variables was assessed using the Shapiro-Wilk test. For data with a normal distribution, we presented mean values along with their standard deviations (SD) and compared them using the T-test. For data not following a normal distribution, we reported median values along with the 25th and 75th percentiles, and conducted comparisons using non-parametric tests (Mann-Whitney U test) for continuous variables between groups. Categorical data were expressed as proportions or percentages (%), with intergroup comparisons conducted using the chi-square test. RCS was employed to examine the linear correlation between trace metal levels and the risk of endometriosis. RCS was plotted using the rms package in R (version 4.2.1), with the 25th, 50th, 75th, and 95th percentiles chosen as fitting nodes for each parameter. Logistic regression was utilized to compute odds ratios (ORs) and 95% confidence intervals (CIs) in order to evaluate the correlation between levels of trace metals and the risk of endometriosis. Continuous variables were transformed into categorical variables based on quartiles, and P for trend tests were conducted [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A significance threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was applied for determining statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Profile of Study Participants\u003c/h2\u003e \u003cp\u003eOut of 1387 patients experiencing infertility, 568 were diagnosed with endometriosis (Endometriosis group), while 819 were identified as the Control group, which included cases of tubal factor infertility or male factor infertility. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e displays the clinical and biochemical profiles of the participants. No significant differences were observed between the two groups regarding mean age and duration of infertility (all p-values\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The mean body mass index (BMI) was significantly lower in the Endometriosis group (21.39\u0026thinsp;\u0026plusmn;\u0026thinsp;2.74) compared to the control group (22.15\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06), with a p-value less than 0.001. There was a significant difference in the type of infertility, with 58.80% of individuals in the Endometriosis group experiencing primary infertility, compared to 41.50% in the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In terms of baseline hormones, the Endometriosis group exhibited significantly higher levels of FSH (P\u0026thinsp;=\u0026thinsp;0.003) and E2 (P\u0026thinsp;=\u0026thinsp;0.013) compared to the control group. Conversely, the Endometriosis group exhibited a significantly lower median level of AMH compared to the control group [3.48 (2.27, 4.81) vs. 3.70 (2.43, 5.39), Endometriosis vs. control, \u0026micro;g/L; P\u0026thinsp;=\u0026thinsp;0.032]. Levels of LH, P, PRL, and T did not exhibit significant differences between the two groups (all p-values\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of Control and Endometriosis groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;819\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEndometriosis\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;568\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et/z/χ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.77\u0026thinsp;\u0026plusmn;\u0026thinsp;3.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.79\u0026thinsp;\u0026plusmn;\u0026thinsp;3.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.068\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.946\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge strata (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.239\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88.90 (728/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90.80 (516/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.10 (91/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.20 (52/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.15\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.39\u0026thinsp;\u0026plusmn;\u0026thinsp;2.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI strata (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.676\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.77 (80/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.50 (71/568)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18.5\u0026ndash;24.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.77 (596/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.58 (435/568)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;24.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.46 (143/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.92 (62/568)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of infertility (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40.132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.50 (340/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.80 (334/568)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.50 (479/819)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.20 (234/568)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertile Duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2, 4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2, 4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline hormones\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFSH (mIU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.56\u0026thinsp;\u0026plusmn;\u0026thinsp;2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.91\u0026thinsp;\u0026plusmn;\u0026thinsp;2.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.962\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLH (mIU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.83\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.96\u0026thinsp;\u0026plusmn;\u0026thinsp;4.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.692\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE2 (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.0 (29.0, 51.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.0 (30.0, 55.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.59 (0.42, 0.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.60 (0.45, 0.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.313\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.754\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePRL (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.27 (11.47, 20.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.67 (11.82, 20.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.621\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.535\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.495\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH (\u0026micro;g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.70 (2.43, 5.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.48 (2.27, 4.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI, body mass index; FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estradiol; P, progesterone; PRL, prolactin; T, testosterone, AMH, anti-mullerian hormone.