Table of Contents

    Topic review

    Hyperglycemia and endometrial cancer risk

    Subjects: Oncology
    View times: 50
    Submitted by: Frances Byrne

    Definition

    Endometrial cancer is one of the most common cancers in women worldwide and its incidence is increasing. Epidemiological evidence shows a strong association between endometrial cancer and obesity, and multiple mechanisms linking obesity and cancer progression have been described. However, it remains unclear which factors are the main drivers of endometrial cancer development. Hyperglycemia and type 2 diabetes mellitus are common co-morbidities of obesity, and there is evidence that hyperglycemia is a risk factor for endometrial cancer independent of obesity. This review will discuss studies that have investigated the links between hyperglycemia and endometrial cancer risk.

    1. Introduction

    Endometrial cancer (EC) is an adenocarcinoma that originates from the epithelial cells lining the uterine cavity. The tumor microenvironment surrounding these cells comprises stromal cells, endothelial cells [1] and many different types of immune cells [2], all of which can influence cancer progression and response to treatment. Although most ECs are early stage and confined to the uterus, others spread by invading the myometrium and metastasizing to distant sites such as lymph nodes, liver and lung [3]. According to GLOBOCAN 2018 statistics, EC is the sixth most common cancer and the 11th leading cause of cancer death in women worldwide, with 382,069 new cases and 89,929 deaths [4].

    2. Classification of Endometrial Cancers

    EC has been classically categorized into two clinicopathological subtypes; Type I and Type II. Type II tumors are generally more invasive, estrogen and progesterone receptor (ER/PR) negative and confer a poor prognosis; but account for less than 15% of all cases [5][6]. Type II ECs include grade 3 endometrioid, papillary serous, clear cell, and carcinosarcoma histologies [7]. In contrast, most EC cases are Type I tumors that are frequently low grade endometrioid tumors, confined to the uterus, ER/PR positive, and have higher survival rates following treatment with primary surgery [6]. Since most EC cases are Type I, the majority of studies sited in this review refer to or contain data from Type I EC, unless otherwise stated. However, recent genetic investigations have supported re-classification of EC into 4 molecular subgroups; (1) DNA-polymerase epsilon (POLE) (ultramutated), (2) microsatellite instability hypermutated, (3) copy-number low (microsatellite stable), and (4) copy-number high (serous-like) [8]. Each subgroup has prognostic significance, with the POLE group having the best prognosis (>95% progression-free survival) and the copy-number high group the worst (5-year progression-free survival of 50%). These molecular subgroups are associated with body mass index (BMI), with women in the POLE cluster having the lowest BMI and those in copy-number low cluster having the highest BMI, suggesting that obesity may impact the genetic landscape of endometrial tumors [9].

    3. Risk Factors for Endometrial Cancer

    Recent epidemiological studies have shown an increasing incidence of EC, especially in countries with rapid socioeconomic transitions [10]. The rate of new cases of EC is expected to rise due to an aging population and an increased prevalence of risk factors, particularly obesity [11]. In addition to obesity, a number of factors have been attributed to an increased likelihood of developing EC, including but not limited to; advancing age, late onset menopause, lower age of menarche, chronic anovulation including polycystic ovarian syndrome, estrogen therapy in the absence of progesterone, tamoxifen therapy, hereditary predisposition (Lynch syndrome), and nulliparity [12][13][14][15]. Several of these factors influence the length of time and level of exposure the uterus has to estrogen and progesterone.

    A number of Mendelian Randomization (MR) studies have identified causal factors for EC (as reviewed [16][17]). MR is an analytical method that uses genetic determinants (variants), typically single nucleotide polymorphisms (SNPs), as instrumental variables for a modifiable risk factor. The MR approach is considered to be less affected by confounding factors or reverse causation but is dependent on assumptions [17]. One study showed that a genetically-predicted increase in age of menarche, adjusted for genetically-predicted body-mass index (BMI), was associated with a lower risk of EC [18]. Another showed that variants in CYP19A1 (the gene that encodes aromatase/estrogen synthetase) were associated with increasing estradiol levels in post-menopausal women, and risk of EC, in women of European ancestry [19]. SNPs associated with obesity (BMI), but not waist:hip ratio, were also shown to be associated with EC, indicating that obesity is a causal factor for EC [20]. Genetically-predicted higher fasting insulin levels (using 18 SNP variants) and post-challenge insulin levels (using 17 SNP variants), but not fasting glucose (using 36 SNP variants) or Type 2 diabetes (using 49 SNP variants), were associated with increased risk of EC [21] (Table 1). A more recent study by O’Mara et al. included the most numbers of cases and controls to date; 12,906 endometrial cancer cases and 108,979 country-matched controls of European ancestry [22]. This study confirmed previous findings (higher BMI associated with increased EC risk and later menarche with lower EC risk) and demonstrated that the protective effect of later menarche is partially mediated by the known relationship between lower BMI and this factor [22]. Overall, these genome-wide association studies may provide vital information to those proposing the development of a risk prediction scoring system for women at high risk of EC [23]. A scoring system such as this could enable prophylactic treatment to reduce the incidence of EC, particularly those with Type I EC [23].

