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Endometrial Cancer Prevention (PDQ®)–Health Professional Version

Who Is at Risk?

Go to Patient Version

Endometrial cancer occurs in postmenopausal women, with an average age at diagnosis of 60 years. Estrogen, both endogenous and exogenous, is associated with endometrial proliferation, hyperplasia, and cancer. Thus, risk factors include endometrial hyperplasia, reproductive factors (nulliparity, early menarche and late menopause), polycystic ovary syndrome, postmenopausal estrogen therapy, obesity with adult weight gain, and tamoxifen use. Women with Lynch syndrome have an increased risk of endometrial cancer, as do women who have a first-degree relative with endometrial cancer.

Overview

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries with information related to endometrial cancer prevention include the following:

Factors With Adequate Evidence for an Increased Risk of Endometrial Cancer

Endometrial hyperplasia

Based on solid evidence, endometrial hyperplasia is associated with concurrent [1] or subsequent development of cancer, an association first recognized in 1932.[2]

Magnitude of Effect: Women with hyperplasia and atypia have a 40% risk of concurrent cancer.[3]

  • Study Design: Prospective cohort series.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Hormone therapy (HT) with estrogen: Unopposed estrogen

Based on solid evidence, unopposed estrogen is associated with an increased risk of endometrial cancer. This excess risk can be eliminated by adding continuous progestin to estrogen therapy, but this combination is associated with an increased risk of breast cancer.[4-7] For more information, see Breast Cancer Prevention.

Magnitude of Effect: The associated risk of endometrial cancer in women who use unopposed estrogen for 5 or more years is at least twofold higher than in women who do not use the hormone. The risk increases with prolonged use of unopposed estrogen.

  • Study Design: Randomized controlled trials, cohort, and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Selective estrogen receptor modulators (SERMs)

Based on solid evidence, more than 2 years of tamoxifen use is associated with an increased risk of endometrial cancer.[8] The use of a similar SERM, raloxifene, is not associated with an increased risk.[9,10]

Magnitude of Effect: Women taking tamoxifen for more than 2 years have a 2.3-fold to 7.5-fold relative risk (RR) of endometrial cancer, including an increased risk of uterine serous carcinoma and carcinosarcoma.[11]

  • Study Design: Multiple randomized controlled trials.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Obesity

Based on solid evidence, being overweight or obese, and adult weight gain are associated with an increased risk of endometrial cancer.[12]

Magnitude of Effect: The risk of endometrial cancer increases 1.5-fold per 5 kg/m2 change in body mass.[12]

  • Study Design: Multiple randomized controlled trials.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Genetic predisposition

Based on solid evidence, women with certain inherited conditions, with highly penetrant genes, and with a family history of endometrial cancer in a first-degree relative have an increased risk of developing endometrial cancer.

Magnitude of Effect: The risk of developing endometrial cancer increased by 1.82-fold (95% confidence interval [CI], 1.65–1.98) and was associated with a history of endometrial cancer in a first-degree relative. The absolute risk of endometrial cancer among women with BRCA1 or BRCA2 was 3%.

  • Study Design: Case controls, cohort studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Factors With Adequate Evidence for a Decreased Risk of Endometrial Cancer

Pregnancy and lactation

Based on solid evidence, increased parity and duration of lactation are associated with a decreased risk of endometrial cancer.[13]

Magnitude of Effect: Parous women have a 35% decreased risk of endometrial cancer (hazard ratio [HR], 0.65; 95% CI, 0.54–0.77) compared with nulliparous women. Duration of breastfeeding has also been associated with a decreased risk, with a 23% risk reduction noted for women who breastfeed longer than 18 months. The risk reduction was attenuated when adjusted for parity.[14,15]

  • Study Design: Prospective cohort study, case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Hormonal contraceptives: Benefits

Based on solid evidence, at least 1-year use of oral contraceptives containing estrogen and progesterone decreases endometrial cancer risk, proportionate to duration of use.[16] The lower risk may persist for more than 30 years after the last use of oral contraceptives.[16,17]

  • Study Design: Case-control studies and cohort studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Magnitude of Effect: Use of oral contraceptives for 5 years was associated with an RR reduction of 24% (risk ratio, 0.76; 95% CI, 0.73–0.78) and persisted for more than 30 years. Ten years of use was associated with an absolute reduction in risk before age 75 years from 2.3 per 100 women to 1.3 per 100 women.

Hormonal contraceptives: Harms

Based on solid evidence, current use of combined oral contraceptives is associated with an increased risk of blood clots,[18] stroke, and myocardial infarction,[19] especially among women who smoke cigarettes and who are older than 35 years.

Magnitude of Effect: Use of oral contraceptives was associated with an absolute increased risk of blood clots of approximately 1 case per 4,465 person-years (95% CI, 4,095–4,797 person-years). Use of oral contraceptives was associated with an increased RR of stroke or myocardial infarction of 60% (risk ratio, 1.6; 95% CI, 1.3–1.9).

  • Study Design: Cohort studies, nested case-control studies, case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Weight loss: Benefits

The evidence is insufficient to conclude whether weight loss is associated with a decreased incidence of endometrial cancer. Based on one study, self-reported intentional weight loss during three age periods was not associated with a decrease in endometrial cancer incidence.[20] Bariatric surgery is associated with a decreased risk of developing endometrial cancer.[21-23] After bariatric surgery, other obesity-related health conditions, such as diabetes and metabolic syndrome are also often improved or resolved.

Magnitude of Effect: RR of endometrial cancer for women who intentionally lost at least 20 pounds was 0.93 (95% CI, 0.6–1.44). The incidence rate of endometrial cancer per 1,000 person-years was 1.1 in those who underwent bariatric surgery compared with 2 in the obese control group who received usual care (HR, 0.56; 95% CI, 0.35–0.89).