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDistribution of serum metal element levels among study participants\u003c/h2\u003e \u003cp\u003eThe distribution of serum metal element concentrations was presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Specifically, the levels of serum Cu, Zn, Fe, and Mg are displayed as the minimum, 25th, 50th (median), 75th, and maximum values. The median Zn concentration showed a significant decrease in the endometriosis group when compared to the control group (14.6 vs. 15.1 \u0026micro;mol/L, Endometriosis vs. Control; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, the levels of three other metallic elements\u0026mdash;Cu (P\u0026thinsp;=\u0026thinsp;0.226), Fe (P\u0026thinsp;=\u0026thinsp;0.363), and Mg (P\u0026thinsp;=\u0026thinsp;0.083)\u0026mdash;exhibited comparable values across both groups. Of particular note, the endometriosis group exhibited a significantly higher Cu to Zn ratio compared to the control group (median of Cu/Zn %: 107.39 vs. 104.83, Endometriosis vs. Control; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of serum metal element concentrations in Control and Endometriosis groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eElements\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;819\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c12\" namest=\"c8\"\u003e \u003cp\u003eEndometriosis\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;568\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP\u003csub\u003e25\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003csub\u003e75\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMax\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eP\u003csub\u003e25\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eP\u003csub\u003e75\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eMax\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCu (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e15.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e17.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e48.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e0.226\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZn (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e14.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e16.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e27.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFe (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e14.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e19.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e71.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e0.363\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMg (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCu/Zn (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e88.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e104.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e119.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e235.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e42.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e93.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e107.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e125.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e291.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"13\"\u003eMin, Minimum; Max, Maximum; P\u003csub\u003e25\u003c/sub\u003e, 25th percentiles; P\u003csub\u003e50\u003c/sub\u003e, 50th percentiles; P\u003csub\u003e75\u003c/sub\u003e, 75th percentiles; Cu, copper; Zn, zinc; Fe, iron; Mg, magnesium.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation of serum metal levels and the risk of endometriosis\u003c/h2\u003e \u003cp\u003eTo determine whether there was a linear correlation between serum metal levels and the risk of endometriosis, we conducted restricted cubic spline analyses (RCS) after controlling for confounding factors (age, BMI, and baseline hormone levels). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Zn levels and the Cu/Zn % exhibited a linear relationship with the risk of endometriosis (Zn: P for nonlinearity\u0026thinsp;=\u0026thinsp;0.154; Cu/Zn %: P for nonlinearity\u0026thinsp;=\u0026thinsp;0.164). Moreover, Zn exhibited a negative association with the risk of endometriosis, whereas the Cu/Zn % demonstrated a positive association. Cu, Fe, and Mg levels showed a non-linear relationship with the risk of endometriosis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe further evaluated the ORs and 95% CIs for the association between serum metal element levels and the risk of endometriosis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Initially, we categorized serum metal element levels into quartiles. Subsequently, we conducted an ordinal trend test using logistic regression models constructed with the median of serum metal element levels and Cu/Zn ratio quartiles. Cu, Fe, and Mg levels exhibited no notable correlation with the risk of endometriosis, whether in univariate or multivariate analysis (all P trend\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Conversely, serum Zn levels were inversely correlated with the risk of developing endometriosis (p trend value\u0026thinsp;=\u0026thinsp;0.005). Compared to individuals in the fourth quartile of Zn, the ORs (95% CIs) for the first and second quartiles were 1.54 (1.13, 2.08) and 1.41 (1.04, 1.91), respectively, although no significance was observed after confounding for age, BMI, and baseline hormones (P trend\u0026thinsp;=\u0026thinsp;0.065). Furthermore, the results showed a positive association between the Cu/Zn ratio and the risk of endometriosis (P trend\u0026thinsp;\u0026lt;\u0026thinsp;0.001), which remained significantly positive after adjusting for age, BMI, and baseline hormones (P trend\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Compared to the first quartile of Cu/Zn ratio after adjustment, the ORs (95% CIs) for the second and fourth quartiles were 1.97 (1.37, 2.83) and 2.63 (1.80, 3.84), respectively.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eOdds ratios (95% confidence intervals) for the association between serum trace metal concentrations and the risk of endometriosis.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"620\" style=\"margin-right: calc(22%); width: 78%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.331723027375201%\" rowspan=\"2\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eElements\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.043478260869565%\" rowspan=\"2\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCases/Total\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" rowspan=\"2\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.67149758454106%\" colspan=\"2\" style=\"width: 29.6337%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.63768115942029%\" colspan=\"3\" style=\"width: 14.0833%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.555555555555555%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.698412698412696%\" style=\"width: 10.8559%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.555555555555555%\" colspan=\"2\" style=\"width: 3.2274%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eCu (\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e139/348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e13.10\u0026nbsp;(5.40, 14.