    Table 1. Hyperglycemia and Endometrial Cancer.

    Author

    Design

    Population

    Measure

    Results

    NNHSS Cohort * [24]

    Prospective Cohort

    24,460 women

    130 EC cases

    Non-fasting blood glucose

    Overweight women 2.45 times more likely to be diagnosed with EC with baseline non-fasting serum glucose ≥5.6 mmol/L (RR, 95%CI 1.11–5.42). No difference in risk found in women with normal BMI.

    EPIC Cohort [25]

    Nested case-control

    284 EC cases

    546 matched control subjects

    Pre-diagnosis blood glucose

    Post-menopausal women 2.6 times more likely to be diagnosed with EC with higher baseline blood glucose (RR, 95%CI 1.46–4.66, p < 0.001). No difference in risk found in pre- or peri-menopausal women.

    WHIOS Cohort [26]

    Prospective Cohort

    250 EC cases

    465 randomly-selected controls §

    Fasting blood glucose

    Fasting serum glucose levels were not associated with EC.

    Me-Can Cohort * [27]

    Prospective Cohort

    290,000 women

    917 EC cases

    Non-fasting blood glucose

    Higher baseline serum glucose associated with EC in the two highest BMI quintiles (RR = 1.17, 95%CI 1.09–1.25). No association seen in lowest BMI quintiles.

    AMORIS Cohort [28]

    Prospective Cohort

    230,737 women

    Blood glucose (fasting and non-fasting)

    Women with impaired glucose metabolism (6.1–6.9 mmol/L) were at 2 times increased risk of EC diagnosis than women with normal glucose metabolism (<6.1 mmol/L). Women with diabetes mellitus (≥7 mmol/L or recorded diagnosis) were 1.75 times more like to be subsequently diagnosed with EC

    (HRs, 95%CI 1.11–3.60 and 0.82–3.75 respectively)

    Alberta Population [29]

    Case-Control

    541 EC cases

    961 age-matched controls

    Fasting blood glucose

    Small association between higher baseline blood glucose and EC diagnosis (OR = 1.15, 95%CI 1.00–1.31)

    SEER Medicare database [30]

    Case-Control

    16,323 EC cases

    100,751 controls

    All women ≥65 years old

    Impaired fasting glucose as recorded in medical notes, including type 2 diabetes diagnosis

    EC risk was associated with impaired fasting glucose (OR = 1.38, 95%CI 1.29–1.42)

    Vasterbotten Intervention Project [31]

    Prospective Cohort

    33,293 women

    117 EC cases with blood glucose measurements

    Fasting blood glucose and blood glucose 2 h post 75 g glucose load

    Significant increasing trend in EC risk with increasing quartiles of fasting and post-load blood glucose with top versus bottom quartile RR of 1.86 (1.09–3.31, p = 0.019) and 1.82 (1.07–3.23, p = 0.028) respectively.

    Modesitt et al. 2012 [32]

    Case-control

    38 morbidly obese women ≥50 years old scheduled for hysterectomy

    22 with EC

    Fasting blood glucose on morning of surgery

    Significantly higher mean blood glucose in EC cases than controls (6.64 mmol/L cases vs. 5.04 mmol/L controls, p = 0.049)

    Shou et al. 2010 [33]

    Retrospective cohort

    123 EC cases

    90 age-matched controls

    Fasting blood glucose

    Significantly more cases than controls with blood glucose ≥ 5.6 mmol/L (50.4% vs. 27.8%, p < 0.05).

    Zhan et al. 2013 [34]

    Case-control

    206 EC cases

    350 controls

    Pre-operative fasting blood glucose or type 2 diabetes diagnosis

    Significantly higher mean blood glucose in EC cases than controls (6.2 vs. 5.4 mmol/L, p < 0.001).

    Ozdemir et al. 2015 [35]

    Case-control

    199 women undergoing endometrial curettage for abnormal uterine bleeding

    146 with normal endometrium

    53 with hyperplasia or carcinoma

    Fasting blood glucose

    Significantly higher mean blood glucose in cases than controls (125.8 vs. 97.8 mg/dL, p < 0.001).

