Pretreatment triglycerides-to-high density lipoprotein cholesterol ratio in postmenopausal women with endometrial cancer.

This case‐control study included lipid profile data on 167 consecutive postmenopausal women with endometrial cancer and 464 matched noncancer controls. After a series of medical work‐ups, such as gynecological examinations, transvaginal ultrasound scanning and laboratory tests, all cancer patients who underwent radical hysterectomy or diagnostic curettage in First Affiliated Hospital of Guangxi Medical University between March 2011 and March 2018 due to newly‐diagnosed endometrial cancer were included. A group of 464 matched noncancer postmenopausal subjects who visited the hospital during the same period for medical check‐up and with normal endometrium or endometritis were randomly selected as controls. Criteria for selecting the patients were as follows. First, all newly diagnosed endometrial cancer patients who were postmenopausal for at least a year and with available pretreatment lipid profiles were selected. Second, cases were excluded if they met any one of the following criteria: other cancer accompanied, lipid‐lowing treatment history, ischemia stroke, thyroid diseases, coronary artery disease, liver diseases, nephrotic syndrome, polycystic ovary syndrome or any other diseases that were related to lipid disorder except for hypertension and diabetes mellitus. TG/HDL‐c ratio was defined as triglycerides‐to‐high density lipoprotein cholesterol ratio. According to a report from WHO consultation, subjects with body mass index (BMI) ≥ 25 kg/m 2 were regarded as overweight/obesity. 13 Comparisons of serum lipid profile and its derived parameter TG/HDL‐c ratio were performed between patient group and control group. The potential associations between TG/HDL‐c ratio and tumor stage, tumor grade, histological classification, carbohydrate antigen 125 (CA‐125) as well as cancer subtype were also assessed in the present study. Patients' baseline characteristics, pathological features, pretreatment lipid profiles, and CA‐125 were extracted from their medical charts in April 2018. Pretreatment lipid profiles were measured in 8‐hour and above fasting blood samples within a week before any intervention. All subjects' uterine specimens were evaluated carefully in the Pathology Department of the First Affiliated Hospital of Guangxi Medical University. Tumor staging was classified in accordance with the 2009 International Federation of Gynaecology and Obstetrics (FIGO) classification. 14 Tumor grade and histological classification were assigned based on the 2003 WHO classification of tumor. 3 Pathogenetic subtype of endometrial cancer were identified based on patients' clinical manifestation, tumor features, and molecular alterations. 15 Lipid profiles of controls were recorded based on their medical work‐up reports. Statistical analyses were performed using SPSS software, version 20.0 and GraphPad Prism 7 ( http://www.graphpad.com/scientifc-software/prism/ ). Categorical data were analyzed with Pearson Chi‐squared tests. The Mann‐Whitney U tests were utilized to evaluate the differences in quantitative data between two groups. The Kruskal‐Wallis tests were used to appraise the associations of TG/HDL‐c ratio with tumor stage, tumor grade, and histological classification. Partial correlation tests with adjustment for confounding factors were used to assess the correlations of TG/HDL‐c ratio with tumor stage, tumor grade, and CA‐125. The receiver operating characteristic (ROC) curve analysis was used to determine the predictive significance of pretreatment TG/HDL‐c ratio for endometrial cancer. The maximum value of the Youden's index was used as a criterion for selecting the optimum cut‐off point for TG/HDL‐c ratio. Associations between high TG/HDL‐c ratio and endometrial cancer were studied by using multivariate logistic regression analysis. The odds ratios (ORs) and 95% confidence intervals (95%CIs) were adjusted for age at diagnosis, menopause age, parity, smoking, BMI, diabetes, hypertension, TC, and LDL‐c. P  < 0.05 was considered statistically significant (two‐tailed). This study was conducted in accordance with medical ethics of the Medical Ethical Review Committee of the First Affiliated Hospital of Guangxi Medical University.

