The Essential Epidemiology of Cancer of the Endometrium: An Update

  • Malcolm C. Pike
  • Karine Chung
  • Sara Olson
  • Celeste L. Pearce
  • Anna H. Wu
Part of the Current Clinical Oncology book series (CCO)


The central epidemiologic features of cancer of the endometrium are the following: a much increased risk associated with obesity, evident both in premenopausal and postmenopausal women; a decreased risk with increasing parity; a decreased risk with increasing duration of use of combination-type oral contraceptives (COCs); an increased risk with menopausal estrogen therapy (ET) use; and a marked reduction in this risk when a progestin is added to ET (estrogen–progestin therapy, EPT) and continuous-combined EPT may be associated with a decreased risk, especially in heavier women. These observations are readily explained by a simple “unopposed estrogen hypothesis”; that is, estrogen “unopposed” by a progestin increases risk. The basis for this hypothesis is that estrogen unopposed by a progestin increases cell division in the endometrium. Analysis shows that reducing the standard dose of ET by as much as a half will have no effect on the ET-associated risk of endometrial cancer. This hypothesis also provides an explanation of why 1 year of COC use has a smaller preventive effect than a birth. It also suggests that the recently introduced COCs with an increase in the number of days of active pill intake from 21 to 24 days per 28-day COC cycle will significantly increase the protective effect of COC use. Use of the progestin-containing intrauterine system (IUS) with its continuous release of progestin reduces the risk of endometrial cancer to a marked extent; a year of such use may provide as much protection as a birth. Some of this progestin-containing IUS effect may, however, not be due to the progestin as non-hormonal IU devices (IUDs) have also been shown to decrease endometrial cancer risk although to a lesser extent. It is now clear that the protective effect of parity is markedly affected by the age at which the last birth occurs: for the same number of total births, there is a 45 % greater effect of a last birth after age 40 than a last birth before age 25. It remains to be seen if this age effect is also seen with the protection afforded by hormonal IUSs or with COCs where the active pills are given for 12 weeks out of every 13.


Endometrial cancer Births Body mass index Weight Estrogen Estrogen therapy 



Research reported in this publication was partially supported by NCI under award number P30CA008748 (PI: Thompson) to Memorial Sloan Kettering Cancer Center.


  1. 1.
    Siiteri PK. Steroid hormones and endometrial cancer. Cancer Res. 1978;38:4360–6.PubMedGoogle Scholar
  2. 2.
    Key TJ, Pike MC. The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer. 1988;57:205–12.CrossRefGoogle Scholar
  3. 3.
    Cairns J. Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proc Natl Acad Sci U S A. 2002;99:10567–70.CrossRefGoogle Scholar
  4. 4.
    Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE. Increased cell division as a cause of human cancer. Cancer Res. 1990;50:7415–21.PubMedGoogle Scholar
  5. 5.
    Waterhouse J, Muir C, Correa P, Powell J. Cancer incidence in five continents. IARC Sci Publ. 1976;15:1–583.Google Scholar
  6. 6.
    Ferenczy A. Studies on the cytodynamics of human endometrial regeneration. I. Scanning electron microscopy. Am J Obstet Gynecol. 1976;124:64–74.CrossRefGoogle Scholar
  7. 7.
    Salamonsen LA. Tissue injury and repair in the female human reproductive tract. Reproduction. 2003;125:301–11.CrossRefGoogle Scholar
  8. 8.
    Whitehead MI, Townsend PT, Pryse-Davies J, Ryder TA, King RJ. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. N Engl J Med. 1981;305:1599–605.CrossRefGoogle Scholar
  9. 9.
    Tseng L, Gurpide E. Induction of human endometrial estradiol dehydrogenase by progestins. Endocrinology. 1975;97:825–33.CrossRefGoogle Scholar
  10. 10.
    Ferenczy A, Bertrand G, Gelfand MM. Proliferation kinetics of human endometrium during the normal menstrual cycle. Am J Obstet Gynecol. 1979;133:859–67.CrossRefGoogle Scholar
  11. 11.
    Goebelsmann UM, Mishell DR. The menstrual cycle. In: Mishell DR, Davajian V, editors. Reproductive endocrinology, infertility and contraception. Philadelphia: F.A. Davis Company; 1979. p. 67–89.Google Scholar
  12. 12.