  • Study Design: Prospective and retrospective cohort studies.
  • Internal Validity: Good.
  • Consistency: Fair.
  • External Validity: Good.

Weight loss: Harms

A variety of procedures are included under the umbrella of bariatric surgery. Bariatric surgery is associated with a potential for short-term surgical complications, and possible medium and long-term risks. Immediate surgical complications may include infections, venous thromboembolism, respiratory or cardiac complications, anastomotic leak, marginal ulcers, stenosis or obstruction, or rarely, death.[24,25] Dumping syndrome and metabolic and nutritional derangements from malabsorption may also occur.[26]

Physical activity: Benefits

Based on solid evidence, increased physical exercise is associated with a decreased risk of endometrial cancer.[27,28]

Magnitude of Effect: Regular exercise may be associated with a 38% to 46% relative decrease in risk. However, a trend in risk reduction with increasing exercise duration or intensity has not been shown.

  • Study Design: Multiple cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Fair.
  • External Validity: Good.

Smoking: Benefits

Based on solid evidence, cigarette smoking is associated with a decreased risk of endometrial cancer.[29]

Magnitude of Effect: Smokers have a reduced risk of endometrial cancer of approximately 20% among prospective studies (RR, 0.81; 95% CI, 0.74–0.88) and case-control studies (odds ratio, 0.72; 95% CI, 0.66–0.79).[29]

  • Study Design: Prospective cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Smoking: Harms

Based on solid evidence, cigarette smoking is associated with cardiovascular disease and cancers of the head and neck, lung, bladder, and pancreas. Cigarette smokers have a decreased life expectancy; they live at least 10 fewer years than nonsmokers.[30]

Intervention With Inadequate Evidence of an Association With Endometrial Cancer

Fruits, vegetables, and vitamins

There is adequate evidence of no association between endometrial cancer and diet or vitamin intake.[31-35]

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Hair products, including dyes, bleach, highlights, straighteners, and permanents

There is insufficient evidence of an association between hair products and endometrial cancer. One retrospective analysis of the Sister Study addressed a possible association between these hair products and uterine cancers, including endometrial cancers.[36]