Baseline characteristics of study subjects and the results of comparison of lipid profiles and TG/HDL‐c ratio between patients and noncancer controls were summarized in Table 1 . Control group consisted of 273 subjects with normal endometrium and 191 patients diagnosed with endometritis. Age at diagnosis and smoking history matched between patients and controls ( P  > 0.05). The proportion of overweight/obesity, hypertension, and diabetes in patient group was higher than in noncancer control group. Compared with controls, TG/HDL‐c ratio, TC, TG, and LDL‐c levels in endometrial cancer patients increased significantly whereas HDL‐c was remarkably lower. Baseline characteristics of study subjects Quantitative data are presented as median (interquartile range). BMI, body mass index; CA‐125, carbohydrate antigen 125; FIGO, International Federation of Gynaecology and Obstetrics; HDL‐c, high density lipoprotein cholesterol; LDL‐c, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; TG/HDL‐c ratio, triglycerides‐to‐high density lipoprotein cholesterol ratio. The P value was calculated by Mann‐Whitney U tests. The P value was calculated by Pearson chi‐squared test. Stratified subjects by overweight/obesity, hypertension, and diabetes, we further compared TG/HDL‐c ratio between endometrial cancer patients and noncancer controls (Figure 1 ). And it was found that significant increases in TG/HDL‐c ratio in endometrial cancer patients remained no matter subjects were diagnosed with overweight/obesity or diabetes or not. However, no significant difference in TG/HDL‐c ratio was observed between controls and cases with hypertension ( P  = 0.052). In contrast, for those subjects without hypertension, TG/HDL‐c ratio was higher in endometrial cancer group than in noncancer control group. Comparisons of TG/HDL‐c ratio between subjects stratified by overweight/obesity, diabetes, and hypertension. TG/HDL‐c ratio, triglycerides‐to‐high density lipoprotein cholesterol ratio We further explored the potential relationship of TG/HDL‐c ratio with tumor features. The data showed that pretreatment TG/HDL‐c ratio increased significantly with advanced tumor stage. Interestingly, TG/HDL‐c ratio of type I endometrial cancer patients was higher than those with type II endometrial cancer (Table 2 ). In contrast, there were no significant difference in TG/HDL‐c ratio among tumor grades and histological classifications. Correlation analyses showed that there were positive associations between pretreatment TG/HDL‐c ratio with tumor stage, tumor grade and CA‐125. However, only the positive association of TG/HDL‐c ratio with tumor stage remained after controlling variables including age at diagnosis, smoking history, BMI, diabetes, hypertension, TC, and LDL‐c (Table 3 ). The relationship of TG/HDL‐c ratio with clinicopathological characteristics in 167 endometrial cancer patients Quantitative data are presented as median (interquartile range). FIGO, International Federation of Gynaecology and Obstetrics; TG/HDL‐c ratio, triglycerides‐to‐high density lipoprotein cholesterol ratio. The P value was calculated by Kruskal‐Wallis tests. The P value was calculated by Mann‐Whitney U tests. Correlations between TG/HDL‐c ratio and tumor features BMI, body mass index; CA‐125, carbohydrate antigen 125; FIGO, International Federation of Gynaecology and Obstetrics; TG/HDL‐c ratio, triglycerides‐to‐high density lipoprotein cholesterol ratio; LDL‐c, low density lipoprotein cholesterol; TC, total cholesterol. Correlation coefficient was Spearman's rank‐order coefficient. Partial correlation controlled age at diagnosis, menopause age, parity, smoking, BMI, diabetes, hypertension, TC, and LDL‐c. ROC curves analysis yielded the cut‐off values of 1.52 for TG/HDL‐c ratio to distinguish patients with cancer from noncancer subjects (area under the curve, 0.689; sensitivity, 51.5%; specificity, 84.1%; Figure 2 ). ROC curve of pretreatment TG/HDL‐c ratio in predicting endometrial cancer. ROC, receiver operating characteristic; TG/HDL‐c ratio, triglycerides‐to‐high density lipoprotein cholesterol ratio After adjusting for age at diagnosis, menopause age, parity, smoking, BMI, diabetes, hypertension, TC, and LDL‐c, the independent association between high TG/HDL‐c ratio (≥1.52) and endometrial cancer (OR, 4.123; 95%CI, 2.633‐6.457; P < 0.001) persisted (Table 4 ). Postmenopausal patients with TG/HDL‐c ratio ≥ 1.52 were 4.123 times more likely to be diagnosed with endometrial cancer than those with TG/HDL‐c ratio < 1.52. Association between high TG/HDL‐c ratio and endometrial cancer BMI, body mass index; CI, confidence interval; LDL‐c, low density lipoprotein cholesterol; OR, odds ratio; TC, total cholesterol; TG/HDL‐c ratio, triglycerides‐to‐high density lipoprotein cholesterol ratio. Unadjusted confounding factors. Adjusted for age at diagnosis, menopause age, parity, smoking, BMI, diabetes, hypertension, TC, and LDL‐c.