     

    Odds ratio of endometrial pathology according to fasting glucose level >88 mg/dL (4.9 mmol/L) was 0.11 (95%CI 0.03–0.3, p < 0.001).

    Nead et al., 2015 [21]

    Mendelian Randomization (MR) analysis

    1287 case patients and 8273 control participants from EC studies in Australia and UK

    Genetically-predicted fasting glucose levels using 36 genetic variants associated with fasting glucose

    Genetically-predicted higher fasting glucose levels were not associated with EC (OR = 1.00, 95% CI = 0.67 to 1.50, p = 0.99).

    Karaman et al., 2015 [36]

    Case-control, retrospective

    35 surgically staged EC patients

    40 healthy controls

    HbA1c levels within 3 months of hysterectomy

    Significantly higher mean HbA1c in cases than controls (6.19% vs. 5.61%, p = 0.027).

    Miao Jonasson et al., 2012 [37]

    Prospective Cohort

    25,476 patients with type 2 diabetes

    183 cases of female genital cancer

    Baseline HbA1c

    No increased risk of female genital cancers with HbA1c ≥7.5% versus <7.5%

    No EC-specific data.

    Traviar et al., 2007 [38]

    Prospective Cohort

    25,814 women

    13 EC cases

     

    Patients with a previous diagnosis of diabetes mellitus were excluded

    Baseline HbA1c

    4.05 –fold increase with baseline HbA1c 6.0–6.9% (HR, 95%CI 1.10–14.88) and 5.07 –fold increase with baseline HbA1c ≥7.0% in EC risk (HR, 95%CI 1.20–21.31) compared to HbA1c <6.0%

    Levran et al., 1984 [39]

    Case-control

    22 EC cases

    939 controls of similar weight

    HbA1 1-10 years after diagnosis

    HbA1 was significantly increased in cases compared to controls (p < 0.01)

    * overlapping populations. § Diabetics and patients with blood glucose > 125 mg/dL (~6.9 mmol/L) were excluded from study.

    3.1. Links between Obesity and Endometrial Cancer

    Worldwide, the prevalence of obesity [body mass index (BMI) > 30 kg/m2] in women has increased five-fold in the last four decades [40]

    Mechanisms linking obesity and cancer have been described in the literature [41][42]. Several of these have been proposed to link obesity to EC development and progression, including: (1) excess estrogen through aromatization of androstenedione to estradiol by adipose-derived aromatase [43], (2) altered secretion of adipokines by adipocytes, specifically lower levels of adiponectin and higher levels of leptin [44] and visfatin [45][46], (3) insulin resistance with associated hyperinsulinemia, increased insulin-like growth factor 1 (IGF-1) and decreased IGF binding protein 1 (IGFBP-1) and sex hormone binding globulin (SHBG) [44], and (4) chronic low grade inflammation from increased levels of proinflammatory cytokines [47][48]. These mechanisms linking obesity and endometrial carcinogenesis are described elsewhere [49][50]. The role of obesity, as a component of metabolic syndrome in EC, is also described in-depth in another review [51].

    3.2. Links between Hyperglycemia and Endometrial Cancer

    Disorders associated with hyperglycemia (Type I and II diabetes mellitus) have an increased risk of EC, indicating that poor control of blood glucose may be an important contributor to the growth of these tumors in women. Three separate meta-analyses on this topic have demonstrated that diabetes mellitus is significantly associated with a twofold risk of developing EC [52][53][54] and several epidemiology studies have also demonstrated that this association is independent of obesity [55][56] [57](Table 1). A case-control study involving 942 cases and 1721 controls conducted by Zhang et al. demonstrated a twofold increase in EC risk in women with type II diabetes mellitus (T2DM) compared to their non-diabetic counterparts [58]. Furthermore, hyperglycemia has been associated with EC independent of obesity [59]. In a previous study by Modesitt et al. comparing women with comparable morbid obesity levels with and without Type I EC, circulating glucose levels were higher in women with cancer (119.5 vs. 90.7 mg/dl for non-cancer; p = 0.049) (Table 1). Interestingly, other serological factors, including estrogen and insulin, were not significantly different between the two groups . Several large prospective cohort and case-control studies have also found an increased risk of EC with higher blood glucose levels(summarized in Table 1), although the strength of these associations varies according to BMI, age, and menopausal status in some populations [24,25,27] (Table 1). One observational study did not find an association, however diabetic patients and patients with a fasting blood glucose ≥6.9 mmol/L at baseline were excluded (Table 1). Observational studies are susceptible to confounding and as such, it is possible that hyperinsulinemia, rather than hyperglycemia, is responsible for the association between T2DM and EC risk, as supported by an MR study (Table 1).

