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Risk of gynaecologic cancers in women with metabolic syndrome: A systematic review & meta-analysis
For correspondence: Dr. Susan Idicula-Thomas, Department of Biomedical Informatics Center, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai 400 012, Maharashtra, India e-mail: thomass@nirrch.res.in
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Received: ,
Accepted: ,
Abstract
Background & objectives
Metabolic syndrome may be associated with the risk of gynaecological cancers. This systematic review aims to evaluate the risk of gynaecological cancers among women with metabolic syndrome.
Methods
Studies published in English using a search strategy across PubMed, Google Scholar, and Scopus were identified from the earliest available indexing of the respective databases up to September 12-14, 2023. After removing duplicates and conducting a detailed screening by two independent reviewers, 25 studies were identified. Critical appraisal was conducted using JBI checklists for case-control and cohort studies and AXIS checklist for cross-sectional studies. Data extraction was conducted for information pertaining to study design, participant demographics, definition of metabolic syndrome, reported summary measures and type of gynaecological cancer.
Results
Random effects models were employed separately for each study design, reported summary measures and the type of gynaecological cancers. In case-control, cross-sectional, and cohort studies, presence of metabolic syndrome was associated with uterine/endometrial cancer [odds ratio (OR) 1.99, P<0.01, OR 2.64, P<0.01, hazard ratio (HR) 1.45, P=0.04], respectively. Case-control and cohort studies in ovarian cancer suggested association (OR 3.44, P<0.01, OR 1.02, P=0.79, and HR 1.02, P=0.80). Cohort studies in cervical cancer patients, yielded HR 1.26, P=0.96 and adjusted HR 1.27, P=0.83. The critical appraisal of the included studies was high. GRADE reported low-quality evidence for cervical, uterine/endometrial, and ovarian cancer.
Interpretation & conclusions
Women with metabolic syndrome are associated with increased risk of gynaecological cancers regardless of study design, type of gynaecological cancer and definitions of metabolic syndrome.
Keywords
Cervical cancer
endometrial cancer
metabolic syndrome
ovarian cancer
risk
vaginal cancer
Metabolic syndrome is a multifactorial disorder comprising of obesity, hyperglycaemia, hypertension, high triglycerides (TG) and low high-density lipoprotein cholesterol (HDLc)1. Various organisations have defined the syndrome through different thresholds and criteria for these components2. Despite the dissimilarities, the definitions converge on the simultaneous occurrence of three out of five components [adult treatment panel III (ATP III), harmonised definition (HD) with either obesity (International Diabetes Federation, IDF) or insulin resistance (World Health Organization, WHO)] as a mandatory component for diagnosis of metabolic syndrome2. The co-occurrence of these metabolic abnormalities increases the risk of cardiovascular diseases, type 2 diabetes and cancers.
Several clinical and epidemiological studies have investigated the risk of gynaecologic cancers and metabolic syndrome worldwide. These studies mainly report inconclusive findings which may be attributed to varying populations, sample size, type of definitions used for the diagnosis of metabolic syndrome and statistical adjustments. For instance, a cross-sectional study in Malaysia, investigating the association of metabolic syndrome (IDF definition) with endometrial cancer, reported a high odds ratio (OR) of 3.423. In contrast, another study involving an African population in Brazil reported a low OR 0.93, implying that the odds of endometrial cancer are higher in the non-metabolic syndrome exposed group4. A study utilising the expansive European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, comprising over half a million participants across ten countries in Western Europe, calculated odds ratios using two distinct metabolic syndrome definitions, namely the ATP and IDF definitions. The risk of EC was 2.1-fold higher using the ATP definition as compared to 1.7-fold increased risk with IDF definition of metabolic syndrome5. In another single hospital-based study in Canada, the risk of endometrial cancer was associated with the IDF definition compared to ATP and HD6. There is a need to systematically assess the risks of gynaecological cancers in women with metabolic syndrome, duly considering factors such as study design, sample size, disease definitions, and ethnicity that can influence the study outcome.