In this hospital‐based study involving 631 postmenopausal women, we evaluated the association between TG/HDL‐c ratio and endometrial cancer in postmenopausal women by comparing TG/HDL‐c ratio between cases and controls, assessing the correlations of TG/HDL‐c ratio with tumor features, and investigating the predictive significance of pretreatment efficacy of TG/HDL‐c ratio. The findings showed that TG/HDL‐c ratio increased significantly in postmenopausal women with endometrial cancer compared with noncancer controls. Further, TG/HDL‐c ratio was correlated with tumor characteristics of endometrial cancer, such as FIGO stage, pathogenetic type. Our data suggest that TG/HDL‐c ratio might be a potential marker for disease progression in postmenopausal patients with endometrial cancer after adjustment for confounding factors. Most of the current studies on TG/HDL‐c ratio pays attention to chronic kidney disease, cardiovascular disease, and insulin resistance and its related disorders. 16 , 17 , 18 Thus far, only one study involved the association of TG/HDL‐c ratio with endometrial cancer. 12 In this study, the authors found that TG/HDL‐c ratio were positively associated with endometrial cancer risk. But the authors had not assessed the association of TG/HDL‐c ratio with endometrial cancer in postmenopausal women. As components of metabolic syndrome, increased TG and decreased HDL‐c had been investigated, separately, as potential risk factors for endometrial cancer. Researches into TG in women with endometrial cancer indicated that hypertriglyceridemia was more common in cancer patients than in controls and that increased TG was associated with endometrial cancer risk. 10 Two recent systematic studies review summarized that high TG levels were associated with increased risk of endometrial cancer. 19 , 20 In contrast to TG, HDL‐c was lower in endometrial cancer than in nonendometrial cancer subjects. 9 , 11 Similarly, it had been reported that serum HDL‐c levels were lower in breast cancer patients and that plasma HDL‐c may be a protective factor against breast carcinogenesis among postmenopausal women. 21 Taken together, as a derived ratio based on TG and HDL‐c, TG/HDL‐c ratio takes both changes of TG and HDL‐c into account and can be a useful marker in endometrial cancer managing. Positive correlation between TG/HDL‐c ratio and tumor stage of the endometrial cancer found in the present study indicated that this ratio elevated in patients with more advanced or aggressive disease evidenced by increased tumor stage. Therefore, the patients with high TG/HDL‐c ratio may represent a high‐risk patient population. While in correlation analysis, the positive association of TG/HDL‐c ratio with tumor grade and CA125 in endometrial cancer was abolished. There is no direct literature addressing the association of TG/HDL‐c ratio with tumor stage. A case‐control study with 16 323 endometrial cancer cases and 100 751 controls by Trabert et al. showed that high TG was positively associated with tumor grade in endometrial carcinoma. 10 Therefore, further researches need to be conducted to confirm our observations. We also found that after adjustment for nine confounding factors, the strong association of TG/HDL‐c ratio with endometrial cancer persisted. Moreover, TG/HDL‐c ratio of type I endometrial cancer patients was higher than those with type II endometrial cancer. The direct explanation for the link between TG/HDL‐c ratio and endometrial cancer has not yet been reported but it can be explored from TG and HDL‐c perspectives. TG is major component of very‐low‐density lipoprotein and chylomicrons. It is also primary fat stored in adipose tissue and high levels of TG may cause fat accumulation in adipocytes, resulting in increasing in cell size and number. 22 The adipose tissue provides an important source of endogenous estrogen in postmenopausal women because it is able to generate aromatase which can convert the androstenedione to estrogen. 23 And then estrogen in the absence of progestin in postmenopausal women has a direct mitogenic effect on endometrial cells, resulting in increased endometrial cancer risk in these women. 24 Type I endometrial cancer is estrogen‐dependent and it is the most frequent subtype of endometrial cancer. 