    Glycosylated hemoglobin (HbA1c) is used as an indicator of blood glucose levels over the preceding 3 months [60]. In Australia, levels ≥6.5% are considered elevated [61]. While HbA1c is a more helpful indicator of long-term glycemic control than fasting or random blood glucose levels, few studies have examined the association between elevated HbA1c and EC (Table 1). However, two small case-control studies showed higher mean HbA1c in EC cases versus controls; and a prospective cohort study in a predominantly Maori population (the Indigenous people of New Zealand) found a four-to-five-fold increase in EC risk with elevated HbA1c (Table 1). Overall, there is evidence to suggest that the chronic elevation of blood glucose may increase the risk of EC.

    The entry is from 10.3390/cancers12051191

    References

    1. Sahoo, S.S.; Zhang, X.D.; Hondermarck, H.; Tanwar, P.S. The Emerging Role of the Microenvironment in Endometrial Cancer. Cancers (Basel) 2018, 10, 408, doi:10.3390/cancers10110408.
    2. Vanderstraeten, A.; Tuyaerts, S.; Amant, F. The immune system in the normal endometrium and implications for endometrial cancer development. J. Reprod. Immunol. 2015, 109, 7–16, doi:https://doi.org/10.1016/j.jri.2014.12.006.
    3. Barlin, J.N.; Wysham, W.Z.; Ferda, A.M.; Khoury-Collado, F.; Cassella, D.K.; Alektiar, K.M.; Hensley, M.L.; Chi, D.S.; Barakat, R.R.; Abu-Rustum, N.R. Location of Disease in Patients Who Die From Endometrial Cancer: A Study of 414 Patients From a Single Institution. Int. J. Gynecol. Cancer 2012, 22, 1527–1531, doi:10.1097/IGC.0b013e31827057e8.
    4. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424, doi:doi:10.3322/caac.21492.
    5. Felix, A.S.; Weissfeld, J.L.; Stone, R.A.; Bowser, R.; Chivukula, M.; Edwards, R.P.; Linkov, F. Factors associated with Type I and Type II endometrial cancer. Cancer Causes Control. 2010, 21, 1851–1856, doi:10.1007/s10552-010-9612-8.
    6. Weigelt, B.; Banerjee, S. Molecular targets and targeted therapeutics in endometrial cancer. Curr. Opin. Oncol. 2012, 24, 554–563, doi:10.1097/CCO.0b013e328354e585.
    7. Amant, F.; Moerman, P.; Neven, P.; Timmerman, D.; Van Limbergen, E.; Vergote, I. Endometrial cancer. Lancet 2005, 366, 491–505.
    8. Kandoth, C.; Schultz, N.; Cherniack, A.D.; Akbani, R.; Liu, Y.; Shen, H.; Robertson, A.G.; Pashtan, I.; Shen, R.; Benz, C.C.; et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013, 497, 67–73, doi:10.1038/nature12113.
    9. Roque, D.R.; Makowski, L.; Chen, T.-H.; Rashid, N.; Hayes, D.N.; Bae-Jump, V. Association between differential gene expression and body mass index among endometrial cancers from The Cancer Genome Atlas Project. Gynecol. Oncol. 2016, 142, 317–322, doi:https://doi.org/10.1016/j.ygyno.2016.06.006.
    10. Lortet-Tieulent, J.; Ferlay, J.; Bray, F.; Jemal, A. International Patterns and Trends in Endometrial Cancer Incidence, 1978–2013. JNCI 2018, 110, 354–361, doi:10.1093/jnci/djx214.
    11. Morice, P.; Leary, A.; Creutzberg, C.; Abu-Rustum, N.; Darai, E. Endometrial cancer. Lancet 2015, 387, 1094–1108, doi:10.1016/S0140-6736(15)00130-0.
    12. Dossus, L.; Lukanova, A.; Rinaldi, S.; Allen, N.; Cust, A.E.; Becker, S.; Tjonneland, A.; Hansen, L.; Overvad, K.; Chabbert-Buffet, N. Hormonal, metabolic, and inflammatory profiles and endometrial cancer risk within the EPIC cohort—a factor analysis. Am. J. Epidemiol. 2013, 177, 787–799.
