Skip to main content

Advertisement

SpringerLink
Log in

Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives

  • Review
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Introduction

Diabetes mellitus, the prevalence of which has increased dramatically worldwide, may put patients at a higher risk of cancer. The aim of our study is the clarification of the possible mechanisms linking diabetes mellitus and gynecological cancer and their epidemiological relationship.

Materials and Methods

This is a narrative review of the current literature, following a search on MEDLINE and the Cochrane Library, from their inception until January 2012. Articles investigating gynecologic cancer (endometrial, ovarian, and breast) incidence in diabetic patients were extracted.

Results

The strong evidence for a positive association between diabetes mellitus and the risk for cancer indicates that energy intake in excess to energy expenditure, or the sequelae thereof, is involved in gynecological carcinogenesis. This risk may be further heightened by glucose which can directly promote the production of tumor cells by functioning as a source of energy. Insulin resistance accompanied by secondary hyperinsulinemia is hypothezised to have a mitogenic effect. Steroid hormones are in addition potent regulators of the balance between cellular differentiation, proliferation, and apoptosis. Inflammatory pathways may also be implicated, as a correlation seems to exist between diabetes mellitus and breast or endometrial carcinoma pathogenesis, although an analogous correlation with ovarian carcinoma is still under investigation. Antidiabetic agents have been correlated with elevated cancer risk, while metformin seems to lower the risk.

Conclusion

Diabetes mellitus is associated with an elevation in gynecologic cancer risk. Moreover, there are many studies exploring the prognosis of patients with diabetes and gynecological cancer, the outcome and the overall survival in well-regulated patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Pollak M (2010) Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev Res 3:1060–1065

    Article  CAS  Google Scholar 

  2. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625

    Article  PubMed  CAS  Google Scholar 

  3. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69:7507–7511

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Abdel-Hamid NM, Nazmy MH, Abdel-Ghany MI, Nazmy WH (2012) Cytokines as important playmakers of experimental hepatocarcinogenesis confounded by diabetes. Ann Hepatol 11:118–127

    PubMed  CAS  Google Scholar 

  5. Zhong Y, Li J, Chen Y, Wang J et al (2012) Activation of endoplasmic reticulum stress by hyperglycemia is essential for muller cell-derived inflammatory cytokine production in diabetes. Diabetes 61:492–504

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Di Bartolo BA, Chan J, Bennett MR et al (2012) TNF-related apoptosis-inducing ligand (TRAIL) protects against diabetes and atherosclerosis in Apoe−/− mice. Diabetologia 54:3157–3167

    Article  Google Scholar 

  7. Geraldes P, King GL (2010) Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res 106:1319–1331

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Zhu W, Jia Q, Wang Y et al (2012) The anthocyanin cyanidin-3-O-β-glucoside, a flavonoid, increases hepatic glutathione synthesis and protects hepatocytes against reactive oxygen species during hyperglycemia: involvement of a cAMP-PKA-dependent signaling pathway. Free Radic Biol Med 52:314–327

    Article  PubMed  CAS  Google Scholar 

  9. Schultze SM, Hemmings BA, Niessen M, Tschopp O (2012) PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis. Expert Rev Mol Med 11(14):e1

    Article  Google Scholar 

  10. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545

    Article  PubMed  CAS  Google Scholar 

  11. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Gapstur SM, Gann PH, Lowe W et al (2000) Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 283:2552–2558

    Article  PubMed  CAS  Google Scholar 

  13. Xue F, Michels KB (2007) Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr 86:823–835

    Google Scholar 

  14. Hjartåker A, Langseth H, Weiderpass E (2008) Obesity and diabetes epidemics: cancer repercussions. Adv Exp Med Biol 630:72–93

    Article  PubMed  Google Scholar 

  15. Liao DJ, Dickson RB (2002) Roles of androgens in the development, growth, and carcinogenesis of the mammary gland. J Steroid Biochem Mol Biol 80:175–189