  • Study Design: Cohort.
  • Internal Validity: Poor.
  • Consistency: No other studies at this time.
  • External Validity: Poor.
References
  1. Widra EA, Dunton CJ, McHugh M, et al.: Endometrial hyperplasia and the risk of carcinoma. Int J Gynecol Cancer 5 (3): 233-235, 1995. [PUBMED Abstract]
  2. Taylor HC: Endometrial hyperplasia and carcinoma of the body of the uterus. Am J Obstet Gynecol 23 (3): 309-32, 1932.
  3. Trimble CL, Kauderer J, Zaino R, et al.: Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 106 (4): 812-9, 2006. [PUBMED Abstract]
  4. Beral V, Bull D, Reeves G, et al.: Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 365 (9470): 1543-51, 2005 Apr 30-May 6. [PUBMED Abstract]
  5. Anderson GL, Limacher M, Assaf AR, et al.: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291 (14): 1701-12, 2004. [PUBMED Abstract]
  6. Furness S, Roberts H, Marjoribanks J, et al.: Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. Cochrane Database Syst Rev (2): CD000402, 2009. [PUBMED Abstract]
  7. Grady D, Gebretsadik T, Kerlikowske K, et al.: Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 85 (2): 304-13, 1995. [PUBMED Abstract]
  8. Fisher B, Costantino JP, Redmond CK, et al.: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86 (7): 527-37, 1994. [PUBMED Abstract]
  9. Cummings SR, Eckert S, Krueger KA, et al.: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281 (23): 2189-97, 1999. [PUBMED Abstract]
  10. DeMichele A, Troxel AB, Berlin JA, et al.: Impact of raloxifene or tamoxifen use on endometrial cancer risk: a population-based case-control study. J Clin Oncol 26 (25): 4151-9, 2008. [PUBMED Abstract]
  11. Brinton LA, Felix AS, McMeekin DS, et al.: Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol 129 (2): 277-84, 2013. [PUBMED Abstract]
  12. Aune D, Navarro Rosenblatt DA, Chan DS, et al.: Anthropometric factors and endometrial cancer risk: a systematic review and dose-response meta-analysis of prospective studies. Ann Oncol 26 (8): 1635-48, 2015. [PUBMED Abstract]
  13. Newcomb PA, Trentham-Dietz A: Breast feeding practices in relation to endometrial cancer risk, USA. Cancer Causes Control 11 (7): 663-7, 2000. [PUBMED Abstract]
  14. Dossus L, Allen N, Kaaks R, et al.: Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 127 (2): 442-51, 2010. [PUBMED Abstract]
  15. Karageorgi S, Hankinson SE, Kraft P, et al.: Reproductive factors and postmenopausal hormone use in relation to endometrial cancer risk in the Nurses' Health Study cohort 1976-2004. Int J Cancer 126 (1): 208-16, 2010. [PUBMED Abstract]
  16. 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 16 (9): 1061-70, 2015. [PUBMED Abstract]
  17. Iversen L, Sivasubramaniam S, Lee AJ, et al.: Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners' Oral Contraception Study. Am J Obstet Gynecol 216 (6): 580.e1-580.e9, 2017. [PUBMED Abstract]
  18. de Bastos M, Stegeman BH, Rosendaal FR, et al.: Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev (3): CD010813, 2014. [PUBMED Abstract]
  19. Roach RE, Helmerhorst FM, Lijfering WM, et al.: Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev (8): CD011054, 2015. [PUBMED Abstract]
  20. Parker ED, Folsom AR: Intentional weight loss and incidence of obesity-related cancers: the Iowa Women's Health Study. Int J Obes Relat Metab Disord 27 (12): 1447-52, 2003. [PUBMED Abstract]
  21. Anveden Å, Taube M, Peltonen M, et al.: Long-term incidence of female-specific cancer after bariatric surgery or usual care in the Swedish Obese Subjects Study. Gynecol Oncol 145 (2): 224-229, 2017. [PUBMED Abstract]
  22. Schauer DP, Feigelson HS, Koebnick C, et al.: Bariatric Surgery and the Risk of Cancer in a Large Multisite Cohort. Ann Surg 269 (1): 95-101, 2019. [PUBMED Abstract]
  23. Aminian A, Wilson R, Al-Kurd A, et al.: Association of Bariatric Surgery With Cancer Risk and Mortality in Adults With Obesity. JAMA 327 (24): 2423-2433, 2022. [PUBMED Abstract]
  24. Flum DR, Belle SH, King WC, et al.: Perioperative safety in the longitudinal assessment of bariatric surgery. N Engl J Med 361 (5): 445-54, 2009. [PUBMED Abstract]
  25. Sanyal AJ, Sugerman HJ, Kellum JM, et al.: Stomal complications of gastric bypass: incidence and outcome of therapy. Am J Gastroenterol 87 (9): 1165-9, 1992. [PUBMED Abstract]
  26. van Beek AP, Emous M, Laville M, et al.: Dumping syndrome after esophageal, gastric or bariatric surgery: pathophysiology, diagnosis, and management. Obes Rev 18 (1): 68-85, 2017. [PUBMED Abstract]
  27. Moradi T, Weiderpass E, Signorello LB, et al.: Physical activity and postmenopausal endometrial cancer risk (Sweden). Cancer Causes Control 11 (9): 829-37, 2000. [PUBMED Abstract]
  28. Schouten LJ, Goldbohm RA, van den Brandt PA: Anthropometry, physical activity, and endometrial cancer risk: results from the Netherlands Cohort Study. J Natl Cancer Inst 96 (21): 1635-8, 2004. [PUBMED Abstract]
  29. Zhou B, Yang L, Sun Q, et al.: Cigarette smoking and the risk of endometrial cancer: a meta-analysis. Am J Med 121 (6): 501-508.e3, 2008. [PUBMED Abstract]
  30. Centers for Disease Control and Prevention: Smoking and Tobacco Use. Atlanta, Ga: Centers for Disease Control and Prevention, Office on Smoking and Health, 2015. Available Online. Last accessed December 18, 2023.
  31. International Agency for Research On Cancer: IARC Handbooks of Cancer Prevention. Volume 8: Fruit and Vegetables. International Agency for Research On Cancer, 2003.
  32. Bandera EV, Kushi LH, Gifkins DM, et al.: WCRF Systematic Literature Review: The Association Between Food, Nutrition, and Physical Activity and the Risk of Endometrial Cancer and Underlying Mechanisms. World Cancer Research Fund, American Institute for Cancer Research, 2006.
  33. Horn-Ross PL, John EM, Canchola AJ, et al.: Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst 95 (15): 1158-64, 2003. [PUBMED Abstract]
  34. Xu WH, Zheng W, Xiang YB, et al.: Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case-control study. BMJ 328 (7451): 1285, 2004. [PUBMED Abstract]
  35. Zeleniuch-Jacquotte A, Gallicchio L, Hartmuller V, et al.: Circulating 25-hydroxyvitamin D and risk of endometrial cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol 172 (1): 36-46, 2010. [PUBMED Abstract]
  36. Chang CJ, O'Brien KM, Keil AP, et al.: Use of Straighteners and Other Hair Products and Incident Uterine Cancer. J Natl Cancer Inst 114 (12): 1636-1645, 2022. [PUBMED Abstract]

Incidence and Mortality

Endometrial cancer is the most common invasive gynecologic cancer in U.S. women, with an estimated 67,880 new cases expected to occur in 2024.[1] This disease primarily affects postmenopausal women at an average age of 60 years at diagnosis.[2] In the United States, it is estimated that approximately 13,250 women will die of endometrial cancer in 2024. Over the past decade, incidence rates of endometrial cancer increased by about 1% per year in White women and by 2% to 3% per year in women of all other racial and ethnic groups. Since the mid-2000s, death rates for endometrial cancer increased by 1.7% per year.[1] Higher mortality from endometrial cancer in African American women compared with White women is only partly attributable to lower socioeconomic issues that impair access to care.[3,4]

Compared with the incidence in White American women, endometrial cancer incidence is lower in Japanese American (relative risk [RR], 0.6; 95% confidence interval [CI], 0.46–0.83) and Latina American women (RR, 0.63; 95% CI, 0.46–0.87), but not in African American (RR, 0.76; 95% CI, 0.53–1.08) or native Hawaiian women (RR, 0.92; 95% CI, 0.58–1.46).[5] When corrected for hysterectomy prevalence among U.S. women, the incidence of all histological subtypes of endometrial cancer has increased approximately 2% per year between 2000 and 2015 among non-Hispanic Black, non-Hispanic Asian or Pacific Islander, and Hispanic women, but has remained stable among non-Hispanic White women.[6] The incidence of endometrioid endometrial cancer has increased 1% to 2% among all racial and ethnic subgroups except non-Hispanic White women, where it has also remained stable across the same period. The greatest increase in incidence across all racial and ethnic subgroups has been seen in nonendometrioid histological subtypes, with an approximate 2% increase in non-Hispanic White women, 3% increase in non-Hispanic Black women, and 4% increase in non-Hispanic Asian or Pacific Islanders and Hispanic women. These findings challenge the supposition that the increase in endometrial cancer incidence was caused by the obesity epidemic, which would have been expected to increase the incidence of the endometrioid subtype more than the nonendometrioid subtypes.[6]

Endometrial cancer risk is associated with endogenous and exogenous factors associated with estrogen effects.[7-9] Thus, risk factors for endometrial cancer include reproductive factors such as nulliparity, early menarche, and late menopause, as well as obesity with adult weight gain, polycystic ovary syndrome, postmenopausal estrogen use, and tamoxifen use.