25 Therefore, the finding of our study that TG/HDL‐c ratio of type I endometrial cancer patients was higher than those with type II endometrial cancer may support the association of high levels of unopposed estrogen and endometrial cancer. Another possible explanation for association between TG and endometrial cancer may involve in peroxisome proliferator‐activated receptors (PPARs), one of nuclear receptors. They can be activated by polyunsaturated fatty acids and have been found to modulate lipid levels. 26 PPAR‐γ, one form of PPAR, may be down‐regulated by increased TG levels and this down regulation supports endometrial cancer. 27 Seth et al. speculated in their study that PPAR‐α, another form of PPAR, may also be activated by TG via fatty acids, leading to upregulation of proteins such as cyclin dependent kinase 1 and cyclin dependent kinase 4，which are over‐expressed in cancer cells. 12 HDL particles transport fat molecules out of artery walls, reduce macrophage accumulation and therefore are sometimes referred to as “good cholesterol”. 28 They carry many lipid and protein species and some of which help to inhibit oxidation, inflammation, activation of the endothelium. 29 This suggested that insufficient HDL in endometrial cancer may increase exposure to oxidation and inflammation which play an important role in cancer development. In this study, several limitations need to be considered. The retrospective design of this study would inevitably introduce some bias into the data analysis. Since serum lipid profile was obtained retrospectively based on medical records, it is difficult to validate and repeat test for pretreatment lipid profile and its derived parameters, which may be a source of uncertainty. Another potential problem is that the scope of our study was restricted to postmenopausal women. The absence of information for menopausal hormone therapy use, fasting blood glucose and waist circumference is another limitation of the present study. In summary, although a large‐scale prospective study with repetitive measurement and verification for lipid profiles is still required, TG/HDL‐c ratio was associated with advanced tumor stage and pathogenetic type in endometrial cancer patients. Therefore, this readily available and reproducible marker shows great promise as a new prognostic marker for progression of endometrial cancer.

Endometrial cancer is a malignant disease forming in the tissues of the endometrium. It is the most common invasive cancer of the female reproductive system and accounts for the substantial majority of tumors affecting uterine corpus. 1 In 2018, it is estimated that there will be 63 230 new cases of uterine cancer and an estimated 11 350 people will die of this disease in United States. 2 Endometrial cancer is diagnosed most often in postmenopausal women. 1 Risk factors of endometrial cancer include obesity, excessive estrogen exposure, being overweight, and diabetes. 3 , 4 According to International Diabetes Federation and World Health Organization (WHO), raised triglycerides (TG) and reduced high density lipoprotein cholesterol (HDL‐c) are components of metabolic syndrome. The syndrome had emerged as a non‐negligible health problem in several countries and was found to be a risk factor of endometrial cancer. 5 , 6 Some attentions have been paid on the potential associations of TG and HDL‐c with cancers, such as breast and prostate cancer. 7 , 8 Several researchers had reported that TG level elevated in endometrial cancer patients than in endometriosis as well as healthy populations. 9 , 10 In contrast, patients with endometrial cancer were more likely to have low HDL‐c levels. 11 To date, only one article has addressed the association of triglycerides‐to‐high density lipoprotein cholesterol ratio (TG/HDL‐c ratio) with endometrial cancer in females aged 25+. 12 Given opposite alteration of TG and HDL‐c was found in metabolic syndrome which was identified to be a risk factor for endometrial cancer, TG/HDL‐c ratio may be a useful biological indicator in managing endometrial cancer. Furthermore, association between pretreatment TG/HDL‐c ratio and endometrial cancer in postmenopausal women has not been reported. Therefore, we compared the difference in TG/HDL‐c ratio between endometrial cancer patients and noncancer controls and evaluated the correlation of TG/HDL‐c ratio with progress of the disease in postmenopausal women.

All authors have no conflict of interest to report.