    Article  PubMed  CAS  Google Scholar 

  16. Ross RK, Paganini-Hill A, Wan PC, Pike MC (2000) Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 92:328–332

    Article  PubMed  CAS  Google Scholar 

  17. Key TJ (1999) Serum oestradiol and breast cancer risk. Endocr Relat Cancer 6:175–180

    Article  PubMed  CAS  Google Scholar 

  18. Cho LW, Kilpatrick ES, Keevil BG et al (2011) Insulin resistance variability in women with anovulatory and ovulatory polycystic ovary syndrome, and normal controls. Horm Metab Res 43:141–145

    Article  PubMed  CAS  Google Scholar 

  19. Persson I, Weiderpass E, Bergkvist L et al (1999) Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control 10:253–260

    Article  PubMed  CAS  Google Scholar 

  20. Rutanen EM (1998) Insulin-like growth factors in endometrial function. Gynecol Endocrinol 12:399–406

    Article  PubMed  CAS  Google Scholar 

  21. Lukanova A, Lundin E, Micheli A et al (2004) Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women. Int J Cancer 108:425–432

    Article  PubMed  CAS  Google Scholar 

  22. Risch HA (1998) Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 90:1774–1786

    Article  PubMed  CAS  Google Scholar 

  23. Kaaks R (1996) Nutrition, hormones, and breast cancer: Is insulin the missing link? Cancer Causes Control 7:605–625

    Article  PubMed  CAS  Google Scholar 

  24. Wolf I, Sadetzki S, Catane R et al (2005) Diabetes mellitus and breast cancer. Lancet Oncol 6:103–111

    Article  PubMed  CAS  Google Scholar 

  25. Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE (2000) The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 21:215–244

    Article  PubMed  CAS  Google Scholar 

  26. Kluge A, Zimmermann R, Munkel B et al (1995) Insulin-like growth factor I is involved in inflammation linked angiogenic processes after microembolisation in porcine heart. Cardiovasc Res 29:407–415

    Article  PubMed  CAS  Google Scholar 

  27. Becker S, Dossus L, Kaaks R (2009) Obesity related hyperinsulinaemia and hyperglycaemia and cancer development. Arch Physiol Biochem 115:86–96

    Article  PubMed  CAS  Google Scholar 

  28. Nestler JE (2000) Obesity, insulin, sex steroids and ovulation. Int J Obes Relat Metab Disord 24:71–73

    Article  Google Scholar 

  29. Kaaks R, Lukanova A (2001) Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc 60:91–106

    Article  PubMed  CAS  Google Scholar 

  30. Ramasamy R, Yan SF, Schmidt AM (2009) RAGE: therapeutic target and biomarker of the inflammatory response the evidence mounts. J Leukoc Biol 86:505–512

    Article  PubMed  CAS  Google Scholar 

  31. Jemal A, Tiwari CG, Murray T et al (2004) Cancer statistics. Cancer J Clin 54:8–29

    Article  Google Scholar 

  32. Coughlin SS, Calle EE, Teras LR et al (2004) Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 159:1160–1167

    Article  PubMed  Google Scholar 

  33. Friberg E, Orsini N, Mantzoros CS, Wolk A (2007) Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 50:1365–1374

    Article  PubMed  CAS  Google Scholar 

  34. Salazar-Martinez E, Lazcano-Ponce EC, Lira-Lira GG et al (2000) Case-control study of diabetes, obesity, physical activity and risk of endometrial cancer among Mexican women. Cancer Causes Control 11:707–711

    Article  PubMed  CAS  Google Scholar 

  35. Xu WH, Matthews CE, Xiang YB et al (2005) Effect of adiposity and fat distribution on endometrial cancer risk in Shanghai women. Am J Epidemiol 161:939–947

    Article  PubMed  Google Scholar 

  36. Berstein LM, Kvatchevskaya JO, Poroshina TE et al (2004) Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer. J Cancer Res Clin Oncol 130:687–693

    Article  PubMed  CAS  Google Scholar 

  37. Gnacinska M, Malgorzewicz S, Stojek M et al (2009) Role of adipokines in complications related to obesity: a review. Adv Med Sci 54:150–157

    Article  PubMed  CAS  Google Scholar 

  38. Hanley AJ, Bowden D, Wagenknecht LE et al (2007) Associations of adiponectin with body fat distribution and insulin sensitivity in nondiabetic Hispanics and African-Americans. J Clin Endocrinol Metab 92:2665–2671