    13. MacMahon, B. Risk factors for endometrial cancer. Gynecol. Oncol. 1974, 2, 122–129.
    14. McGonigle, K.F.; Karlan, B.Y.; Barbuto, D.A.; Leuchter, R.S.; Lagasse, L.D.; Judd, H.L. Development of endometrial cancer in women on estrogen and progestin hormone replacement therapy. Gynecol. Oncol. 1994, 55, 126–132.
    15. Rose, P.G. Endometrial carcinoma. New Engl. J. Med. 1996, 335, 640–649.
    16. O'Mara, T.A.; Glubb, D.M.; Kho, P.F.; Thompson, D.J.; Spurdle, A.B. Genome-Wide Association Studies of Endometrial Cancer: Latest Developments and Future Directions. Cancer Epidemiol. Biomark. Prev. 2019, 28, 1095–1102, doi:10.1158/1055-9965.Epi-18-1031.
    17. Pierce, B.L.; Kraft, P.; Zhang, C. Mendelian Randomization Studies of Cancer Risk: A Literature Review. Curr. Epidemiol. Rep. 2018, 5, 184–196, doi:10.1007/s40471-018-0144-1.
    18. Day, F.R.; Thompson, D.J.; Helgason, H.; Chasman, D.I.; Finucane, H.; Sulem, P.; Ruth, K.S.; Whalen, S.; Sarkar, A.K.; Albrecht, E.; et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat. Genet. 2017, 49, 834–841, doi:10.1038/ng.3841.
    19. Thompson, D.J.; O'Mara, T.A.; Glubb, D.M.; Painter, J.N.; Cheng, T.; Folkerd, E.; Doody, D.; Dennis, J.; Webb, P.M.; Gorman, M.; et al. CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer. Endocr. Relat. Cancer 2016, 23, 77, doi:10.1530/erc-15-0386.
    20. Painter, J.N.; O'Mara, T.A.; Marquart, L.; Webb, P.M.; Attia, J.; Medland, S.E.; Cheng, T.; Dennis, J.; Holliday, E.G.; McEvoy, M.; et al. Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer. Cancer Epidemiol. Biomark. Prev. 2016, 25, 1503–1510, doi:10.1158/1055-9965.Epi-16-0147.
    21. Nead, K.T.; Sharp, S.J.; Thompson, D.J.; Painter, J.N.; Savage, D.B.; Semple, R.K.; Barker, A.; Group, T.A.N.E.C.S.; Perry, J.R.B.; Attia, J.; et al. Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. JNCI 2015, 107, doi:10.1093/jnci/djv178.
    22. O’Mara, T.A.; Glubb, D.M.; Amant, F.; Annibali, D.; Ashton, K.; Attia, J.; Auer, P.L.; Beckmann, M.W.; Black, A.; Bolla, M.K.; et al. Identification of nine new susceptibility loci for endometrial cancer. Nat. Commun. 2018, 9, 3166, doi:10.1038/s41467-018-05427-7.
    23. Kitson, S.J.; Evans, D.G.; Crosbie, E.J. Identifying High-Risk Women for Endometrial Cancer Prevention Strategies: Proposal of an Endometrial Cancer Risk Prediction Model. Cancer Prev. Res. 2017, 10, 1–13, doi:10.1158/1940-6207.Capr-16-0224.
    24. Furberg, A.S.; Thune, I. Metabolic abnormalities (hypertension, hyperglycemia and overweight), lifestyle (high energy intake and physical inactivity) and endometrial cancer risk in a Norwegian cohort. Int. J. Cancer 2003, 104, 669–676, doi:http://dx.doi.org/10.1002/ijc.10974.
    25. Cust, A.E.; Kaaks, R.; Friedenreich, C.; Bonnet, F.; Laville, M.; Tjonneland, A.; Olsen, A.; Overvad, K.; Jakobsen, M.U.; Chajes, V.; et al. Metabolic syndrome, plasma lipid, lipoprotein and glucose levels, and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr. Relat. Cancer 2007, 14, 755–767, doi:http://dx.doi.org/10.1677/ERC-07-0132.
    26. Gunter, M.J.; Hoover, D.R.; Yu, H.; Wassertheil-Smoller, S.; Manson, J.E.; Li, J.; Harris, T.G.; Rohan, T.E.; Xue, X.; Ho, G.Y.F.; et al. A Prospective Evaluation of Insulin and Insulin-like Growth Factor-I as Risk Factors for Endometrial Cancer. Cancer Epidemiol. Biomark. Prev. 2008, 17, 921–929, doi:10.1158/1055-9965.Epi-07-2686.