A systematic review by Esposito et al7 included five studies on metabolic syndrome and the incidence of endometrial cancer and ovarian cancer, along with other organ-specific cancers7. The review did not include other gynaecological cancers, such as cervical cancer, probably due to the limited availability of clinical reports at that time. Over the last decade, several publications have reported an association between gynaecological cancers and metabolic syndrome, presenting an opportunity to synthesise research findings through systematic review and meta-analysis8-10. We did not identify any registered protocols or in-progress reviews on this topic in Epistemonikos, PROSPERO, PubMed (MEDLINE), JBI Evidence Synthesis, and Cochrane Database of Systematic Reviews. The objective of this systematic review is to present current evidence of the risk of gynaecological cancers among women with metabolic syndrome.
Materials & Methods
This systematic review was registered with the International Prospective Registry of Systematic Reviews (PROSPERO: CRD 42022333645), and conducted following the JBI Methodology for Systematic Reviews of Etiology and Risk and Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) guidelines11,12. The review process and analysis are reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines13.
Review question
What is the association of metabolic syndrome among women with gynaecological cancers?
Inclusion criteria
This review included studies on women aged ≥18 diagnosed with any three of the five components of metabolic syndrome, such as obesity, hyperglycaemia, hypertension, high triglycerides (TG) and low high-density-lipoprotein (HDL). Studies must report the risk of gynaecological cancers and/or equivalent estimates along with 95 per cent confidence interval (CI) to be considered in the review.
Sarcomas are a type of cancer that originates in the connective tissues, muscles, or bones, whereas cancers in these locations are mostly carcinomas, which arise from the epithelial cells lining the organs14. Sarcomas are rare in these areas, representing a small percentage of all cancers in the female reproductive system. Hence, studies reporting sarcomas were excluded.
Exposure of interest
Women with metabolic syndrome [diagnosed based on any of the standard definitions established by international consensus such as World Health Organization (WHO), International Diabetes Federation (IDF), National Cholesterol Education Program’s Adult Treatment Panel (NCEP-ATP III), American Heart Association, Japanese Society of Internal Medicine, Chinese Diabetes Society (CDS)] and gynaecological cancers such as ovarian cancer, fallopian tube cancer, uterine/endometrial cancer, vaginal cancer, cervical cancer, and vulvar cancer.
Outcomes
This review presented the risk for the presence of gynaecological cancers in terms of odds ratio, relative risk, hazard ratio, and standardised incidence ratio (SIR) in women with metabolic syndrome.
Types of studies
Studies with cohort, cross-sectional and case-control study designs were included.
Search strategy
Month and year of the study period
Research articles published in PubMed (MEDLINE), Scopus, and Google Scholar from their earliest available indexing of the respective databases up to September 2023 were searched. Query was performed without specifying a start date filter. Details of the search strategy across these databases are available in Supplementary material 1. Included articles and systematic reviews on metabolic syndrome and gynaecological cancers were referred for additional articles through their citations (forward referencing) and references (backward referencing).
Study screening
After an initial pilot, two independent reviewers (IK and IA) screened articles for inclusion/exclusion, and a third reviewer resolved the conflicts (DJ and KP). All original only English language articles were included. Studies wherein the participants had metabolic syndrome along with other comorbidities or previous history of cancers, were excluded.
Data extraction
Data related to study design, study site, ethnicity, recruitment strategy, number of participants and reported risk with 95 per cent CI were extracted by two independent reviewers (IK and IA) from the selected articles as per JBI methodology for systematic reviews of aetiology and risk11. Data extraction was conducted by two reviewers (IK and IA) until inter rate reliability (k>0.60) was established. Risk estimates such as odds ratio, relative risk, hazards ratio, standardised incidence ratio, were extracted along with adjustments for age, education, and smoking.
