Journal of Andrology & Gynaecology
Controversies in EndometrialCancer with Metabolic Syndrome
- Obstetrics Gynecology, Mahatma Gandhi Institute of Medical Sciences, Maharashtra, India
*Address for Correspondence: S. Chhabra, Obstetrics Gynecology, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Maharashtra, India, E-mail: firstname.lastname@example.org
Citation: Chhabra S. Controversies in Endometrial Cancer with Metabolic Syndrome. J Androl Gynaecol. 2018;5(1): 4.
Copyright: © 2018 Chhabra S. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Journal of Andrology & Gynaecology | ISSN: 2332-3442 | Volume: 5, Issue: 1
Submission: 16 April, 2018 | Accepted: 18 May, 2018 | Published: 28 May, 2018
Metabolic syndrome; Endometrial cancer; Obesity; Diabetes
Introduction: All dysfunctions that contribute to metabolic syndrome have been found to be independently associated with increased risk of endometrial cancer. Also metabolic syndrome on its own with dyslipidaemia seems to increase the risk of many cancers, particularly EC.
Objective: Was to look into existing challenges about association of metabolic syndrome and EC.
Results: Diabetes Mellitus (DM), Hypertension (HTN), Polycystic Ovarian Syndrome (PCOS), Tamoxifen use and others are known to be associated with increased incidence of EC. However observations linking hypertension, glucose metabolism, and insulin resistance to EC have come mostly from retrospective studies. It has been assumed that elevated endogenous estrogen in PCOS patients led to EC. Obesity and insulin resistance were not fully recognized as potential risk factors for EC. Also DM has been found to be a risk factor for Type I EC (Oestrogen dependent), but not Type II EC (nonoestrogen dependent) and needs more research. Impact of metformin on ovarian or EC, outcomes, recurrence or overall survival has also been reported. Weight loss and exercise, the most effective steps which women could take to prevent developing metabolic syndrome, could reduce EC too, but still a lot needs to be known.
Conclusion: Literature reveals metabolic syndrome with or without obesity has linkage to EC but a lot of research is still needed.
Metabolic syndrome (also known as syndrome X or dysmetabolic syndrome) is a cluster of health consequences associated with increased BMI, high blood pressure, abnormal levels of cholesterol and triglycerides in the blood, and insulin resistance (Table 1). Metabolic syndrome is being linked to many cancers and whatever dysfunctions constitute. Metabolic syndrome have been linked to endometrial cancer separately too. Actually it was decades back that Sommers SC et al. reported that EC patients were prone to a ‘habitus’ which consisted of obesity, glucose intolerance or diabetes, and hypertension . Even after the researchers accounted for excess weight, Metabolic syndrome was still linked to up to a 21% increased risk of EC . Studies reported direct association between EC risk and individual components of the Metabolic syndrome i.e. obesity, diabetes, hypertension, and dyslipidemia, however a few epidemiological studies considered the association with overall Metabolic syndrome . Variations seem to be because different definitions of Metabolic syndrome have been suggested. Over the years various researchers recognized many risk factors, like diabetes mellitus , hypertension [5,6], PCOS , and tamoxifen [8,9]. However findings linking blood pressure, glucose metabolism, and insulin resistance to EC came mostly from retrospective studies which provided less conclusive evidence because of self-reported disease history and anthropometry or an absence of adjustment for body mass . And a lot does not seem to be known.
Was to look at association of endometrial cancer and Metabolic syndrome.
The researchers have observed that each distinct metabolic syndrome condition that they could evaluate within the database, excessive weight, high blood pressure, high triglycerides, and impaired fasting glucose was associated with an increased risk for EC. However it has also been reported that about one-fourth of people who do not have diabetes have Metabolic syndrome . Trabert B et al. performed a case-control study using data from the SEER-Medicare linked database . They analyzed data of 16,323 women diagnosed with EC and 100,751 women without EC between 1993 and 2007. A diagnosis of Metabolic syndrome was associated with an increased EC risk of 39 percent and 103 percent, respectively.