Women with Lynch syndrome have a lifetime risk of endometrial cancer of up to 60%.[10] For additional information about inherited risk, see Genetics of Breast and Gynecologic Cancers.

References
  1. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed June 21, 2024.
  2. American Cancer Society: Detailed Guide: Endometrial Cancer: What are the Risk Factors for Endometrial Cancer? Atlanta, Ga: American Cancer Society, 2005. Available online. Last accessed December 18, 2023.
  3. Madison T, Schottenfeld D, James SA, et al.: Endometrial cancer: socioeconomic status and racial/ethnic differences in stage at diagnosis, treatment, and survival. Am J Public Health 94 (12): 2104-11, 2004. [PUBMED Abstract]
  4. Long B, Liu FW, Bristow RE: Disparities in uterine cancer epidemiology, treatment, and survival among African Americans in the United States. Gynecol Oncol 130 (3): 652-9, 2013. [PUBMED Abstract]
  5. Setiawan VW, Pike MC, Kolonel LN, et al.: Racial/ethnic differences in endometrial cancer risk: the multiethnic cohort study. Am J Epidemiol 165 (3): 262-70, 2007. [PUBMED Abstract]
  6. Clarke MA, Devesa SS, Harvey SV, et al.: Hysterectomy-Corrected Uterine Corpus Cancer Incidence Trends and Differences in Relative Survival Reveal Racial Disparities and Rising Rates of Nonendometrioid Cancers. J Clin Oncol 37 (22): 1895-1908, 2019. [PUBMED Abstract]
  7. Zeleniuch-Jacquotte A, Akhmedkhanov A, Kato I, et al.: Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study. Br J Cancer 84 (7): 975-81, 2001. [PUBMED Abstract]
  8. Lukanova A, Lundin E, Micheli A, et al.: Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women. Int J Cancer 108 (3): 425-32, 2004. [PUBMED Abstract]
  9. Brown SB, Hankinson SE: Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. Steroids 99 (Pt A): 8-10, 2015. [PUBMED Abstract]
  10. Watson P, Vasen HF, Mecklin JP, et al.: The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96 (6): 516-20, 1994. [PUBMED Abstract]

Factors With Adequate Evidence for an Increased Risk of Endometrial Cancer

Endogenous Hyperplasia

Reproductive factors resulting in increased duration of exposure to endogenous estrogen, such as early menarche, nulliparity, and late menopause, are associated with an increased risk of endometrial cancer. Early menarche when compared with late menarche has been associated with a 39% relative increased risk of endometrial cancer among participants in the European Prospective Investigation into Cancer and Nutrition.[1] In the same study, late menopause and nulliparity were associated with a 2.2-fold and 1.6-fold increased risk, respectively. Other factors associated with increased risk, such as obesity and polycystic ovary syndrome, may also be related to increased estrogen exposure.[2] Polycystic ovary syndrome has been associated with a threefold increased risk of endometrial cancer in a meta-analysis.[3]

Hormone Therapy (HT) With Estrogen: Unopposed Estrogen

An association between postmenopausal estrogen replacement therapy and endometrial cancer was reported in 1975 [4] and confirmed soon after.[5,6] In these three studies, the overall risk ratio ranged from 4.5 to 8.0. Further studies documented an association with duration of use (10-fold to 30-fold with 5 years or more of use),[7-10] and a persistent effect lasting more than 10 years after 1 year of use.[11] When these findings were publicized, prescriptions for estrogen declined sharply, followed rapidly by a drop in endometrial cancer incidence.[12]

Postmenopausal estrogen was long recognized to be associated with the risk of endometrial hyperplasia, often a precursor of endometrial cancer.[13] In addition, progestational agents were known to be effective in the treatment of uterine neoplasms.[14-16] Consequently, combined estrogen-progesterone postmenopausal hormone therapy (HT) avoids the endometrial cancer risk associated with unopposed estrogen and actually reduces the risk by 35%.[17] Tibolone, a synthetic steroid with estrogenic, progestogenic, and androgenic properties, has been associated with an increased incidence rate ratio of endometrial cancer of 3.56 (95% confidence interval [CI], 3.08–4.69) for current users compared with never-users. Tibolone is approved for use to manage menopausal symptoms or to prevent osteoporosis in many countries. However, it is not approved for use in Canada or the United States. Other combined therapy with estrogen and progestin may also increase the risk of breast cancer, so the risks and benefits must be considered.[18,19] The Women’s Health Initiative (WHI) study was a randomized trial that compared combination estrogen and progestin therapy with no hormone replacement. The absolute excess risk of breast cancer attributable to estrogen/progestin use was 8 more invasive breast cancers per 10,000 person-years.[19]

Selective Estrogen Receptor Modulators (SERMs)

Tamoxifen and raloxifene are SERMs, drugs that have divergent estrogen agonist and antagonist effects in different target organs. The association between endometrial cancer and tamoxifen was first recognized in 1985 when three cases of endometrial cancer were described in women who had been treated with tamoxifen for breast cancer.[20] Since then, confirmation of the association has been provided by randomized clinical trials using tamoxifen for breast cancer treatment and prevention [21-24] and by case-control, observational, and laboratory studies.