    27. Bjørge, T.; Stocks, T.; Lukanova, A.; Tretli, S.; Selmer, R.; Manjer, J.; Rapp, K.; Ulmer, H.; Almquist, M.; Concin, H.; et al. Metabolic Syndrome and Endometrial Carcinoma. Am. J. Epidemiol. 2010, 171, 892–902, doi:10.1093/aje/kwq006.
    28. Lambe, M.; Wigertz, A.; Garmo, H.; Walldius, G.; Jungner, I.; Hammar, N. Impaired glucose metabolism and diabetes and the risk of breast, endometrial, and ovarian cancer. Cancer Causes Control 2011, 22, 1163–1171, doi:10.1007/s10552-011-9794-8.
    29. Friedenreich, C.M.; Langley, A.R.; Speidel, T.P.; Lau, D.C.W.; Courneya, K.S.; Csizmadi, I.; Magliocco, A.M.; Yasui, Y.; Cook, L.S. Case-control study of markers of insulin resistance and endometrial cancer risk. Endocr. Relat. Cancer 2012, 19, 785–792, doi:10.1530/ERC-12-0211.
    30. Trabert, B.; Wentzensen, N.; Felix, A.S.; Yang, H.P.; Sherman, M.E.; Brinton, L.A. Metabolic Syndrome and Risk of Endometrial Cancer in the United States: A Study in the SEER–Medicare Linked Database. Cancer Epidemiol. Biomark. Prev. 2015, 24, 261–267, doi:10.1158/1055-9965.Epi-14-0923.
    31. Stattin, P.; Björ, O.; Ferrari, P.; Lukanova, A.; Lenner, P.; Lindahl, B.; Hallmans, G.; Kaaks, R. Prospective Study of Hyperglycemia and Cancer Risk. Diabetes Care 2007, 30, 561–567, doi:10.2337/dc06-0922.
    32. Modesitt, S.C.; Geffel, D.L.; Via, J.; A, L.W. Morbidly obese women with and without endometrial cancer: Are there differences in measured physical fitness, body composition, or hormones? Gynecol. Oncol. 2012, 124, 431–436, doi:10.1016/j.ygyno.2011.11.013.
    33. Shou, H.F.; Ni, J.; Zhu, T.; Chen, J.H.; Zhang, X.; Xu, X.X.; Chen, L.; Yu, H. Association between endometrial cancer and metabolic syndrome. Chin. J. Obstet. Gynecol. 2010, 45, 128–131.
    34. Zhan, Y.; Wang, J.; Ma, Y.; Liu, Z.; Xu, H.; Lu, S.; Lu, B. Serum insulin-like, growth factor binding protein-related protein 1 (IGFBP-rP1) and endometrial cancer risk in Chinese women. Int. J. Cancer 2013, 132, 411–416, doi:10.1002/ijc.27622.
    35. Özdemir, S.; Batmaz, G.; Ates, S.; Celik, C.; Incesu, F.; Peru, C. Relation of metabolic syndrome with endometrial pathologies in patients with abnormal uterine bleeding. Gynecol. Endocrinol. 2015, 31, 725–729, doi:10.3109/09513590.2015.1058355.
    36. Karaman, E.; Karaman, Y.; Numanoglu, C.; Ark, H.C. Evaluation of Hemoglobin A1c Levels in Endometrial Cancer Patients: A Retrospective Study in Turkey. Asian Pac. J. Cancer Prev. 2015, 16, 1817–1820.
    37. Miao Jonasson, J.; Cederholm, J.; Eliasson, B.; Zethelius, B.; Eeg-Olofsson, K.; Gudbjornsdottir, S. HbA1C and cancer risk in patients with type 2 diabetes--a nationwide population-based prospective cohort study in Sweden. PLoS ONE 2012, 7, e38784, doi:10.1371/journal.pone.0038784.
    38. Travier, N.; Jeffreys, M.; Brewer, N.; Wright, C.S.; Cunningham, C.W.; Hornell, J.; Pearce, N. Association between glycosylated hemoglobin and cancer risk: A New Zealand linkage study. Ann. Oncol. 2007, 18, 1414–1419, doi:10.1093/annonc/mdm135.
    39. Levran, D.; Modan, M.; Menczer, J.; Dulitzy, M. Increased Rate of Glucose Intolerance in Endometrial Cancer – a Community-Based Study. Gynecol. Obstet. Investig. 1984, 18, 190–193, doi:10.1159/000299079.
    40. (NCD-RisC), N.R.F.C. Trends in adult body-mass index in 200 countries from 1975 to 2014: A pooled analysis of 1698 population-based measurement studies with 19•2 million participants. Lancet 2016, 387, 1377–1396, doi:https://doi.org/10.1016/S0140-6736(16)30054-X.