Critical appraisal
The critical appraisal of the selected articles was assessed as per the JBI checklists for case-control and cohort and appraisal tool for cross-sectional studies (AXIS) checklist11,15.
Data synthesis
Included studies were grouped based on study design, reported summary measure [OR, relative risk (RR), hazard ratio (HR)], and type of gynaecological cancers. Within each group, the risk estimates were pooled using the metagen (https://rdrr.io/cran/meta/man/metagen.html) function of meta R package. The estimation of variance within each group was calculated using DerSimonian-Laird estimator, and confidence intervals were determined based on a classic random effects model. Subgroup analysis was conducted based on the type of metabolic syndrome definition. Additionally, sensitivity analysis was carried out utilising the leave-one-out method implemented in the metainf (https://rdrr.io/cran/meta/man/metainf.html) function of the meta R package. As all data for meta-analysis from the included studies were available, the risk of bias due to missing results was not assessed.
Certainty of evidence
Two investigators (DJ and PK) conducted separate assessments of the certainty of evidence for each result. Any differences were settled by a third reviewer (SIT/DJ). The certainty of evidence was assessed using the grading of recommendations assessment, development and evaluation (GRADE) methodology, which categorises evidence into four degrees of certainty: very low, low, moderate, and high12.
Results
The initial query yielded 1,590 articles. After excluding 506 duplicate studies, 1,084 titles/abstracts were screened. After excluding 25 non-English and 194 non-research articles at the title/abstract level, 862 studies were screened using full texts, and 10 studies were included. 13,732 articles were retrieved through forward and backward referencing of the included articles (n=10), and systematic reviews and meta-analysis reports (n=194), resulting in 15 included studies. A total of 25 studies3-6,8-10,16-33 (4 cross-sectional, 8 case-control, and 13 cohort studies) were included for further analysis (Fig. 1).
- PRISMA flow diagram illustrating the screening process adopted for the systematic review.
The cross-sectional studies reported crude/unadjusted ORs for endometrial cancer and metabolic syndrome association in participants from Brazil, Turkey, Malaysia and China3,4,28,32. Two out of the eight case-control studies from the USA and China reported adjusted ORs of the association of metabolic syndrome with ovarian cancer17,24, five studies from Europe, Canada, Italy, and the USA reported age-adjusted ORs for metabolic syndrome and endometrial cancer5,6,10,19,29, and one study from the USA reported an OR for risk of cervical cancer33. Nine cohort studies from Korea, Italy, the USA and Europe reported the association between metabolic syndrome and uterine/endometrial cancer9,16,18,20-22,26,27,30, six studies from Europe, Korea and Italy focused on ovarian cancer8,16,18,23,26,27, and six studies from Europe, Korea and Italy on cervical cancer8,16,18,25-27. Additionally, one cohort study from Europe examined the risk of rare gynaecological cancers, including vulvar and vaginal cancer, in women with metabolic syndrome31. Table provides the characteristics of the included studies.
Association of uterine/endometrial cancer with metabolic syndrome
Sixteen studies, comprising five case-control, four cross-sectional and nine cohort designs, reported the association of uterine/endometrial cancer with metabolic syndrome. All cross-sectional studies reported ORs, and the case-control studies reported ORs and age, diagnosis time-adjusted ORs. In case of cohort studies, OR, HR, or RR summary measures were used. Five cohort studies, with a median follow up of nine years reported both ORs and adjusted ORs, but the crude OR lacked CI; therefore, adjusted ORs were used for meta-analyses5,6,10,19,29. Ozdemir et al32 used a cross-sectional study design and reported an OR, but the upper CI was less than the lower, hence it was recalculated, and the author was contacted for corrections. Among the cohort studies, Arthur et al20 reported an age-adjusted an (OR 2.22 (95% CI:1.67-3.09), Bjorge et al21 reported RR of 1.37 (95% CI: 1.28 -1.46), Ko et al26 reported an HR of 1.82 (95% CI: 0.96- 3.48), Russo et al27 reported an SIR 156 (95% CI: 95-241), Stocks et al18 reported an adjusted RR 1.14 (95% CI: 0.95-1.38) individually for endometrium and other parts of uterus, and Stocks et al16 reported an HR 1.56 (95% CI: 1.42-1.7). These studies were excluded from the meta-analysis, as there was only one study in each summary measure type. Bjorge et al21 had reported risk of incidence of endometrial cancer and risk of fatal uterine corpus cancer, only the reported risk of endometrial cancer is included in the study. The study by Lopez-Jimenez et al10, reported OR but did not report the CI therefore it was not included in the meta-analysis.