    Article  PubMed  CAS  Google Scholar 

  39. Finucane FM, Luan J, Wareham NJ et al (2009) Correlation of the leptin: adiponectin ratio with measures of insulin resistance in non-diabetic individuals. Diabetologia 52:2345–2349

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Ashizawa N, Yahata T, Quan J, Adachi S, Yoshihara K, Tanaka K (2010) Serum leptin–adiponectin ratio and endometrial cancer risk in postmenopausal female subjects. Gynecol Oncol 119:65–69

    Article  PubMed  CAS  Google Scholar 

  41. Dal Maso L, Augustin LS, Karalis A et al (2004) Circulating adiponectin and endometrial cancer risk. J Clin Endocrinol Metab 89:1160–1163

    Article  PubMed  CAS  Google Scholar 

  42. Painter JN, O’Mara TA, Batra J et al (2015) Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. Hum Mol Genet 24:1478–1492

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Spurdle AB, Thompson DJ, Ahmed S et al (2011) Genome-wide association study identifies a common variant associated with risk of endometrial cancer. Nat Genet 43:451–454

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Gogas H, Shapiro F, Aghajanian C et al (1996) The impact of diabetes mellitus on the toxicity of therapy for advanced ovarian cancer. Gynecol Oncol 61:22–26

    Article  PubMed  CAS  Google Scholar 

  45. Fasching PA, Gayther S, Pearce L et al (2009) Role of genetic polymorphisms and ovarian cancer susceptibility. Mol Oncol 2:171–181

    Article  Google Scholar 

  46. Lee AW, Tyrer JP, Doherty JA et al (2015) Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study. Gynecol Oncol 136:542–548

    Article  PubMed  CAS  Google Scholar 

  47. Parazzini F, Moroni S, La Vecchia C et al (1997) Ovarian cancer risk and history of selected medical conditions linked with female hormones. Eur J Cancer 33:1634–1637

    Article  PubMed  CAS  Google Scholar 

  48. Weiderpass E, Ye W, Vainio H et al (2002) Diabetes mellitus and ovarian cancer. Cancer Causes Control 13:759–764

    Article  PubMed  Google Scholar 

  49. Hemminki K, Li X, Sundquist J, Sundquist K (2010) Risk of cancer following hospitalization for type 2 diabetes. Oncologist 15:548–555

    Article  PubMed  PubMed Central  Google Scholar 

  50. Bakhru A, Buckanovich R, Griggs J (2011) The impact of diabetes on survival in women with ovarian cancer. Gynecol Oncol 121:106–111

    Article  PubMed  Google Scholar 

  51. Bordeleau L, Lipscombe L, Lubinski J, Hereditary Breast Cancer Clinical Study Group et al (2011) Diabetes and breast cancer among women with BRCA1 and BRCA2 mutations. Cancer 117:1812–1818

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Yakar S, Pennisi P, Zhao H, et al (2004) Circulating IGF-1 and its role in cancer: lessons from the IGF-1 gene deletion (LID) mouse. Novartis Found Symp 262:3–9 (discussion 9–18, 265–268)

  53. Seldin DC, Landesman-Bollag E, Farago M et al (2005) CK2 as a positive regulator of Wnt signalling and tumourigenesis. Mol Cell Biochem 274:63–67

    Article  PubMed  CAS  Google Scholar 

  54. Wideroff L, Gridley G, Mellemkjaer L et al (1989) Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 89:1360–1365

    Article  Google Scholar 

  55. Weiss HA, Brinton LA, Potischman NA et al (1999) Breast cancer risk in young women and history of selected medical conditions. Int J Epidemiol 28:816–823

    Article  PubMed  CAS  Google Scholar 

  56. Talamini R, Franceschi S, Favero A et al (1997) Selected medical conditions and risk of breast cancer. Br J Cancer 75:1699–1703

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Jee SH, Ohrr H, Sull JW et al (2005) Fasting serum glucose level and cancer risk in Korean men and women. JAMA 293:194–202

    Article  PubMed  CAS  Google Scholar 

  58. Rapp K, Schroeder J, Klenk J et al (2006) Fasting blood glucose and cancer risk in a cohort of more than 140,000 adults in Austria. Diabetologia 49:945–952

