Correlation between lipid metabolism and endometriosis: a meta-analysis

To analyze and evaluate the correlation between different lipid metabolism levels and endometriosis. The literatures on lipid metabolism and endometriosis published in databases were searched and collected. The search was conducted up to December 2023. The meta-analysis was conducted using Review Manager 5.4.1 software, with odds ratios (ORs) or standardized mean difference (SMD), confidence intervals (CIs), and heterogeneity (I2) being calculated. The literature bias was evaluated by drawing funnel plot. Five hundred and eighty-four literatures were retrieved, and finally, 7 literatures were included in this study. Meta-analysis showed that the level of total cholesterol (TC) in endometriosis groups was higher than control group [SMD = 1.70, 95%CI (0.60-2.80), p = 0.003], while triglyceride (TG) [SMD=-0.24, 95%CI (-0.68-0.21), p = 0.300], low-density lipoprotein (LDL) [SMD = 0.22, 95%CI (-0.34 − 0.78), p = 0.440] and high-density lipoprotein (HDL) [SMD = 0.06, 95%CI (-0.14 − 0.25), p = 0.550] was not statistically significant. Sensitivity analysis indicated that the combined effect size results were stable and reliable [SMD = 1.70, 95%CI (0.60-2.80), p = 0.030]. Funnel plot results showed publication bias. Patients with endometriosis have abnormal blood lipid level, and higher TC level may be a risk factor for endometriosis. The impact of blood lipid metabolism on endometriosis may provide new insights into the pathogenesis and treatment prognosis of endometriosis.

Endometriosis is defined as a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process [Citation1], affects about 5–10% of women [Citation2]. It is often accompanied by pelvic pain, infertility and other symptoms [Citation3–5]. The pathogenesis of endometriosis has not yet been clarified. Although several theories exist to explain the cause of endometriosis, the most widely accepted is Sampson’s retrograde menstruation theory [Citation6,Citation7]. Recently, many studies have shown that oxidative stress and inflammation may be related to the occurrence and progression of endometriosis[Citation8,Citation9]. Gonadotropin-releasing hormone agonists (GnRH-a), contraceptives and progesterone have been routine drugs used in the adjuvant treatment of endometriosis [Citation10,Citation11]. Currently, it has been widely believed that the low estrogen state caused by medicine may lead to lipid metabolism disorders [Citation12–15]. However, there is still controversy about whether serum endocrine hormone levels in women with endometriosis differ from those of normal women [Citation16–19]. In addition, the conclusion of these reports is inconsistent due to the discrepancy in time, region and sample size. Endometriosis is a chronic estrogen-dependent disease [Citation20]. There is a strong association between cholesterol as a precursor for estrogen synthesis and the development of endometriosis. Apolipoprotein B (ApoB) is the major protein of low-density lipoprotein (LDL), which is involved in the formation of atherosclerosis, and oxidized LDL causes endothelial cell damage, which promotes the migration of leukocytes and macrophages [Citation21]. The release of monocytes with cytokines, platelet aggregation, and chemokines facilitates the internalization of oxidized LDL particles and the migration of genetically modified cells from the media to the intimal layer of the arteries, resulting in the formation of atherosclerotic plaques [Citation22]. Thus, elevated LDL levels may be a stimulus for the cell proliferation process, which may also occur in endometriosis. Whether there is a correlation between lipid metabolism levels and endometriosis needs to be confirmed by further large-scale clinical studies. Therefore, the meta-analysis method is applied in this paper and evaluate the correlation between different lipid metabolism levels and endometriosis, providing evidence-based basis for assessing the risk of developing endometriosis and confirming the diagnosis based on blood lipids.