Meta-analyses produced an overall OR of 1.99 (95% CI: 1.61-2.45), P<0.01, 2.64 (95% CI: 1.26-5.52), P<0.01, and an HR of 1.45 (95% CI: 1.35-1.56), P=0.043 for case-control, cross-sectional, and cohort studies, respectively (Fig. 2A). Heterogeneity, assessed through random-effects models, was observed as 93 per cent with P<0.01, 77 per cent with P<0.01, and 63 per cent with P< 0.0001 in case-control, cross-sectional, and cohort studies, respectively (Fig. 2A).
- Meta-analysis of association of metabolic syndrome with (A) uterine/endometrial cancer, and (B) ovarian cancer.
In case-control studies, when stratified by metabolic syndrome definition, the risk was highest in studies with the IDF definition. The pooled OR was 2.84 (95% CI: 2.26-2.45) and 2.10 (95% CI: 1.73-2.55), P= 0.06, compared to studies with the HD definition: 1.56 (95% CI: 1.23-1.98), P= 0.77; and ATP definition: 1.91(95% CI: 1.25-2.91), P<0.01 (Supplementary Fig. 1).
Critical appraisal revealed high-quality evidence for the association between metabolic syndrome and endometrial cancer across case-control and cohort studies. For cross-sectional studies, except Tong et al28 all other studies did not have justified sample sizes. Apart from this, the study aim, design, participant selection process, analysis and data reporting were of high quality (Supplementary material 2).
Association of ovarian cancer with metabolic syndrome
In the case of ovarian cancer, there were two case-control studies with adjusted ORs17,24, and four cohort studies with median follow up of 11 years- two reported adjusted ORs23,26, and two reported HR scores16,26 (Table)3-6,8-10,16-31. Among cohort studies, Cao et al8 reported an adjusted HR of 1.06 (CI: 0.84-1.33), and Russo et al27 reported a standardised incidence ratio (SIR) of 106(CI:51-194). These studies were excluded in the meta-analysis, as only one study for each summary measure was available. Following the meta-analysis of four studies, case-control studies yielded an overall OR of 3.44 (95% CI: 1.12-10.54), P<0.01; cohort studies produced an OR of 1.02 (95% CI: 0.90-1.15), P= 0.79; and an HR of 1.02 (95% CI: 0.91-1.14), P=0.80 (Fig. 2B). Critical appraisal revealed high quality of evidence for the association of metabolic syndrome with ovarian cancer for case-control and cohort studies (Supplementary material 2).