    Thorneycroft IH, Mishell Jr DR, Stone SC, Kharma KM, Nakamura RM. The relation of serum 17-hydroxyprogesterone and estradiol-17-beta levels during the human menstrual cycle. Am J Obstet Gynecol. 1971;111:947–51.CrossRefGoogle Scholar
  13. 13.
    Endogenous Hormones and Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95:1218–26.CrossRefGoogle Scholar
  14. 14.
    Pardridge WM. Serum bioavailability of sex steroid hormones. Clin Endocrinol Metab. 1986;15:259–78.CrossRefGoogle Scholar
  15. 15.
    Sodergard R, Backstrom T, Shanbhag V, Carstensen H. Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem. 1982;16:801–10.CrossRefGoogle Scholar
  16. 16.
    Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53:58–68.CrossRefGoogle Scholar
  17. 17.
    Friedenreich C, Cust A, Lahmann PH, Steindorf K, Boutron-Ruault MC, Clavel-Chapelon F, et al. Anthropometric factors and risk of endometrial cancer: the European prospective investigation into cancer and nutrition. Cancer Causes Control. 2007;18:399–413.CrossRefGoogle Scholar
  18. 18.
    Henderson BE, Casagrande JT, Pike MC, Mack T, Rosario I, Duke A. The epidemiology of endometrial cancer in young women. Br J Cancer. 1983;47:749–56.CrossRefGoogle Scholar
  19. 19.
    Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, Baron JA. Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden). Cancer Causes Control. 2000;11:185–92.CrossRefGoogle Scholar
  20. 20.
    Hartz AJ, Barboriak PN, Wong A, Katayama KP, Rimm AA. The association of obesity with infertility and related menstrual abnormalities in women. Int J Obes. 1979;3:57–73.PubMedGoogle Scholar
  21. 21.
    Siiteri PK. Extraglandular oestrogen formation and serum binding of oestradiol: relationship to cancer. J Endocrinol. 1981;89:119–29.Google Scholar
  22. 22.
    Pike MC, Peters RK, Cozen W, Probst-Hensch NM, Felix JC, Wan PC, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst. 1997;89:1110–6.CrossRefGoogle Scholar
  23. 23.
    Beresford SAA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet. 1997;349:458–61.CrossRefGoogle Scholar
  24. 24.
    Persson I, Weiderpass E, Bergkvist L, Bergstrom R, Schairer C. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control. 1999;10:253–60.CrossRefGoogle Scholar
  25. 25.
    Cushing KL, Weiss NS, Voigt LF, McKnight B, Beresford SA. Risk of endometrial cancer in relation to use of low-dose, unopposed estrogens. Obstet Gynecol. 1998;91:35–9.CrossRefGoogle Scholar
  26. 26.
    Brinton LA, Hoover RN. Estrogen replacement therapy and endometrial cancer risk: unresolved issues. Obstet Gynecol. 1993;81:265–71.PubMedGoogle Scholar
  27. 27.
    Beral V, Bull D, Reeves G, Collaborators MWS. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005;365:1543–51.CrossRefGoogle Scholar
  28. 28.
    Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA. Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17B-estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol. 1985;152:1099–106.CrossRefGoogle Scholar
  29. 29.
    Schiff I, Sela HK, Cramer D, Tulchinskiy D, Ryan KJ. Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril. 1982;37:79–82.CrossRefGoogle Scholar
  30. 30.
    Selby PL, Peacock M. Dose dependent response of symptoms, pituitary, and bone to transdermal oestrogen in postmenopausal women. BMJ. 1986;293:1337–9.CrossRefGoogle Scholar
  31. 31.
    Nachtigall LE, Raju U, Banerjee S, Wan L, Levitz M. Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels. Menopause. 2000;7:243–50.CrossRefGoogle Scholar
  32. 32.
    Ropponen A, Aittomaki K, Vihma V, Tikkanen MJ, Ylikorkala O. Effects of oral and transdermal estradiol administration on levels of sex hormone-binding globulin in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy. J Clin Endocrinol Metab. 2005;90:3431–4.CrossRefGoogle Scholar
  33. 33.
    Whitehead MI, Townsend PT, Pryse-Davies J, Ryder T, Lane G, Siddle N, et al. Actions of progestins on the morphology and biochemistry of the endometrium of postmenopausal women receiving low-dose estrogen therapy. Am J Obstet Gynecol. 1982;142:791–5.CrossRefGoogle Scholar
  34. 34.
    King RJB, Townsend PT, Siddle N, Whitehead MI, Taylor RW. Regulation of estrogen and progesterone receptor levels in epithelium and stroma from pre- and postmenopausal endometrial. J Steroid Biochem. 1982;16:21–9.CrossRefGoogle Scholar
  35. 35.