This meta-analysis strictly followed the criteria outlined in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [Citation23]. A protocol was formulated and put into action prior to the commencement of the study.

sources and retrieval strategies A comprehensive search was conducted from the inception of the databases until December 2023, utilizing seven electronic sources, namely CNKI, Wanfang, Wipu Chinese science and technology journals, China Biomedical Database, Pubmed, Web of science, and Cochrane library. The Chinese search terms were “lipids”, “total cholesterol”, “triglycerides”, “low density lipoprotein”, “high density lipoprotein”, and “endometriosis”. “Lipids”, “total cholesterol”, “triglycerides”, “low density lipoprotein”, “high density lipoprotein”, and “endometriosis” are used as English search keywords, which are connected with “AND”. Inclusion and exclusion criteria Eligible articles were selected based on the following inclusion criteria: (1) The research content of the article was about the relationship between blood lipid level and endometriosis; (2) The test group was pathologically diagnosed as endometriosis after laparotomy or laparoscopic surgery and the control group was non-endometriosis patients or healthy women; (3) The outcome indexes were total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels; (5) If part of the data from the same author was repeatedly reported, the study with the latest publication was selected. The exclusion criteria comprised of five categories: (1) duplicate, irrelevant studies and review literatures; (2) non-randomized controlled trials; (3) animal study; (4) inconsistent outcome indicators; (5) incomplete data. Literature screening and data extraction Two members of the research group screened independently according to the eligibility criteria. First, the title and abstract were reviewed, and the full text was reviewed if necessary. In the process, third-party experts were consulted if there was any disagreement. They resolved disagreements to reduce the possible biases. The literature that met the inclusion criteria was extracted the content research including first author, year of publication, design type, total sample size, and outcome indicators according to the literature feature table established in advance. Literature quality evaluation The modified Jadad scale was used to measure literature quality. The total score of this scale is 7 points, including whether the study is random, whether it is double-blind, and whether the withdrawal and follow-up are handled. 0 points are not included in the study, 1 to 3 points are included in the study and evaluated as low-quality studies, and 4 to 7 points are included in the study and evaluated as high-quality studies. Statistical methods NoteExpress 3.2 and Review Manager 5.4.1 software were used for literature management and statistical analysis. Q test and I2 test were used to assess the heterogeneity across studies. When p > 0.10 or I2<50% indicated homogeneity, the fixed effect model (FEM) was used for analysis. Conversely, if homogeneity was not observed, random effect model (REM) was utilized. The odds ratio (OR) and 95% confidence interval (CI) were used to describe the results, and the forest map was drawn. At the same time, the literature sensitivity analysis was done, and the publication bias was evaluated by funnel plot. Test level α = 0.05 (bilateral).

Literature search results Five hundred and eighty-four articles were retrieved, and the duplicated literatures were deleted. Then according to the inclusion and exclusion criteria a total of 7 literatures were finally included. The Lu BC paper had two separate study cohorts used in this analysis. The literature screening process was shown in . Basic characteristics and quality evaluation of literature The baseline data mainly included gender, age, course of disease, treatment plan. The baseline data were described in detail in the 7 literatures included. The quality of the 7 included studies was evaluated by the modified Jadad scale. The basic characteristics of literature and quality evaluation was in .

of meta-analysis Relationship between TC and endometriosis A total of 7 literatures have compared the relationship between TC and endometriosis. There were 755 cases in the endometriosis group and 909 cases in the control group. Heterogeneity test was carried out on the included studies, and the results showed that p < 0.00001 and I2 = 99%, indicating that there was statistical heterogeneity among different literature studies, so REM was used for the combined study of literature data. The Meta-analysis indicated that compared with control group, the TC level in the endometriosis group was higher [SMD = 1.70, 95%CI (0.60−2.80), p = 0.003], as shown in . Relationship between TG and endometriosis A total of 7 literatures compared the relationship between TG and endometriosis. There were 755 cases in the endometriosis group and 734 cases in the control group. Heterogeneity test was carried out on the included literatures, and the results showed that p < 0.00001 and I2=98%, indicating that there was statistical heterogeneity among different literature studies, so REM was used for the combined study of literature data. The results of meta-analysis showed that SMD=−0.24, 95%CI (−0.68 − 0.21), p = 0.30, as shown in . Relationship between LDL and endometriosis A total of 7 articles have compared the relationship between LDL and endometriosis. There were 572 cases in the endometriosis group and 539 cases in the control group. Heterogeneity test was performed on the included literatures, and the results showed that p < 0.00001 and I2=96%, indicating statistical heterogeneity among different literature studies. Therefore, REM was used for the combined study of literature data. The results of meta-analysis showed that SMD = 0.22, 95%CI (−0.34 − 0.78), p = 0.44, as shown in . Relationship between HDL and endometriosis A total of 7 articles have compared the relationship between HDL and endometriosis. There were 572 cases in the endometriosis group and 539 cases in the control group. Heterogeneity test was performed on the included literatures, and the results showed that p < 0.00001 and I2=96%, indicating statistical heterogeneity among different literature studies. Therefore, REM was used for the combined study of literature data. The results of meta-analysis showed that SMD = 0.06, 95%CI (-0.14 − 0.25), p = 0.55, as shown in . Sensitivity analysis The sensitivity of total cholesterol as an outcome index was analyzed. After deleting the literature with the largest proportion weight and recombining the literature effect size, SMD (95%CI) was 1.70 (0.60-2.80), p = 0.03. This indicated that the results of this study were credible, as shown in .