    41. Avgerinos, K.I.; Spyrou, N.; Mantzoros, C.S.; Dalamaga, M. Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism 2019, 92, 121–135, doi:10.1016/j.metabol.2018.11.001.
    42. Vucenik, I.; Stains, J.P. Obesity and cancer risk: Evidence, mechanisms, and recommendations. Ann. N. Y. Acad. Sci. 2012, 1271, 37–43, doi:10.1111/j.1749-6632.2012.06750.x.
    43. Passarello, K.; Kurian, S.; Villanueva, V. Endometrial Cancer: An Overview of Pathophysiology, Management, and Care. Semin. Oncol. Nurs. 2019, 35, 157–165, doi:10.1016/j.soncn.2019.02.002.
    44. Gong, T.T.; Wu, Q.J.; Wang, Y.L.; Ma, X.X. Circulating adiponectin, leptin and adiponectin-leptin ratio and endometrial cancer risk: Evidence from a meta-analysis of epidemiologic studies. Int J. Cancer 2015, 137, 1967–1978, doi:10.1002/ijc.29561.
    45. Wang, Z.; Gao, S.; Sun, C.; Li, J.; Gao, W.; Yu, L. Clinical significance of serum adiponectin and visfatin levels in endometrial cancer. Int. J. Gynaecol. Obs. 2019, 145, 34–39, doi:10.1002/ijgo.12772.
    46. Tian, W.; Zhu, Y.; Wang, Y.; Teng, F.; Zhang, H.; Liu, G.; Ma, X.; Sun, D.; Rohan, T.; Xue, F. Visfatin, a potential biomarker and prognostic factor for endometrial cancer. Gynecol. Oncol. 2013, 129, 505–512, doi:10.1016/j.ygyno.2013.02.022.
    47. Nieman, K.M.; Romero, I.L.; Van Houten, B.; Lengyel, E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta (BBA) Mol. Cell Biol. Lipids 2013, 1831, 1533–1541, doi:10.1016/j.bbalip.2013.02.010.
    48. Dossus, L.; Rinaldi, S.; Becker, S.; Lukanova, A.; Tjonneland, A.; Olsen, A.; Stegger, J.; Overvad, K.; Chabbert-Buffet, N.; Jimenez-Corona, A.; et al. Obesity, inflammatory markers, and endometrial cancer risk: A prospective case-control study. Endocr. Relat. Cancer 2010, 17, 1007–1019, doi:10.1677/ERC-10-0053.
    49. Schmandt, R.E.; Iglesias, D.A.; Co, N.N.; Lu, K.H. Understanding obesity and endometrial cancer risk: Opportunities for prevention. Am. J. Obstet. Gynecol. 2011, 205, 518–525, doi:https://doi.org/10.1016/j.ajog.2011.05.042.
    50. Onstad, M.A.; Schmandt, R.E.; Lu, K.H. Addressing the Role of Obesity in Endometrial Cancer Risk, Prevention, and Treatment. J. Clin. Oncol. 2016, 34, 4225–4230, doi:10.1200/JCO.2016.69.4638.
    51. Yang, X.; Wang, J. The Role of Metabolic Syndrome in Endometrial Cancer: A Review. Front. Oncol. 2019, 9, 744, doi:10.3389/fonc.2019.00744.
    52. Friberg, E.; Orsini, N.; Mantzoros, C.S.; Wolk, A. Diabetes mellitus and risk of endometrial cancer: A meta-analysis. Diabetologia 2007, 50, 1365–1374, doi:10.1007/s00125-007-0681-5.
    53. Noto, H.; Osame, K.; Sasazuki, T.; Noda, M. Substantially increased risk of cancer in patients with diabetes mellitus: A systematic review and meta-analysis of epidemiologic evidence in Japan. J. Diabetes Its Complicat. 2010, 24, 345–353, doi:https://doi.org/10.1016/j.jdiacomp.2010.06.004.
    54. Zhang, Z.-H.; Su, P.-Y.; Hao, J.-H.; Sun, Y.-H. The Role of Preexisting Diabetes Mellitus on Incidence and Mortality of Endometrial Cancer: A Meta-Analysis of Prospective Cohort Studies. Int. J. Gynecol. Cancer 2013, 23, 294–303, doi:10.1097/IGC.0b013e31827b8430.