    Lane G, Siddle NC, Ryder TA, Pryse-Davies J, King RJB, Whitehead MI. Dose dependent effects of oral progesterone on the oestrogenised postmenopausal endometrium. BMJ. 1983;287:1241–5.CrossRefGoogle Scholar
  36. 36.
    King RJB, Whitehead MI. Assessment of the potency of orally administered progestins in women. Fertil Steril. 1986;46:1062–6.CrossRefGoogle Scholar
  37. 37.
    Lane G, Siddle NC, Ryder TA, Pryse-Davies J, King RJB, Whitehead MI. Is provera the ideal progestogen for addition to postmenopausal estrogen therapy? Fertil Steril. 1986;45:345–52.CrossRefGoogle Scholar
  38. 38.
    Flowers CE, Wilborn WH, Hyde BM. Mechanisms of uterine bleeding in postmenopausal patients receiving estrogen alone or with a progestin. Obstet Gynecol. 1983;61:135–43.PubMedGoogle Scholar
  39. 39.
    Paterson MEL, Wade-Evans T, Sturdee DW, Thom MH, Studd JWW. Endometrial disease after treatment with oestrogens and progestogens in the climacteric. BMJ. 1980;22:822–4.CrossRefGoogle Scholar
  40. 40.
    King RJB, Whitehead MI. Progestin action in relation to the prevention of endometrial abnormalities. In: Raynaud JP, Ojasoo T, Martini L, editors. Medical Management of Endometriosis. Raven Press: New York, 1984;67–77.Google Scholar
  41. 41.
    Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1739–48.CrossRefGoogle Scholar
  42. 42.
    Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288:58–66.CrossRefGoogle Scholar
  43. 43.
    Weiderpass E, Baron JA, Adami HO, Magnusson C, Lindgren A, Bergstrom R, et al. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet. 1999;353:1824–8.CrossRefGoogle Scholar
  44. 44.
    Doherty JA, Cushing-Haugen KL, Saltzman BS, Voigt LF, Hill DA, Beresford SA, et al. Long-term use of postmenopausal estrogen and progestin hormone therapies and the risk of endometrial cancer. Am J Obstet Gynecol. 2007;197:139.e1–7.CrossRefGoogle Scholar
  45. 45.
    Allen NE, Tsilidis KK, Key TJ, Dossus L, Kaaks R, Lund E, et al. Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition. Am J Epidemiol. 2010;172:1394–403.CrossRefGoogle Scholar
  46. 46.
    Newcomb PA, Trentham-Dietz A. Patterns of postmenopausal progestin use with estrogen in relation to endometrial cancer (United States). Cancer Causes Control. 2003;14:195–201.CrossRefGoogle Scholar
  47. 47.
    Razavi P, Pike MC, Horn-Ross PL, Templeman C, Bernstein L, Ursin G. Long-term postmenopausal hormone therapy and endometrial cancer. Cancer Epidemiol Biomarkers Prev. 2010;19:475–83.CrossRefGoogle Scholar
  48. 48.
    Jain MG, Rohan TE, Howe GR. Hormone replacement therapy and endometrial cancer in Ontario, Canada. J Clin Epidemiol. 2000;53:385–91.CrossRefGoogle Scholar
  49. 49.
    Langer RD, Landgren BM, Rymer J, Helmond FA, Investigators O. Effects of tibolone and continuous combined conjugated equine estrogen/medroxyprogesterone acetate on the endometrium and vaginal bleeding: results of the OPAL study. Am J Obstet Gynecol. 2006;195:1320–7.CrossRefGoogle Scholar
  50. 50.
    Dahmoun M, Odmark IS, Risberg B, Karlsson MG, Pavlenko T, Backstrom T. Apoptosis, proliferation, and sex steroid receptors in postmenopausal endometrium before and during HRT. Maturitas. 2004;49:114–23.CrossRefGoogle Scholar
  51. 51.
    Albrektsen G, Heuch I, Tretli S, Kvale G. Is the risk of cancer of the corpus uteri reduced by a recent pregnancy? A prospective study of 765,756 Norwegian women. Int J Cancer. 1995;61:485–90.CrossRefGoogle Scholar
  52. 52.
    Collaborative Group on Epidemiological Studies on Endometrial Cancer. Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies. Lancet Oncol. 2015;16:1061–70.CrossRefGoogle Scholar
  53. 53.