Endometriosis is a common chronic gynecological disease dependent on estrogen. Drugs (gonadotropin-releasing hormones) are used to treat patients with endometriosis. Similarly, pregnrienone or danazol after induction of a hypoestrogenic kinin state can lead to the increase of blood lipid level and the decrease of bone density in patients [Citation31–33]. Our study conducted a meta-analysis of the literature on the relationship between lipid levels and endometriosis published in Chinese language and international journals to clarify the relationship between lipid levels and endometriosis. Our meta-analysis showed that the level of TC in endometriosis groups was higher than that in control group. In recent years, many scholars have studied the correlation between endometriosis and lipid indexes, but the results are quite different [Citation34,Citation35]. Studies have shown that drug treatment can lead to significant imbalance of lipid metabolism in patients with endometriosis [Citation36]. On the contrary, it has also been reported that patients with endometriosis have abnormal changes in blood lipid metabolism before drug and hormone therapy [Citation37,Citation38]. And it is believed that oxidation and inflammation in the body of patients with endometriosis can affect their lipid metabolism [Citation39]. Lipids can play a role in tissue reconstruction and maintain homeostasis in the body during inflammation [Citation40]. Apolipoprotein A (ApoA) has anti-inflammatory properties and can also serve as a stage protein involved in wound healing [Citation41,Citation42]. Similarly, ApoB is a component of atherosclerotic lipoproteins, such as very low-density lipoprotein (VLDL) and LDL, both of which are involved in cholesterol transport [Citation43]. As a chronic inflammatory disease, the onset and recovery stages of endometriosis may be closely related to the status of these metabolites. Previous studies have shown that other biomarkers such as ferritin and iron levels in the peritoneal fluid were significantly higher in the endometriosis group [Citation44]. It was shown that amino acids, including threonic acid and 3-hydroxybutyric acid, succinate, citrate, lactate, acetone, 3-hydroxybutyrate, acylcarnitines and sphingomyelins potential metabolomic biomarkers could be used for the diagnosis of endometriosis [Citation45]. The disturbance of metabolite levels reflects the disruption of metabolic pathways during the existence of diseases. Our study certainly has some limitations. Firstly, bias was found in the meta-analysis, which may be related to the long-time span of the literature included in this study and the insufficient sample size. In addition, only Chinese and English databases were used for the search, and the sampling bias caused by the selective inclusion of literature in each database was also one of the reasons and directions for the bias in the results of this study. Thirdly, due to not all studies providing raw data, we are unable to calculate the aggregated data of cohorts. In summary, patients with endometriosis have abnormal blood lipid levels, and high TC levels may be a risk factor for endometriosis. The results of this study indicated a close relationship between lipid metabolism indicators and the onset of endometriosis, and it is possible that lipid metabolism may also undergo corresponding changes as the disease progresses. The impact of blood lipid metabolism on endometriosis may provide new insights into the pathogenesis and treatment prognosis of endometriosis. Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xuanru Yang, Xiaoou Xue and Yuying Zhu. The first draft of the manuscript was written by Xuanru Yang and Zhihang Zhang commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgments The authors are grateful to all participants in the present study. Disclosure statement No potential conflict of interest was reported by the author(s). Data availability statement The data involved in the present study can be provided under reasonable request. Additional information Funding

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