The National Surgical Adjuvant Breast and Bowel Project, Breast Cancer Prevention Trial P-1 Study in women at high risk of invasive breast cancer demonstrated that tamoxifen decreased breast cancer incidence by 49%, but confirmed an increased incidence of endometrial cancer. The annual rate was 2.2 cases per 1,000 women for those who received tamoxifen versus 0.68 cases per 1,000 women for those who received placebo. Significantly increased risks were restricted to women aged 50 years or older at study entry. Of the 53 invasive cancers associated with tamoxifen use, 52 were stage I.[25] Tamoxifen use has also been shown to be associated with high-risk histological subtypes, with an odds ratio (OR) of 3.2 for uterine serous carcinoma and 5.4 for uterine carcinosarcoma; however, the absolute risk of these rare histological subtypes remains low.[26]

Raloxifene is a second-generation SERM approved for prophylaxis against postmenopausal osteoporosis. Unlike tamoxifen, it does not have an estrogenic effect on the uterus. The Multiple Outcomes of Raloxifene randomized trial, after 40 months of follow-up, showed that raloxifene reduced the risk of estrogen receptor–positive breast cancer, without increasing endometrial cancer (relative risk [RR], 0.8; 95% CI, 0.2–2.7).[27] A population-based case-control study included 547 women with endometrial cancer and 1,410 controls. The study reported a reduction in risk of endometrial cancer with raloxifene use (OR, 0.50; 95% CI, 0.29–0.85) and confirmed an increased risk associated with tamoxifen use.[28]

Obesity

Elevated body mass index (BMI), obesity, and weight gain are associated with an increased risk of endometrial cancer. One of the possible mechanisms for the observed association is an increased level of serum estrone in women with obesity as a result of aromatization of androstenedione in adipose tissue, which increases the production of estrogen.[29] Alternatively, obesity has been associated with a reduction in levels of sex hormone-binding globulin (SHBG), which may protect against endometrial cancer by decreasing bioavailable estrogen.[30] Obesity has been associated with several factors known to increase the risk of endometrial cancer, including upper-body or central adiposity, polycystic ovary syndrome, and physical inactivity.[31,32]

Body weight is a modifiable risk factor, which accounts for a substantial proportion of endometrial cases worldwide. A study conducted among European countries estimated that between 26% and 47% of endometrial cancer cases can be attributed to overweight and obesity. The same group conducted a meta-analysis of 12 studies (5 cohort and 7 case-control), which examined the relationship between obesity and endometrial cancer. Eleven of the 12 studies concluded that there is a positive association between endometrial cancer and excess weight.[33]

RRs associated with obesity range from 2 to 10. Some studies show that upper-body and central weight confer a higher risk than peripheral body weight, even after consideration of BMI.[34-36] However, other studies have failed to confirm such an association. Several studies have observed a stronger association between endometrial cancer and obesity near the time of diagnosis compared with obesity earlier in life.[37-40] An increased risk is observed across all measures of adiposity, such as BMI, waist circumference, waist-to-hip ratio, and weight gain.[41]

A meta-analysis of prospective studies observed an RR of 1.39 (95% CI, 1.29–1.49) among nonusers and 1.09 (95% CI, 1.02–1.16) among HT users for each 5 kg increase in adult weight gain.[42] Another meta-analysis also observed a stronger association between BMI and the risk of endometrial cancer in never-users of HT than in ever-users of HT.[43]

A meta-analysis examined the association between metabolic syndrome and endometrial cancer risk. The study observed an increased risk associated with metabolic syndrome (RR, 1.89; 95% CI, 1.34–2.67) and with each component of the syndrome (BMI and/or waist circumference, blood pressure, and triglyceride levels), except low high-density lipoprotein cholesterol.[44] In a meta-analysis of studies of the association between diabetes and cancer, endometrial cancer was associated with a hazard ratio (HR) of approximately 2.[45] However, data from the WHI suggest that the association between diabetes and endometrial cancer is largely mediated through the risk of obesity.[46]

Genetic Predisposition

Women with inherited conditions such as Lynch syndrome, Cowden syndrome, and polycystic ovary syndrome have an increased risk of endometrial cancer. For more information, see Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer. However, in addition to inherited syndromes with highly penetrant genes (including BRCA1 and BRCA2), having a family history of endometrial cancer in a first-degree relative also is associated with an increased risk of cancer.[47] A meta-analysis, including case-control and cohort studies, observed an increased risk of 1.82 (95% CI, 1.65–1.98) associated with a history of endometrial cancer in a first-degree relative, with an estimated cumulative absolute risk of about 3% (95% CI, 2.8%–3.4%).[47] A Dutch multicenter cohort study of women with germline BRCA1 and BRCA2 pathogenic variants concluded that the absolute risk of endometrial cancer was approximately 3%.[48]

This familial risk may result from inherited genetic predisposition and other common factors that exist in families, such as shared culture or learned behaviors.