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.00 (1.00,\u0026nbsp;1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e148/356\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e14.98 (14.09, 15.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.19 (0.88, 1.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.28 (0.89,1.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.185\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e148/337\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e16.53 (15.73, 17.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.31\u0026nbsp;(0.97, 1.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.55 (1.07,2.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e142/346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e18.82 (17.47, 48.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.17\u0026nbsp;(0.86, 1.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.62 (1.10,2.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e for trend\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.371\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eZn (\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e164/352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e12.30\u0026nbsp;(5.60, 13.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.54 (1.13, 2.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.59 (1.10, 2.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e158/355\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e14.20\u0026nbsp;(13.40, 14.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.41 (1.04, 1.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.44 (0.999, 2.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e121/335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e15.70\u0026nbsp;(15.00, 16.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e0.99 (0.73, 1.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.976\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.19 (0.82, 1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.352\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e125/345\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e18.10\u0026nbsp;(16.60, 27.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e for trend\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eFe (\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e156/348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e8.30 (1.00, 10.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.27 (0.94, 1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.27 (0.88, 1.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.196\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e128/354\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e13.00 (11.00, 14.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e0.88 (0.65, 1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.428\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e0.90 (0.62, 1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.568\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e150/342\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e17.00 (14.95, 19.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.22 (0.90, 1.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.35 (0.94, 1.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e134/343\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e23.2 (19.30, 71.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e for trend\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eMg\u0026nbsp;(mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e138/361\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e0.83 (0.69, 0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e141/360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e0.89 (0.87, 0.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.04 (0.77, 1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.796\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.20 (0.83, 1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.328\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e144/346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e0.94 (0.92, 0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.15 (0.85, 1.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.357\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.26 (0.88, 1.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.215\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e145/320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e1.00 (0.97, 1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.34 (0.99, 1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.55 (1.06,2.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e for trend\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.245\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eCu/Zn (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e117/347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e80.95 (29.67, 90.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e158/347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e98.28 (90.59, 105.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.64 (1.21, 2.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.97 (1.37, 2.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e123/347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e112.38 (105.67, 122.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.08 (0.79, 1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e0.632\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e1.22 (0.83, 1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e0.321\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003eQ4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e170/346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e138.85 (122.14, 291.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e1.90 (1.40, 2.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e2.63 (1.80, 3.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.35483870967742%\" style=\"width: 14.5234%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e for trend\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.064516129032258%\" style=\"width: 12.9097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.774193548387096%\" style=\"width: 15.6971%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.806451612903226%\" style=\"width: 19.5113%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" style=\"width: 10.2691%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.612903225806452%\" style=\"width: 11.5894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.903225806451613%\" colspan=\"2\" style=\"width: 7.0417%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBased on the distribution characteristics, the levels of serum metal elements and the copper-to-zinc ratio were divided into four quartiles, represented as Q1, Q2, Q3, and Q4.