    Article  PubMed  CAS  Google Scholar 

  59. Stattin P, Bjor O, Ferrari P et al (2007) Prospective study of hyperglycemia and cancer risk. Diab Care 30:561–567

    Article  Google Scholar 

  60. Mink PJ, Shahar E, Rosamond WD et al (2002) Serum insulin and glucose levels and breast cancer incidence: the atherosclerosis risk in communities study. Am J Epidemiol 156:349–352

    Article  PubMed  Google Scholar 

  61. Kabat GC, Kim M, Caan BJ et al (2009) Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer. Int J Cancer 125:2704–2710

    Article  PubMed  CAS  Google Scholar 

  62. Larsson SC, Mantzoros CS, Wolk A (2007) Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 121:856–862

    Article  PubMed  CAS  Google Scholar 

  63. Cantrell LA, Zhou C, Mendivil A et al (2010) Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy. Gynecol Oncol 116:92–98

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Romero IL, McCormick A, McEwen KA et al (2012) Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol 119:61–67

    Article  PubMed  PubMed Central  Google Scholar 

  65. Rattan R, Giri S, Hartmann LC, Shridhar V (2011) Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med 15:166–178

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Abe R, Yamagishi S (2008) AGE–RAGE system and carcinogenesis. Curr Pharm Des 14:940–945

    Article  PubMed  CAS  Google Scholar 

  67. Hirsch HA, Iliopoulos D, Tsichlis PN et al (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69:7507–7511

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  68. Gotlieb WH, Saumet J, Beauchamp MC et al (2008) In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol 110:246–250

    Article  PubMed  CAS  Google Scholar 

  69. Libby G, Donnelly LA, Donnan PT et al (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diab Care 32:1620–1625

    Article  CAS  Google Scholar 

  70. Goodwin PJ, Stambolic V, Lemieux J et al (2011) Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat 126:215–220

    Article  PubMed  CAS  Google Scholar 

  71. Teng JA, Hou RL, Li DL et al (2011) Glargine promotes proliferation of breast adenocarcinoma cell line MCF-7 via AKT activation. Horm Metab Res 43:519–523

    Article  PubMed  CAS  Google Scholar 

  72. Jonasson JM, Ljung R, Talback M et al (2009) Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden. Diabetologia 52:1745–1754

    Article  PubMed  CAS  Google Scholar 

  73. Colhoun HM, SDRN Epidemiology Group (2009) Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 52:1755–1765

    Article  Google Scholar 

  74. Kim HJ, Kwon H, Lee JW et al (2015) Metformin increases survival in hormone receptor-positive, Her2-positive breast cancer patients with diabetes. Breast Cancer Res 17:64

    Article  PubMed  PubMed Central  Google Scholar 

  75. Oppong BA, Pharmer LA, Oskar S et al (2014) The effect of metformin on breast cancer outcomes in patients with type 2 diabetes. Cancer Med 3:1025–1034

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. 2nd Department of Obstetrics and Gynecology, Aretaieio Hospital, University of Athens Medical School, Athens, Greece

    Nikolaos Vrachnis, Christos Iavazzo, Zoe Iliodromiti, Charalambos Grigoriadis, Dimitrios Botsis & George Creatsas

  2. Department of Obstetrics and Gynecology, University Hospital of Heraklion, Crete, 71201, Heraklion, Greece

    Stavros Sifakis

  3. 1st Department of Surgery, Laiko Hospital, University of Athens Medical School, Athens, Greece

    Andreas Alexandrou

  4. 3rd Department of Obstetrics and Gynecology, University of Athens, Athens, Greece

    Charalambos Siristatidis

Authors
  1. Nikolaos Vrachnis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christos Iavazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zoe Iliodromiti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stavros Sifakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andreas Alexandrou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charalambos Siristatidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charalambos Grigoriadis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dimitrios Botsis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. George Creatsas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stavros Sifakis.

Ethics declarations

Conflict of interest

The authors report no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vrachnis, N., Iavazzo, C., Iliodromiti, Z. et al. Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives. Arch Gynecol Obstet 293, 239–246 (2016). https://doi.org/10.1007/s00404-015-3858-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-015-3858-z

Keywords

Search

Navigation