References
  1. Dossus L, Allen N, Kaaks R, et al.: Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 127 (2): 442-51, 2010. [PUBMED Abstract]
  2. Brown SB, Hankinson SE: Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. Steroids 99 (Pt A): 8-10, 2015. [PUBMED Abstract]
  3. Haoula Z, Salman M, Atiomo W: Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod 27 (5): 1327-31, 2012. [PUBMED Abstract]
  4. Smith DC, Prentice R, Thompson DJ, et al.: Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293 (23): 1164-7, 1975. [PUBMED Abstract]
  5. Mack TM, Pike MC, Henderson BE, et al.: Estrogens and endometrial cancer in a retirement community. N Engl J Med 294 (23): 1262-7, 1976. [PUBMED Abstract]
  6. Ziel HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293 (23): 1167-70, 1975. [PUBMED Abstract]
  7. Walker AM, Jick H: Cancer of the corpus uteri: increasing incidence in the United States, 1970--1975. Am J Epidemiol 110 (1): 47-51, 1979. [PUBMED Abstract]
  8. Gray LA, Christopherson WM, Hoover RN: Estrogens and endometrial carcinoma. Obstet Gynecol 49 (4): 385-9, 1977. [PUBMED Abstract]
  9. McDonald TW, Annegers JF, O'Fallon WM, et al.: Exogenous estrogen and endometrial carcinoma: case-control and incidence study. Am J Obstet Gynecol 127 (6): 572-80, 1977. [PUBMED Abstract]
  10. Antunes CM, Strolley PD, Rosenshein NB, et al.: Endometrial cancer and estrogen use. Report of a large case-control study. N Engl J Med 300 (1): 9-13, 1979. [PUBMED Abstract]
  11. Shapiro S, Kelly JP, Rosenberg L, et al.: Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 313 (16): 969-72, 1985. [PUBMED Abstract]
  12. Austin DF, Roe KM: The decreasing incidence of endometrial cancer: public health implications. Am J Public Health 72 (1): 65-8, 1982. [PUBMED Abstract]
  13. Gusberg SB: Precursors of corpus carcinoma estrogens and adenomatous hyperplasia. Am J Obstet Gynecol 54(6): 905-927, 1947.
  14. Gusberg SB: Hormone-dependence of endometrial cancer. Obstet Gynecol 30 (2): 287-93, 1967. [PUBMED Abstract]
  15. Bonte J: Medroxyprogesterone in the management of primary and recurrent or metastatic uterine adenocarcinoma. Acta Obstet Gynecol Scand Suppl 19: 21-4, 1972. [PUBMED Abstract]
  16. KISTNER RW: Histological effects of progestins on hyperplasia and carcinoma in situ of the endometrium. Cancer 12: 1106-22, 1959 Nov-Dec. [PUBMED Abstract]
  17. Chlebowski RT, Anderson GL, Sarto GE, et al.: Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women's Health Initiative Randomized Trial. J Natl Cancer Inst 108 (3): , 2016. [PUBMED Abstract]
  18. Løkkegaard ECL, Mørch LS: Tibolone and risk of gynecological hormone sensitive cancer. Int J Cancer 142 (12): 2435-2440, 2018. [PUBMED Abstract]
  19. Simin J, Tamimi R, Lagergren J, et al.: Menopausal hormone therapy and cancer risk: An overestimated risk? Eur J Cancer 84: 60-68, 2017. [PUBMED Abstract]
  20. Killackey MA, Hakes TB, Pierce VK: Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat Rep 69 (2): 237-8, 1985. [PUBMED Abstract]
  21. Fornander T, Rutqvist LE, Cedermark B, et al.: Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1 (8630): 117-20, 1989. [PUBMED Abstract]
  22. Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 85 (17): 1398-406, 1993. [PUBMED Abstract]
  23. Andersson M, Storm HH, Mouridsen HT: Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer. J Natl Cancer Inst 83 (14): 1013-7, 1991. [PUBMED Abstract]
  24. Fisher B, Costantino JP, Redmond CK, et al.: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86 (7): 527-37, 1994. [PUBMED Abstract]
  25. Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97 (22): 1652-62, 2005. [PUBMED Abstract]
  26. Brinton LA, Felix AS, McMeekin DS, et al.: Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol 129 (2): 277-84, 2013. [PUBMED Abstract]
  27. Cummings SR, Eckert S, Krueger KA, et al.: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281 (23): 2189-97, 1999. [PUBMED Abstract]
  28. DeMichele A, Troxel AB, Berlin JA, et al.: Impact of raloxifene or tamoxifen use on endometrial cancer risk: a population-based case-control study. J Clin Oncol 26 (25): 4151-9, 2008. [PUBMED Abstract]
  29. Enriori CL, Reforzo-Membrives J: Peripheral aromatization as a risk factor for breast and endometrial cancer in postmenopausal women: a review. Gynecol Oncol 17 (1): 1-21, 1984. [PUBMED Abstract]
  30. Davidson BJ, Gambone JC, Lagasse LD, et al.: Free estradiol in postmenopausal women with and without endometrial cancer. J Clin Endocrinol Metab 52 (3): 404-8, 1981. [PUBMED Abstract]
  31. Troisi R, Potischman N, Hoover RN, et al.: Insulin and endometrial cancer. Am J Epidemiol 146 (6): 476-82, 1997. [PUBMED Abstract]
  32. Barry JA, Azizia MM, Hardiman PJ: Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 20 (5): 748-58, 2014 Sep-Oct. [PUBMED Abstract]
  33. Bergström A, Pisani P, Tenet V, et al.: Overweight as an avoidable cause of cancer in Europe. Int J Cancer 91 (3): 421-30, 2001. [PUBMED Abstract]
  34. Swanson CA, Potischman N, Wilbanks GD, et al.: Relation of endometrial cancer risk to past and contemporary body size and body fat distribution. Cancer Epidemiol Biomarkers Prev 2 (4): 321-7, 1993 Jul-Aug. [PUBMED Abstract]
  35. Elliott EA, Matanoski GM, Rosenshein NB, et al.: Body fat patterning in women with endometrial cancer. Gynecol Oncol 39 (3): 253-8, 1990. [PUBMED Abstract]
  36. Schapira DV, Kumar NB, Lyman GH, et al.: Upper-body fat distribution and endometrial cancer risk. JAMA 266 (13): 1808-11, 1991. [PUBMED Abstract]
  37. Olson SH, Trevisan M, Marshall JR, et al.: Body mass index, weight gain, and risk of endometrial cancer. Nutr Cancer 23 (2): 141-9, 1995. [PUBMED Abstract]
  38. Weiderpass E, Persson I, Adami HO, et al.: Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden). Cancer Causes Control 11 (2): 185-92, 2000. [PUBMED Abstract]
  39. Le Marchand L, Wilkens LR, Mi MP: Early-age body size, adult weight gain and endometrial cancer risk. Int J Cancer 48 (6): 807-11, 1991. [PUBMED Abstract]
  40. Shu XO, Brinton LA, Zheng W, et al.: Relation of obesity and body fat distribution to endometrial cancer in Shanghai, China. Cancer Res 52 (14): 3865-70, 1992. [PUBMED Abstract]
  41. Aune D, Navarro Rosenblatt DA, Chan DS, et al.: Anthropometric factors and endometrial cancer risk: a systematic review and dose-response meta-analysis of prospective studies. Ann Oncol 26 (8): 1635-48, 2015. [PUBMED Abstract]
  42. Keum N, Ju W, Lee DH, et al.: Leisure-time physical activity and endometrial cancer risk: dose-response meta-analysis of epidemiological studies. Int J Cancer 135 (3): 682-94, 2014. [PUBMED Abstract]
  43. Crosbie EJ, Zwahlen M, Kitchener HC, et al.: Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 19 (12): 3119-30, 2010. [PUBMED Abstract]
  44. Esposito K, Chiodini P, Capuano A, et al.: Metabolic syndrome and endometrial cancer: a meta-analysis. Endocrine 45 (1): 28-36, 2014. [PUBMED Abstract]
  45. Friberg E, Orsini N, Mantzoros CS, et al.: Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 50 (7): 1365-74, 2007. [PUBMED Abstract]
  46. Luo J, Beresford S, Chen C, et al.: Association between diabetes, diabetes treatment and risk of developing endometrial cancer. Br J Cancer 111 (7): 1432-9, 2014. [PUBMED Abstract]
  47. Win AK, Reece JC, Ryan S: Family history and risk of endometrial cancer: a systematic review and meta-analysis. Obstet Gynecol 125 (1): 89-98, 2015. [PUBMED Abstract]
  48. de Jonge MM, de Kroon CD, Jenner DJ, et al.: Endometrial Cancer Risk in Women With Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study. J Natl Cancer Inst 113 (9): 1203-1211, 2021. [PUBMED Abstract]