\u0026nbsp;Univariate, unadjusted for confounders; Multivariate, adjusted for\u0026nbsp;age, BMI,\u0026nbsp;and baseline hormones (FSH, LH, E2, P, PRL, T, AMH).\u0026nbsp;\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to explore the association between Cu, Zn, Fe, Mg, and the Cu/Zn ratio with the risk of endometriosis. We examined 819 participants with tubal or male factor infertility, as well as 568 individuals diagnosed with endometriosis. Our results revealed indicated a significant decrease in serum Zn levels and a notable elevation in the Cu/Zn ratio in individuals with endometriosis compared to the individuals without endometriosis. Logistic regression analysis showed a significant positive association between the Cu/Zn ratio and the risk of endometriosis.\u003c/p\u003e \u003cp\u003eEndometriosis is a prevalent and intricate syndrome, with its pathogenesis remaining largely elusive. Among the numerous candidate factors in pathophysiology, oxidative stress is purported to exert a significant influence [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Reports suggest that individuals with endometriosis may exhibit elevated oxidative stress parameters, accompanied by a notable decrease in plasma superoxide dismutase 1 (SOD1) levels and an increase in lipid peroxidation enzymes [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Extensive literature substantiates the involvement of trace elements in oxidative stress pathways [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In recent years, there has been a growing focus on the association between imbalances in trace element homeostasis and the risk of endometriosis.\u003c/p\u003e \u003cp\u003eCu ranks as the third most prevalent trace metal in the human body, serving as a crucial cofactor for numerous key enzymes essential in various cellular processes and metabolic functions [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. It can act both as an antioxidant, reducing oxidative damage, and as a pro-oxidant, leading to OS and disease progression, such as Alzheimer's disease [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Certain studies have observed higher levels of Cu in the serum of individuals with endometriosis compared to healthy women [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. This implies that elevated serum Cu levels might be linked to an increased risk of endometriosis, although the specific mechanisms require further investigation. In our study, while the serum Cu concentrations in the endometriosis group exhibited a slight increase compared to those in the control group, no significant statistical disparity was detected (median of Cu: 15.77 vs. 15.6, Endometriosis vs. Control). The latest case-control study, involving 451 blood samples, reported findings consistent with ours [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. It's important to note that in both our study and the aforementioned case-control study [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], the control group consisted of infertility patients rather than healthy women. This difference in control group selection could have contributed to the absence of statistically significant differences in serum Cu levels, warranting further investigation.\u003c/p\u003e \u003cp\u003eZn is an indispensable micronutrient essential for various physiological functions in the human body, encompassing enzymatic reactions, DNA synthesis, immune responses, wound healing, as well as growth and development processes. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. As a cofactor for numerous enzymes, Zn plays a crucial role in preserving the structural integrity of proteins and cell membranes [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Furthermore, Zn assumes a critical role in modulating oxidative-reductive balance, exerting antioxidant effects, and shielding cells from oxidative damage, often in conjunction with other antioxidants like vitamin E [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Zinc levels impact the activity of various antioxidant enzymes, such as Cu/Zn superoxide dismutase, which contributes to preventing DNA damage [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Multiple clinical observations have indicated decreased serum Zn concentrations in individuals afflicted with endometriosis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Messalli et al. compared serum Zn levels between 42 patients with endometriosis and 44 healthy patients. They noted a significant difference, with serum zinc concentration being lower in the endometriosis group (1294 +/- 62.22 microg/l) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In a cross-sectional study, Lai et al. likewise found markedly lower median blood Zn concentrations in infertile women with endometriosis compared to those without the condition (11.62 vs. 4.47 mg/L) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, a case-control study by Su et al. yielded opposite results, showing that women with endometriosis had significantly higher median Zn levels (8666.14 \u0026micro;g/L vs. 4847.88 \u0026micro;g/L) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In this study, we observed that the zinc concentration in the serum was significantly lower in the Endometriosis group compared to the Control group (14.6 vs. 15.1 \u0026micro;mol/L). Furthermore, serum Zn levels exhibited a negative correlation with the risk of endometriosis, although no significance was observed after adjusting for age, BMI, and baseline hormones. Overall, there are inconsistencies in Zn concentrations in the blood of patients with endometriosis, but the abnormal activity of Zn correlates with the condition, suggesting Zn's involvement in the multifaceted pathogenesis of the disease.\u003c/p\u003e \u003cp\u003eThe human body employs a sophisticated mechanism to regulate trace metal elements, and one common imbalance observed is elevated Cu levels alongside reduced Zn levels. Indeed, in clinical settings, the Cu/Zn ratio often holds greater significance than independent concentrations [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Recent studies have revealed complex interactions involving the serum Cu/Zn ratio across various diseases. In breast cancer patients, a higher Cu/Zn ratio was found to be correlated with lower overall survival rates following diagnosis, indicating its potential as an independent predictive marker [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Similarly, in chronic obstructive pulmonary disease (COPD), elevated serum Cu/Zn ratios were linearly associated with an increased risk of COPD in men [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Additionally, the serum Cu/Zn ratio has shown promise as a diagnostic marker for ectopic pregnancy, with higher ratios associated with the condition [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Moreover, during pregnancy, a higher plasma Cu/Zn ratio has been independently linked to pregnancy-specific psychological distress symptoms, suggesting a potential role for micronutrients as novel biomarkers for perinatal mood disorders [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Overall, a common feature across these diseases is an increase in the Cu/Zn ratio attributed to either decreased serum Zn or increased serum Cu. In this context, the plasma Cu/Zn ratio may represent downstream outcomes of a series of complex mechanisms. These findings suggest that the Cu/Zn ratio may serve as a valuable tool in clinical research as a prognostic and predictive factor for various pathological and pre-pathological states. However, the serum Cu/Zn ratio is rarely mentioned in endometriosis. Our results revealed that the endometriosis group exhibited a higher Cu/Zn ratio compared to the control group. RSC indicates that an increased Cu/Zn ratio is linearly associated with a higher risk of endometriosis. Further logistic regression analysis confirmed a positive correlation between the Cu/Zn ratio and the risk of endometriosis.