| Type of cancer | Study design | Author, yr; country | Metabolic syndrome definition | Sample size | Results | Adjustments | Notes | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Non gynaecological cancers with metabolic syndrome | Non gynaecological cancers without metabolic syndrome | Gynaecological cancers with metabolic syndrome | Gynaecological cancers without metabolic syndrome | |||||||
| Uterine/Endometrial cancer | Case-Control |
Cust et al5, 2007; Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, & UK |
ATP | 122 | 102 | OR 2.12 (1.51-2.97) | Yes | |||
| IDF | 151 | 109 | OR 1.68 (1.23-2.31) | |||||||
|
Friedenreich et al6, 2011; Canada |
HD | 367 | 595 | 318 | 197 | OR 1.53 (1.17-2) | Yes | |||
| IDF | 336 | 626 | 298 | 217 | OR 2.58 (2.07-3.22) | |||||
| ATP | 417 | 545 | 335 | 180 | OR 2.45 (1.96-3.07) | |||||
| IDF(BMI) | 296 | 666 | 285 | 230 | OR 2.82 (2.26-3.58) | |||||
| Rosato et al 29 , 2011; Italy | HD | 40 | 444 | 47 | 260 | OR 1.67 (0.99 -2.81) | Yes | |||
| Trabert et al 19 , 2015; Maryland | ATP | 9930 | 90821 | 2505 | 13818 | OR 1.39 (1.32-1.47) | Yes | |||
| IDF | 2105 | 98646 | 753 | 15570 | OR 2.03 (1.84 - 2.23) | |||||
| Lopez-Jimenez T et al 10 , 2022; Spain | HD | 5555 | 15989 | 2011 | 3375 | OR 1.635 | No | CI is not provided, hence not included in meta-analysis | ||
| Cross-sectional | Fernandes et al 4 , 2022; Brazil | IDF | 191 | 122 | OR 0.93 (0.46-1.9) | No | ||||
| Shafiee et al 3 , 2020; Turkey | IDF(BMI) | 65 | 54 | OR 3.42 (1.12-10.46) | No | |||||
| Tong et al 28 , 2020; Malaysia | CDS | 89 | 384 | OR 2.86 (1.73 – 4.69) | No | |||||
| Ozdemir et al 32 , 2015; China | ATP | 39 | 105 | 37 | 17 | OR 5.53 (2.8-10.8) | No | Reported upper CI was 0.8; it was lower than lower CI hence recalculated & authors were contatcted | ||
| Cohort | Tran et al 9 , 2023; Korea (KNHIS) | ATP | 768 | 2568 | HR 1.58 (1.45-1.72) | Yes | ||||
| Jo et al 30 , 2022; Korea (KNHIS) | ATP | 735143 | 2083360 | 1703 | 3901 | HR 1.36 (1.28-1.45) | Yes | |||
| Park et al 22 , 2022; Korea (NHID) | ATP | 147825 | 4595064 | 1987 | 4810 | HR 1.44 (1.36 -1.52) | Yes | |||
| Arthur et al 20 , 2019; USA | ATP | 4927 | 7958 | 99 | 77 | OR 2.77 (1.67 – 3.09) | Yes | Only endometrial cancer cohort study with reported OR, hence excluded from meta-analysis | ||
| Bjorge et al 21 , 2010; Norway, Austria & Sweden (Me-Can) | HD | RR 1.37 (1.28 -1.46) | No | Excluded from meta-analysis as it was single endometrial cancer cohort study with reported unadjusted RR | ||||||
| Stocks et al 18 , 2009; Norway, Austria & Sweden (Me-Can) | WHO | RR 1.14 (0.95-1.38) | Yes | Adjusted for 1mmol/l glucose increment value, hence not included in meta-analysis | ||||||
| Stocks et al 16 , 2015; Norway, Austria & Sweden (Me-Can) | WHO | HR 1.56 (1.42 – 1.7) | No | Excluded from meta-analysis as it was single endometrial cancer cohort study with reported unadjusted HR | ||||||
| Russo et al 27 , 2008; Italy | ATP | 20 | SIR 156 (95-241) | No | Single study for uterine cancer with reported SIR, hence no meta-analyis could be performed | |||||
| Bjorge et al 21 , 2010; Norway, Austria & Sweden (Me-Can) | HD | RR (1.56-1.32) | No | The uterine cancer reported in the study is not for incidence of the cancer, hence not merged with other risk reports | ||||||
| Ko et al 26 , 2016; Korea (KNHIS) | WHO | 52 | HR 1.82 (0.96-3.48) | No | ||||||
| Stocks et al 18 , 2009; Norway, Austria & Sweden (Me-Can) | ATP | RR 1.14 (0.95-1.38) | Yes | Adjusted for 1mmol/l glucose increment value; hence not included in meta-analysis | ||||||
| Ovarian cancer | Case-control | Chenet al 17 , 2017; Tianjin | ATP | 80 | 159 | OR 5.5 (4.09 – 7.39) | Yes | |||