Factors With Adequate Evidence for a Decreased Risk of Endometrial Cancer

Pregnancy and Lactation

Decreased risk of endometrial cancer is associated with parity and lactation, perhaps by inhibiting ovulation. The European Prospective Investigation into Cancer and Nutrition observed a decreased risk associated with parity compared with nulliparous women (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.54–0.77). The study also observed a trend of decreased risk with increasing number of full-term pregnancies (P < .0001).[1] A pooled analysis of 11 cohort and 19 case-control studies evaluated associations between specific pregnancy outcomes and endometrial cancer.[2] The risk reduction associated with pregnancy was greatest for the first full-term birth (odds ratio [OR], 0.78; 95% CI, 0.72–0.84). Each additional full-term pregnancy was associated with an additional approximately 15% risk reduction up to eight full-term pregnancies (OR, 0.20; 95% CI, 0.14–0.28). Multiple gestation pregnancies did not appear to provide additional benefit beyond that of a singleton birth. Incomplete pregnancies were also associated with a decreased risk of endometrial cancer, with a 7% reduction per episode and an OR of 0.89 (95% CI, 0.84–0.95) for the first incomplete pregnancy. When evaluated by type of incomplete pregnancy, the associated risk reductions for spontaneous abortions (OR, 0.83; 95% CI, 0.76–0.90) and induced abortions (OR, 0.89; 95% CI, 0.79–1.01) were identified.

Data was pooled from 17 studies that participated in the Epidemiology of Endometrial Cancer Consortium. After adjusting for age, parity, use of oral contraception and duration of use, body mass index (BMI), and education level, parous women who reported breast feeding had an 11% reduction in risk of endometrial cancer (pooled OR, 0.89; 95% CI, 0.81–0.98).[3] The risk reduction associated with increasing total duration of breastfeeding was not linear. The greatest reduction in risk occurred after a total duration of breastfeeding of greater than 36 months (adjusted pooled OR, 0.67; 95% CI, 0.53–0.83). However, for individual episodes of breastfeeding, breastfeeding one child beyond 3 months was associated with a 5% reduction in risk (adjusted pooled OR, 0.95; 95% CI, 0.91–0.99).[3]

Hormonal Contraceptives

Oral contraceptives were first approved by the U.S. Food and Drug Administration in 1960. For many years, they were the mainstay of hormonal contraception. More recently, hormonal contraception has expanded to include combination transdermal patches or vaginal rings, injections, and progestogen-releasing long-acting reversible contraceptives, including single-rod implants and intrauterine systems (IUS).[4]

Oral contraceptive usage confers a long-term reduction in the risk of endometrial cancer. A large population-based study from the United Kingdom prospectively collected information on combined oral contraception use for 46,022 women and followed them for 44 years. In this study, after adjusting for age, parity, smoking, and social class, ever-users of combined estrogen/progesterone oral contraceptive pills had an incidence rate ratio of 0.66 (95% CI, 0.48–0.89) compared with never-users.[5] The benefit of oral contraceptive pill use is associated with duration of use, with increasing benefit reported for women who were obese, current smokers, and those who rarely exercise and who used oral contraceptives for 10 years or more.[6] A meta-analysis combined data from 36 epidemiological studies that included 27,276 women. The study observed a risk reduction of 0.76 (95% CI, 0.73–0.78) for every 5 years of oral contraceptive use. The lower risk persisted for more than 30 years after the last use of oral contraceptives.[5,7] Among women from highly developed countries, 10 years of oral contraceptive use was associated with an absolute risk reduction of endometrial cancer before age 75 years from 2.3 to 1.3 cases per 100 women.[7]