According to the results of a study women with Metabolic syndrome who were of age 65 or older, had an increased risk of EC. The increased risk was found regardless of their BMI . Trabert B et al. have reported that Metabolic syndrome was associated with a 39% to 103% increased risk for EC in women aged 65 years and older . It was revealed that among women of age 65 and older, metabolic syndrome, and its components individually, increased risk of EC, similarly across EC subtypes. A recent study suggested that women under 50 years with PCOS were at four times risk of EC compared with controls. Increased risk remained even when Body Mass Index (BMI), was controlled, however there was no adjustment made for IR . A 10-fold increased risk has been reported with a family history of EC at age younger than 50 years or breast or ovarian cancer [14,15].
Obesity has been known as a risk factor for EC, however Metabolic syndrome, regardless of whether the woman is obese or not has higher risk for EC. Weiderpass E et al. reported an increased association of hypertension with EC in obese women and many others have also reported the same [7,16-18]. However, obesity and IR have not been fully recognized as potential risk factors for EC. Brinton LA et al. reported that women with a BMI of 32 kg/m2 or greater were four times as likely to develop EC as women with a BMI of less than 23 kg/m2 . Women with a BMI of 35 kg/m2 or greater, had six times the risk. Swanson CA et al. also reported that heaviest women were at the highest risk of developing EC . Many researchers have reported that a woman’s current weight and weight gain throughout adulthood were most predictive of risk of developing EC. Larger weight gains over a woman’s life have been reported to increase the risk . As such obesity as a risk factor for EC has been reported to account for 17 to 46% of all cases . Researchers have reported an increase in obesity and Metabolic syndrome amongst married women of reproductive age from 11% to 15% in India, and the rural population was not an exception and research needed to be continued about effects on EC burden [22,23]. Saltzman BS et al. reported an effect of hypertension among obese women, compatible with the hypothesis that metabolic syndrome including obesity, hypertension and insulin resistance were the risk factors for EC .
Many authors have reported Type 2 diabetes to be an independent risk factor for developing EC [10,25]. These studies found a persistent elevated risk of developing EC in diabetic patients, when either adjusting for weight or studying nonobese women . Vigneri P et al. reported that the relative risk for EC was greatest (about twofold or higher) with diabetes . There was further evidence that obese diabetic women, had the highest risk of developing EC . Ko EM et al. also reported DM as a risk factor for Type I EC, however the association was not found in Type II EC . The same was also supported by Nevadunsky NS et al. . As such Type IEC and Type II EC seem to be completely different in etiology and behavior.
In a study 66% of patients were found to have IR at the time of diagnosis of EC. Interestingly, half of the women with IR did not have a history of diabetes in another study . High endogenous estrogen related to IR, obesity and PCOS are both known to be associated with IR, which lead to elevated insulin levels and increased insulin-like growth factor I (IGF-I) expression. Elevated IGF-I expression, which may occur through decreased sex hormone-binding globulin, the phosphorylated-akt (p-akt) pathway, and/or the aromatase pathway, caused high local and/or systemic estrogen concentrations . Further work is needed to know the exact role of IR in the development of EC. Soliman PT et al. reported that women with EC were more likely to have low adiponectin levels than controls, even after adjusting for BMI . This suggested that IR was independently associated with EC.
A relationship between EC and polycystic ovary syndrome (PCOS) was first suggested in the 1940s - 1950s . Some studies revealed up to 30% premenopausal patients of EC having PCOS . It was assumed that elevated endogenous estrogen in PCOS patients led to EC. Given that many women with PCOS are obese and have IR, it is unclear whether PCOS is truly an independent risk factor. Friedenreich CM et al. reported that Metabolic syndrome with dyslipidaemia increased the risk of developing various cancers specially EC . Three prospective studies have evaluated circulating estrogen levels and EC risk in postmenopausal women, with consistent strong positive association, but the relationship was not studied in premenopausal women [36-38].
Data from a case-control study of 454 women with EC and 798 controls admitted to the same hospitals as cases for acute conditions, revealed a direct association between various components of metabolic syndrome besides overweight, and risk of EC . Metabolic Syndrome marked by a combination of different medical conditions, low levels of high-density lipoprotein (HDL), the so-called ‘good’ component of cholesterol, and high levels of circulating triglycerides have been found to be associated with a 39% increased risk of EC, or a 21% increased risk after taking into account whether a woman was obese or overweight .