\u003c/p\u003e \u003cp\u003eWe also analyzed two other trace elements, Fe and Mg. There were no significant differences in the distribution of Fe and Mg between the endometriosis and control groups. Additionally, no significant correlations were found between Fe and Mg levels and the risk of endometriosis. Overall, among the four trace elements examined in this study, Cu showed a slight increase in endometriosis patients, while Zn levels were significantly lower. Fe and Mg did not show notable differences. Importantly, our findings highlight the predictive value of the Cu/Zn ratio in assessing the risk of endometriosis.\u003c/p\u003e \u003cp\u003eThis study included a substantial number of participants, enhancing the reliability and generalizability of the findings. To our knowledge, this is the first study to evaluate the relationship between the Cu/Zn ratio and the risk of endometriosis, adding a new dimension to the understanding of endometriosis. These findings offer practical insights that could influence future diagnostic and therapeutic strategies. However, several limitations need to be noted. Firstly, it was a single-center retrospective analysis, thus inherently constituting bias and confounding factors despite our adjustments for potential confounders. Secondly, we selectively studied basic trace elements in serum, while the levels in follicular fluid, urine, and endometrial tissue were also worth investigating, as this would have provided a more comprehensive understanding. Lastly, unfortunately, we did not measure oxidative stress markers, which would have facilitated serum Cu/Zn correlation analysis, potentially limiting interpretation and inference. Therefore, future research will necessitate multicenter, multi-tissue, multi-parameter, and more comprehensive studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study revealed an association between decreased serum Zn levels and increased Cu/Zn ratio with the risk of endometriosis, emphasizing the predictive potential of the Cu/Zn ratio. The study provided valuable real-world data on the role of trace metal elements in the pathogenesis of endometriosis. Considering the limitations of this study, further multicenter prospective research incorporating additional tissues such as follicular fluid, urine, and endometrial tissue, as well as more parameters including oxidative stress-related markers, is necessary. Moreover, investigating the causal relationships and biological mechanisms involved is warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization: Y. L., H. L. and Q. M.; Methodology, Y. L. and G. C.; Software: Y. L.; Validation: Y. L. and G. C.; Writing\u0026mdash;original draft preparation, Y. L.; Writing\u0026mdash;review and editing: H. L. and Q. M.; Supervision: H. L. and Q. M.; All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was funded by The National Key Research and Development Program of China (2022YFC2702901) and Gusu Health Talents Project (GSWS2023012 and GSWS2023111).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eData is available upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eThe research involving human participants received ethical approval from the Reproductive Medicine Ethics Committee of Suzhou Municipal Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ec\u003c/strong\u003e\u003cstrong\u003eonsent:\u0026nbsp;\u003c/strong\u003eThe participants consented in writing to take part in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGiudice LC, Kao LC (2004) Endometriosis. 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Nutrition 109:111938. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.nut.2022.111938\u003c/span\u003e\u003cspan address=\"10.1016/j.nut.2022.111938\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Endometriosis, Copper, Zinc, Copper/zinc ratio, Infertility","lastPublishedDoi":"10.21203/rs.3.rs-4511841/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4511841/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe significance of trace metal elements in the development of endometriosis has garnered increasing interest. We aimed to investigate the relationship between serum copper (Cu), zinc (Zn), iron (Fe), magnesium (Mg) levels, and the Cu/Zn ratio with the risk of endometriosis. This study involved 568 infertile patients diagnosed with endometriosis, compared to 819 infertile patients without endometriosis (Control group). Basic characteristics, hormonal parameters, and essential trace elements of the patients were measured and analyzed. The findings indicated a notable decrease in serum Zn levels in the endometriosis group compared to controls, alongside a significant increase in the Cu/Zn ratio (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Restricted cubic spline analysis (RCS) revealed a linear relationship between Zn levels and the Cu/Zn ratio with the risk of endometriosis. Moreover, Zn levels exhibited a negative correlation with endometriosis risk (P trend\u0026thinsp;=\u0026thinsp;0.005), while the Cu/Zn ratio displayed a positive correlation with endometriosis risk, even after adjusting for age, body mass index (BMI), and baseline hormones (P trend\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Compared to the first quartile of Cu/Zn ratio after adjustment, the odds ratios (ORs) with 95% confidence intervals (CIs) for the second and fourth quartiles were 1.97 (1.37, 2.83) and 2.63 (1.80, 3.84), respectively. This study provided evidence of decreased serum Zn levels and increased Cu/Zn ratio being associated with an elevated risk of endometriosis among infertile patients.\u003c/p\u003e","manuscriptTitle":"Serum Copper to Zinc Ratio and Risk of Endometriosis: Insights from a Case-Control Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-20 16:08:21","doi":"10.21203/rs.3.rs-4511841/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2799d014-5e7a-434d-ad72-0f9ce8531c8d","owner":[],"postedDate":"June 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-31T02:18:48+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-20 16:08:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4511841","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4511841","identity":"rs-4511841","version":["v1"]},"buildId":"0U-iFTyB6qxOgVj8rjrZV","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}