    55. Barone, B.B.; Yeh, H.-C.; Snyder, C.F.; Peairs, K.S.; Stein, K.B.; Derr, R.L.; Wolff, A.C.; Brancati, F.L. Long-term All-Cause Mortality in Cancer Patients With Preexisting Diabetes Mellitus: A Systematic Review and Meta-analysis. JAMA 2008, 300, 2754–2764, doi:10.1001/jama.2008.824.
    56. Lindemann, K.; Vatten, L.J.; Ellstrøm-Engh, M.; Eskild, A. Body mass, diabetes and smoking, and endometrial cancer risk: A follow-up study. Br. J. Cancer 2008, 98, 1582–1585, doi:10.1038/sj.bjc.6604313.
    57. Lucenteforte, E.; Bosetti, C.; Talamini, R.; Montella, M.; Zucchetto, A.; Pelucchi, C.; Franceschi, S.; Negri, E.; Levi, F.; Vecchia, C.L. Diabetes and endometrial cancer: Effect modification by body weight, physical activity and hypertension. Br. J. Cancer 2007, 97, 995–998, doi:10.1038/sj.bjc.6603933.
    58. Zhang, Y.; Liu, Z.; Yu, X.; Zhang, X.; Lü, S.; Chen, X.; Lü, B. The association between metabolic abnormality and endometrial cancer: A large case-control study in China. Gynecol. Oncol. 2010, 117, 41–46, doi:https://doi.org/10.1016/j.ygyno.2009.12.029.
    59. Esposito, K.; Chiodini, P.; Capuano, A.; Bellastella, G.; Maiorino, M.I.; Giugliano, D. Metabolic syndrome and endometrial cancer: A meta-analysis. Endocrine 2014, 45, 28–36, doi:http://dx.doi.org/10.1007/s12020-013-9973-3.
    60. Bunn, H.F.; Gabbay, K.H.; Gallop, P.M. The glycosylation of hemoglobin: Relevance to diabetes mellitus. Science 1978, 200, 21–27.
    61. The Royal Australian College of General Practitioners. General practice management of type 2 diabetes: 2016-18; RACGP: East Melbourne, Vic, 2016.
    62. Zhang, Z.-H.; Su, P.-Y.; Hao, J.-H.; Sun, Y.-H. The Role of Preexisting Diabetes Mellitus on Incidence and Mortality of Endometrial Cancer: A Meta-Analysis of Prospective Cohort Studies. Int. J. Gynecol. Cancer 2013, 23, 294–303, doi:10.1097/IGC.0b013e31827b8430.
    63. Barone, B.B.; Yeh, H.-C.; Snyder, C.F.; Peairs, K.S.; Stein, K.B.; Derr, R.L.; Wolff, A.C.; Brancati, F.L. Long-term All-Cause Mortality in Cancer Patients With Preexisting Diabetes Mellitus: A Systematic Review and Meta-analysis. JAMA 2008, 300, 2754–2764, doi:10.1001/jama.2008.824.
    64. Lindemann, K.; Vatten, L.J.; Ellstrøm-Engh, M.; Eskild, A. Body mass, diabetes and smoking, and endometrial cancer risk: A follow-up study. Br. J. Cancer 2008, 98, 1582–1585, doi:10.1038/sj.bjc.6604313.
    65. Lucenteforte, E.; Bosetti, C.; Talamini, R.; Montella, M.; Zucchetto, A.; Pelucchi, C.; Franceschi, S.; Negri, E.; Levi, F.; Vecchia, C.L. Diabetes and endometrial cancer: Effect modification by body weight, physical activity and hypertension. Br. J. Cancer 2007, 97, 995–998, doi:10.1038/sj.bjc.6603933.
    66. Zhang, Y.; Liu, Z.; Yu, X.; Zhang, X.; Lü, S.; Chen, X.; Lü, B. The association between metabolic abnormality and endometrial cancer: A large case-control study in China. Gynecol. Oncol. 2010, 117, 41–46, doi:https://doi.org/10.1016/j.ygyno.2009.12.029.
    67. Esposito, K.; Chiodini, P.; Capuano, A.; Bellastella, G.; Maiorino, M.I.; Giugliano, D. Metabolic syndrome and endometrial cancer: A meta-analysis. Endocrine 2014, 45, 28–36, doi:http://dx.doi.org/10.1007/s12020-013-9973-3.
    68. Bunn, H.F.; Gabbay, K.H.; Gallop, P.M. The glycosylation of hemoglobin: Relevance to diabetes mellitus. Science 1978, 200, 21–27.
    69. The Royal Australian College of General Practitioners. General practice management of type 2 diabetes: 2016-18; RACGP: East Melbourne, Vic, 2016.
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