Because of the higher risk of developing cardiovascular events, EC and peripheral vascular disease in patients with Metabolic syndrome it is becoming a rising issue in woman’s health. A new study from the National Institutes of Health demonstrated that Metabolic syndrome was associated with increased risk of EC. The researchers found women with Metabolic syndrome as determined by the ATP III criteria were 39% more likely to develop EC, and those with Metabolic syndrome as determined by International Diabetes Foundation criteria were 109% more likely to develop EC. After accounting for overweight or obesity among the women, the risk of developing EC was 21% and 17% higher, respectively .
Theoretically, metformin, a drug widely used to treat infertile women with PCOS, might have a role in preventing endometrial hyperstimulation by lowering insulin concentrations and restoring ovulation. However, the long-term effects of this drug in women with PCOS are not known and more studies are required before suggesting its use for preventing EC . Several studies have evaluated the impact of metformin on ovarian or EC outcomes, cancer recurrence or overall survival [41,42]. However, there has been scant evidence regarding the impact of metformin upon the development of EC. Koet EM al. reported that in a population-based cohort of >500,000 women, patients using metformin compared to those using sulfonylurea were not associated with a reduced risk of developing EC . Trabert B et al. have reported weight loss and exercise, the most effective steps, women could take to prevent developing metabolic syndrome and may be EC too .
More research is needed to better understand the association between Metabolic syndrome and EC as the strategies to reduce the prevalence of Metabolic syndrome might potentially have a favorable effect on the reduction of EC.
- Trabert B, Eldridge RC, Pfeiffer RM, Shiels MS, Kemp TJ, et al. (2017) Prediagnostic circulating inflammation markers and endometrial cancer risk in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. Int J Cancer 40: 600-610.
- Sommers SC, Meissner WA (1957) Endocrine abnormalities accompanying human endometrial cancer. Cancer 10: 516-521.
- Rosato V, Zucchetto A, Bosetti C, Dal Maso L, Montella M, et al. (2011) Metabolic syndrome and endometrial cancer risk. Ann Oncol 22: 884-889.
- Kessler II (1971) Cancer and diabetes mellitus. A review of the literature. J Chronic Dis 23: 579-600.
- MacMahon B (1974) Risk factors for endometrial cancer. Gynecol Oncol 2: 122-129.
- Furberg AS, Thune I (2003) Metabolic abnormalities (hypertension, hyperglycemia and overweight), lifestyle (high energy intake and physical inactivity) and endometrial cancer risk in a Norwegian cohort. Int J Cancer 104: 669-676.
- Coulam CB, Annegers JF, Kranz JS (1983) Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol 61: 403-407.
- Mignotte H, Lasset C, Bonadona V, Lesur A, Luporsi E, et al. (1998) Iatrogenic risks of endometrial carcinoma after treatment for breast cancer in a large French case‐control study. National Federation of Centers for the Fight against Cancer. Int J Cancer 76: 325-330.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, Gray R, Clarke M, et al. (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378: 771-784.
- Elwood JM, Cole P, Rothman KJ, Kaplan SD (1977) Epidemiology of endometrial cancer. J Natl Cancer Inst 59: 1055-1060.
- Azvolinsky A (2015) Metabolic syndrome linked to higher endometrial cancer risk. Cancer Netw.
- Trabert B, Wentzensen N, Felix AS, Yang HP, Sherman ME, et al. (2015) Metabolic syndrome and risk of endometrial cancer in the United States: a study in the SEER-Medicare linked database. Cancer Epidemiol Biomarkers Prev 24: 261-267.
- Fearnley EJ, Marquart L, Spurdle AB, Weinstein P, Webb PM, et al. (2010) Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case-control study. Cancer Causes Control 21: 2303-2308.
- NCCN (2014) NCCN clinical practice guidelines in oncology: uterine neoplasms.
- Schmandt RE, Iglesias DA, Co NN, Lu KH (2011) Understanding obesity and endometrial cancer risk: opportunities for prevention. Am J Obstet Gynecol 205: 518-525.
- Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, et al. (2000) Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden). Cancer Causes Control 11: 185-192.
- Ramzy I, Nisker JA (1979) Histologic study of ovaries from young women with endometrial adenocarcinoma. Am J Clin Pathol 71: 253-256.
- Escobedo LG, Lee NC, Peterson HB, Wingo PA (1991) Infertility-associated endometrial cancer risk may be limited to specific subgroups of infertile women. Obstet Gynecol 77: 124-128.