| IDF | 74 | 143 | OR 5.25 (3.86 – 7.14) | |||||||
| CDS | 79 | 144 | OR 4.88 (3.61 – 6.59) | |||||||
| Michels et al 24 , 2019; Rockville | ATP | 64540 | 217338 | 3724 | 13126 | OR 1.02 (0.96 – 1.07) | Yes | |||
| Cohort | Bjorge et al 23 , 2011; Norway, Austria & Sweden (Me-Can) | HD | 62 | 563 | OR age >50 -1.09 (0.86-1.4) ; age >50 0.99 (0.86-1.15) | Yes | ||||
| Ko et al 26 , 2016; Korea (KNHIS) | ATP | 82 | OR 1.03 (0.53 -2.03); HR 0.94 (0.5-1.77) | Yes | ||||||
| Stocks et al 16 , 2015; Norway, Austria & Sweden (Me-Can) | WHO | HR 1.02 (0.91-1.15) | No | Single ovarian cancer cohort study with reported HR therefore not included in meta-analysis | ||||||
| Russo et al 27 , 2008; Italy | SIR 106 (51 -194) | No | Single cohort study for ovarian cancer with reported SIR; hence not included in meta-analysis | |||||||
| Cao et al 8 , 2020; England, Scotland and Wales (UK Biobank) | HR 1.17 (0.9-1.51) | Yes | Single study of ovarian cancer to report adjusted HR; hence not included in meta-analysis | |||||||
| Stocks et al 18 , 2009; Norway, Austria & Sweden (Me-Can) | RR 0.85 (0.66 – 1.1) | Yes | Adjusted for 1mmol/l glucose increment value; hence not included in meta-analysis | |||||||
| Cervical cancer | Case- control | Penaranda et al 33 , 2013; USA | HD | OR 1.9 (1.06-3.42) | No | Single case-control study for cervical cancer; hence not included in meta-analysis | ||||
| Cohort | Ko et al 26 , 2016; Korea (KNHIS) | ATP | 94 | HR 1.27 (1.09 -1.47) | No | |||||
| Stocks et al 16 , 2015; Norway, Austria & Sweden (Me-Can) | WHO | HR 1.27 (1.09-1.47) | No | |||||||
| Cao et al 8 , 2020; England, Scotland & Wales (UK Biobank) | ATP |
HR 1.36 (0.69 -2.7) |
Yes | |||||||
| Ulmer et al 25 , 2012; Norway, Austria, & Sweden (Me-Can) | WHO | HR 1.26 (1.09-1.47) | Yes | |||||||
| Stocks et al 18 , 2009; Norway, Austria & Sweden (Me-Can) | WHO | RR 0.85 (0.59 – 1.21) | Yes | Single cohort study for cervical cancer with reported RR; hence not included in meta-analysis | ||||||
| Russo et al 27 , 2008; Italy | ATP | SIR 59 (7.2 -214) | No | Single cohort study for cervical cancer with reported SIR; hence not included in meta-analysis | ||||||
| Vulvar cancer | Cohort | Nagel et al 31 , 2011; Norway, Austria & Sweden (Me-Can) | WHO | HR 1.49 (1.2 -1.84) | Yes | Single study for vulvar cancer, hence no meta-analyis could be performed | ||||
| Vaginal cancer | Cohort | Nagel et al 31 , 2011; Norway, Austria & Sweden (Me-Can) | WHO | HR 1.54 (1.05 – 2.25) | Yes | Single study for vaginal cancer, hence no meta-analyis could be performed | ||||
KNHIS, Korean National Health Insurance Service; Me-Can, Metabolic syndrome and cancer project cohort; NHID, Korea National Health Information Database; ATP, adult treatment panel; WHO, World Health Organisation; IDF, International Diabetes Federation; HD, harmonised definition for metabolic syndrome diagnosis; OR, odds ratio; HR, hazards ratio; RR, risk ratio; SIR, standard incidence ratio; CI, confidence interval
Association of cervical cancer with metabolic syndrome
Russo et al27 reported an SIR 59 (95% CI: 7.2-214), and Stocks et al18 reported an adjusted RR 0.85 (95% CI: 0.59-1.21); both were excluded from meta-analysis. Four cohort studies, two with HRs and two with adjusted HRs were included in the meta-analysis8,16,25,26. The pooled estimates yielded an HR of 1.26 (95% CI: 1.09-1.46), P=0.96 and an adjusted HR of 1.27 (95% CI: 1.10-1.47), P=0.83 (Supplementary Fig. 2). Critical appraisal revealed high quality of evidence for the association of metabolic syndrome with cervical cancer for these two cohort studies (Supplementary material 2).