    Pike MC. Age-related factors in cancers of the breast, ovary, and endometrium. J Chronic Dis. 1987;40 Suppl 2:59S–69.CrossRefGoogle Scholar
  54. 54.
    Guttinger A, Critchley HO. Endometrial effects of intrauterine levonorgestrel. Contraception. 2007;75(6 Suppl):S93–8.CrossRefGoogle Scholar
  55. 55.
    Whiteman MK, Zapata LB, Tepper NK, Marchbanks PA, Curtis KM. Use of contraceptive methods among women with endometrial hyperplasia: a systematic review. Contraception. 2010;82:56–63.CrossRefGoogle Scholar
  56. 56.
    Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol. 2002;186:651–7.CrossRefGoogle Scholar
  57. 57.
    Orbo A, Rise CE, Mutter GL. Regression of latent endometrial precancers by progestin infiltrated intrauterine device. Cancer Res. 2006;66:5613–7.CrossRefGoogle Scholar
  58. 58.
    Fotherby K, Koetsawang S, Mathrubutham M. Pharmacokinetic study of different doses of depo provera. Contraception. 1980;22:527–36.CrossRefGoogle Scholar
  59. 59.
    WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer. 1991;49:186–90.CrossRefGoogle Scholar
  60. 60.
    Beining RM, Dennis LK, Smith EM, Dokras A. Meta-analysis of intrauterine device use and risk of endometrial cancer. Ann Epidemiol. 2008;18:492–9.CrossRefGoogle Scholar
  61. 61.
    Felix AS, Gaudet MM, La Vecchia C, Nagle CM, Shu XO, Weiderpass E, et al. Intrauterine devices and endometrial cancer risk: a pooled analysis of the Epidemiology of Endometrial Cancer Consortium. Int J Cancer. 2015;136:E410–22.CrossRefGoogle Scholar
  62. 62.
    Guleria K, Agarwal N, Mishra K, Gulati R, Mehendiratta A. Evaluation of endometrial steroid receptors and cell mitotic activity in women using copper intrauterine device: can Cu-T prevent endometrial cancer? J Obstet Gynaecol Res. 2004;30:181–7.CrossRefGoogle Scholar
  63. 63.
    Zhou B, Yang L, Sun Q, Cong R, Gu H, Tang N, et al. Cigarette smoking and the risk of endometrial cancer: a meta-analysis. Am J Med. 2008;121:501–8. e3.CrossRefGoogle Scholar
  64. 64.
    Al-Zoughool M, Dossus L, Kaaks R, Clavel-Chapelon F, Tjonneland A, Olsen A, et al. Risk of endometrial cancer in relationship to cigarette smoking: results from the EPIC study. Int J Cancer. 2007;121:2741–7.CrossRefGoogle Scholar
  65. 65.
    Felix AS, Yang HP, Gierach GL, Park Y, Brinton LA. Cigarette smoking and endometrial carcinoma risk: the role of effect modification and tumor heterogeneity. Cancer Causes Control. 2014;25:479–89.CrossRefGoogle Scholar
  66. 66.
    Friedman AJ, Ravnikar VA, Barbieri RL. Serum steroid hormone profiles in postmenopausal smokers and nonsmokers. Fertil Steril. 1987;47:398–401.CrossRefGoogle Scholar
  67. 67.
    Khaw K-T, Tazuke S, Barrett-Connor E. Cigarette smoking and levels of adrenal androgens in postmenopausal women. N Engl J Med. 1988;318:1705–9.CrossRefGoogle Scholar
  68. 68.
    Cauley JA, Gutai JP, Kuller LH, LeDonne D, Powell JG. The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol. 1989;129:1120–31.CrossRefGoogle Scholar
  69. 69.
    Schlemmer A, Jensen J, Riis BJ, Christiansen C. Smoking induces increased androgen levels in early post-menopausal women. Maturitas. 1990;12:99–104.CrossRefGoogle Scholar
  70. 70.
    Allen NE, Key TJ, Dossus L, Rinaldi S, Cust A, Lukanova A, et al. Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer. 2008;15:485–97.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Malcolm C. Pike
    • 1
  • Karine Chung
    • 2
  • Sara Olson
    • 1
  • Celeste L. Pearce
    • 3
  • Anna H. Wu
    • 4
  1. 1.Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Department of Obstetrics and Gynecology, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Department of Epidemiology, School of Public HealthUniversity of MichiganAnn ArborUSA
  4. 4.Department of Preventive Medicine, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

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