- Brinton LA, Berman ML, Mortel R, Twiggs LB, Barrett RJ, et al. (1992) Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. Am J Obstet Gynecol 167: 1317-1325.
- Swanson CA, Potischman N, Wilbanks GD, Twiggs LB, Mortel R, et al. (1993) Relation of endometrial cancer risk to past and contemporary body size and body fat distribution. Cancer Epidemiol Biomarkers Prev 2: 321-327.
- Boren T, Miller D (2010) An update on endometrial cancer. Tex Med 106: 50-55.
- Ramachandran A, Snehalatha C (2010) Rising burden of obesity in Asia. J Obes : 868573.
- Kalra S, Unnikrishnan AG (2012) Obesity in India: the weight of the nation. J Med Nutr Nutraceut 1: 37-41.
- Saltzman BS, Doherty JA, Hill DA, Beresford SA, Voigt LF, et al. (2008) Diabetes and endometrial cancer: an evaluation of the modifying effects of other known risk factors. Am J of Epidemiol 167: 607-614.
- Parazzini F, La Vecchia C, Negri E, Riboldi GL, Surace M, et al. (1999) Diabetes and endometrial cancer: an Italian case‐control study. Int J Cancer 81: 539-542.
- Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16: 1103-1123.
- Anderson KE, Anderson E, Mink PJ, Hong CP, Kushi LH, et al. (2001) Diabetes and endometrial cancer in the Iowa women’s health study. Cancer Epidemiol Biomarkers Prev 10: 611-616.
- Ko EM, Walter P, Clark L, Jackson A, Franasiak J, et al. (2014) The complex triad of obesity, diabetes and race in Type I and II endometrial cancers: prevalence and prognostic significance. Gynecol Oncol 133: 28-32.
- Nevadunsky NS, Van Arsdale A, Strickler HD, Moadel A, Kaur G, et al. (2014) Metformin use and endometrial cancer survival. Gynecol Oncol 132: 236-240.
- Burzawa JK, Schmeler KM, Soliman PT, Meyer LA, Bevers MW, et al. (2011) Prospective evaluation of insulin resistance among endometrial cancer patients. Am J Obstet Gynecol 204: 355.e1-e7.
- Kaaks R, Lukanova A, Kurzer MS (2002) Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev 11: 1531-1543.
- Soliman PT, Wu D, Tortolero‐Luna G, Schmeler KM, Slomovitz BM, et al. (2006) Association between adiponectin, insulin resistance, and endometrial cancer. Cancer 106: 2376-2381.
- Dockerty MB, Jackson RL (1957) The Stein-Leventhal syndrome: analysis of 43 cases with special reference to association with endometrial carcinoma. Am J Obstet Gynecol 73: 161-173.
- Purdie DM, Green AC (2001) Epidemiology of endometrial cancer. Best Pract Res Clin Obstet Gynaecol 15: 341-354.
- Friedenreich CM, Biel RK, Lau DC, Csizmadi I, Courneya KS, et al. (2011) Case-control study of the metabolic syndrome and metabolic risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev 20: 2384-2395.
- Eliassen AH, Hankinson SE (2007) Endogenous hormone levels and risk of breast, endometrial and ovarian cancers: prospective studies. Adv Exp Med Biol 630: 148-165.
- Luhn P, Dallal CM, Weiss JM, Black A, Huang WY, et al. (2013) Circulating adipokine levels and endometrial cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 22: 1304-1312.
- Brown SB, Hankinson SE (2015) Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. Steroids 99: 8-10.
- (2015) Metabolic syndrome associated with increased risk of endometrial cancer. Oncology Nurse Advisor.
- Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, Zabińska-Popiela M, Bereza T, et al. (2005) Molecular action of insulin-sensitizing agents. Endokrynol Pol 56: 308-313.
- Ko EM, Walter P, Jackson A, Clark L, Franasiak J, et al. (2014) Metformin is associated with improved survival in endometrial cancer. Gynecol Oncol 132: 438-442.
- Nevadunsky NS, Van Arsdale A, Strickler HD, Moadel A, Kaur G, et al. (2014) Metformin use and endometrial cancer survival. Gynecol Oncol 132: 236-240.
- Ko EM, Stürmer T, Hong JL, Castillo WC, Bae-Jump V, et al. (2015) Metformin and the risk of endometrial cancer: a population-based cohort study. Gynecol Oncol 136: 341-347.