Association of vaginal and vulvar cancers with metabolic syndrome
There was only one study on vaginal and vulvar cancer with 11 yr of follow up, reported an adjusted HR of 1.54 (95% CI: 1.05 – 2.25) and 1.49 (95% CI: 1.2-1.84), respectively31.Critical appraisal revealed high quality of evidence for the association of metabolic syndrome with vaginal and vulvar cancers for these two cohort studies (Supplementary material 2).
Sensitivity analysis
The sensitivity analysis suggests a lack of large-study bias and no single study had influence on pooled estimates (Fig. 3).
- Sensitivity analysis of association of metabolic syndrome with (A) uterine/endometrial cancer, and (B) ovarian cancer.
Quality of evidence
The quality of evidence, assessed using the GRADE framework, indicates very low-quality evidence across all included studies (Supplementary material 3). Quality assessment of study design and imprecision parameters was not serious, but for inconsistency and indirectness, the parameters had serious concerns.
Discussion
This systematic review and meta-analysis aimed to compile existing literature on the risk factors for gynaecological cancers in women with metabolic syndrome indicates a higher risk of gynaecological cancers in women with metabolic syndrome. The pooled association remains consistently positive, irrespective of study design or the specific type of gynaecological cancers, and study quality. The pooled odds ratio (OR) in case-control studies exhibits variations across different cancer types. Notably, the risk is markedly higher in ovarian cancer17,24 compared to endometrial cancer5,6.19.20. In contrast, the HR from cohort studies depicts a distinct pattern, with the highest risk in uterine/endometrial cancer9,22,26,30 compared for ovarian23,26 and cervical cancer16,26.
The scarcity of studies employing analogous methodologies and summarising metrics makes it challenging to summarise the results of meta-analysis through comparison of risk scores. Since gynaecological cancers as an outcome of metabolic syndrome exposure are not rare, different summary measures were not combined in the analysis. It is essential to note the reported heterogeneity in risk. In uterine/endometrial cancer, the heterogeneity was 93, 77 and 63 per cent in case-control5,6,19,29, cross-sectional3,4,28,32 and cohort9,22,26,30 studies, respectively. For ovarian cancer, among the case-control studies the heterogeneity was 99 per cent17,24. This substantial variability among the studies warrants caution in interpreting the pooled estimate, underscoring the need for a nuanced understanding of these complex relationships.
Based on the findings from these systematic reviews, the elevated risk of gynaecological cancers in women with metabolic syndrome could be explained based on the interlinked pathophysiologies of the diseases. The key contributors of metabolic syndrome such as insulin resistance, inflammation and obesity can support increased proliferative, anti-apoptotic, and metastatic activities conducive to cancer development34. Insulin, recognised as a pivotal component of the growth factor system, can modify proliferation signals via the PI3K/Akt and MAPK/ERK pathways, exerting anti-apoptotic influence on cancer cells35. Elevated circulating insulin levels indirectly reduce the hepatic synthesis of sex hormone-binding globulin, leading to increase serum oestrogen and testosterone levels, thereby escalating the risk of ovarian cancer and endometrial cancer36. Obesity significantly influences the sex hormone milieu. It is linked to increased serum androgen levels in women37. Adipose tissue expansion also results in the secretion of adipokines and pro-inflammatory factors, potentially influencing the regulation of cell growth and apoptosis in uterine and ovarian tissues, thereby impacting gynaecological cancers risk.
The strengths of our analysis include the use of primary endpoints based on prospective analyses with adjustments wherever necessary, and uniform methods to better define associations across gynaecological cancers, between cancer subsites, and definitions of metabolic syndrome.
This systematic review has several limitations. First, included studies were restricted to those written in English, potentially excluding studies from regions with high prevalence of gynaecological cancers, such as Asia and Eastern Europe38,39. Apart from language restrictions, the search for articles was limited to freely accessible databases such as PubMed and Google Scholar. However, a substantial number of additional papers were identified through forward and backward citation tracking, which likely mitigated this limitation. Secondly, significant heterogeneity in recruitment strategies resulted in a wide range of sample sizes, ranging from 1,000 in a hospital-based recruitment to 600,000 in a registry-based recruitment, which complicated the accurate estimation of the true risk. Smaller studies may lack statistical power, while larger studies could introduce variability and confounding factors40. Variations in diagnostic criteria for metabolic syndrome and a lack of individual patient data hindered detailed meta-regression analysis. Moreover, the lack of consistent reporting across studies regarding adjustments for confounding variables, such as lifestyle factors, socioeconomic status, and other relevant covariates, introduces uncertainty in the interpretation of the pooled estimates. Additionally, due to the limited number of studies on each gynaecological cancer, meta-regression, publication bias, and subgroup analyses could not be performed. The included studies were predominantly from South/North Korea, Europe and the Americas, therefore, there is a possibility of population bias, which may affect the applicability of the findings to more diverse or underrepresented populations from African and South Asia, and other low-and middle-income countries.
In our systematic review, a total of 54 studies from India were screened for inclusion, of which 31 studies were excluded because they did not include women with metabolic syndrome, and 20 were non-cancerous related studies. One study was on oral cancer, a non-gynaecological cancer, hence not included. Three studies had fewer than three components of metabolic syndrome and, therefore, could not be diagnosed as having metabolic syndrome according to any of the standard definitions; consequently, they were excluded.
Additionally, it is well documented that medications used to manage metabolic syndrome, including metformin, statins may have a preventive effect on cancer development41-43. In light of these existing findings, addressing and managing metabolic syndrome should be an integral part of the strategies employed to prevent and treat gynaecologic cancer. So far, only limited data are available regarding risk of gynaecological cancers and metabolic syndrome in developing countries, and further research is required for robust conclusions.
The results of this comprehensive study, which incorporates numerous recently published studies, indicate that there is a relatively low to moderate heightened susceptibility to gynaecological malignancies in women with metabolic syndrome. There is a pressing need for preventive techniques, specifically primary prevention and early identification of cancer. This need has also been indicated for people with fully developed disorders like diabetes44. Furthermore, it is advisable for women with metabolic syndrome to undergo the recommended cancer tests appropriate for their age. Crucially, we require information regarding the therapies that reduce metabolic syndrome in women also lower the risk of developing cancer.
Financial support & sponsorship
The study received funding support from the Department of Biotechnology, Ministry of Science and Technology, Government of India (BT/PR40165/BTIS/137/12/2021), Science and Engineering Research Board, India (No. STR/2020/000034) and the Indian Council of Medical Research, India (BMI/11(51)/2022).
Conflicts of Interest
None.
Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation
The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.
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