Data suggest that use of levonorgestrel-releasing intrauterine systems (LNG-IUS) is associated with a statistically significant reduction in the risk of developing endometrial cancer. Use of LNG-IUS is an effective treatment for endometrial hyperplasia, which in some cases is a precursor to endometrial cancer and early-stage low-risk endometrial cancer.[8-10] A population-based prospective cohort study in Norway evaluated a cohort of 104,380 women, which included 9,146 women who identified as ever-users of LNG-IUS. The incidence rate of endometrial cancer per 100,000 person-years was 13.9 for ever-users of LNG-IUS (95% CI, 7.8–23.0), compared with 70.0 (95% CI, 65.4–74.9) for never-users. After adjusting for age and menopausal status at the start of follow-up, BMI, physical activity level, use of oral contraceptive pills, and parity, the relative risk (RR) of endometrial cancer was 0.22 (95% CI, 0.13–0.40) for ever-users of LNG-IUS.[11] In an observational nationwide cohort study from Finland, women using LNG-IUS for treatment of menorrhagia from 1994 to 2007 were identified from administrative registers and linked with the Finnish Cancer Registry.[12] In this study, 93,843 users of LNG-IUS were followed for 855,324 women-years at risk. The standardized incidence ratio for endometrial cancer after at least one purchase of LNG-IUS was 0.46 (95% CI, 0.33–0.64; 37 observed cases compared with 80 expected cases). Although not statistically different, the standardized incidence ratio decreased further in women who had purchased two LNG-IUS (0.25; 95% CI, 0.05–0.73; 3 observed cases compared with 12 expected cases). These data represent an attempt to demonstrate a dose effect, as LNG-IUS are considered effective for 5 years.

Weight Loss

While it is known that obesity is associated with increased endometrial cancer risk, only one study examines the potential benefit of intentional weight loss. In the Iowa Women’s Health Study (IWHS) of 21,707 postmenopausal women,[13] participants completed a self-report questionnaire about intentional weight loss between ages 18 and 39 years, between ages 40 and 54 years, and after age 55 years. Multivariate models adjusting for age, BMI, and BMI2 found no association between endometrial cancer incidence and intentional weight loss of at least 20 pounds (RR, 0.93; 95% CI, 0.60–1.44). However, one study included 36,793 women from the Women's Health Initiative (WHI) cohort [14] whose weight was measured at baseline and at 3-year follow-up and was combined with self-reported intentionality of weight loss. The analysis showed an association between intentional weight loss of 10 pounds or more and lower endometrial cancer incidence (multivariable-adjusted RR, 0.61; 95% CI, 0.40–0.92).

Both of these analyses share substantial limitations. Missing covariate data resulted in excluding nearly 25% of participants from each study, and only small percentages of the remaining participants (17% IWHS/8% WHI) were classified into the intentional weight loss category. This resulted in very low numbers of endometrial cancer cases driving the analyses. Both studies used self-report to characterize intentionality of weight loss, which can lead to potential misclassification, although the retrospective nature of the questioning in the IWHS makes the problem more acute in that analysis. Both analyses also adjusted for self-reported physical activity and smoking status, among other covariates. With such small numbers of cases and the potential for residual confounding, the contradictory results of these two analyses suggest that there is scant evidence to conclude that nonsurgical weight loss is protective for endometrial cancer.

Bariatric surgery is associated with more sustained weight loss compared with nonsurgical intentional weight loss.[15] Evidence suggests an association between bariatric surgery and a decreased risk of endometrial cancer.[16-18] In a prospective cohort study from Sweden, 1,420 women with obesity who underwent bariatric surgery and 1,447 matched controls who underwent conventional obesity treatment were followed for a median of 18.1 years.[16] Mean weight loss after bariatric surgery was 21 kilograms at 10 years, compared with almost no change in weight in the usual care cohort. In this study, bariatric surgery was associated with a reduced risk of endometrial cancer (HR, 0.56; 95% CI, 0.35–0.89). Of note, this was not a prespecified study end point or powered to evaluate incidence of cancer. A retrospective cohort study through the Kaiser Permanente health system evaluated 22,198 individuals who had bariatric surgery and 66,427 nonsurgical individuals who were matched on sex, age, study site, BMI, and Elixhauser comorbidity index.[17] More than 80% of the cohort was female. After a mean follow-up time of 3.5 years, there was a 50% reduction in the incidence of endometrial cancer (HR, 0.50; 95% CI, 0.37–0.67) in the cohort who underwent bariatric surgery. A systematic review, which included five observational studies with a control group, reported a decrease in the odds of developing endometrial cancer after bariatric surgery (OR, 0.32; 95% CI, 0.16–0.63).[18] A large retrospective cohort study from England, which followed patients for a median of 3 years in the surgery group and 2.5 years in the no-surgery group, did not find an association with a decreased risk of endometrial cancer after bariatric surgery compared with obese controls.[19] The association of bariatric surgery and decrease in the incidence of endometrial cancer may be caused by secondary effects of weight loss. In one study, women who underwent bariatric surgery had a 35% decrease in blood estradiol levels 1 year after surgery.[20] Bariatric surgery has also been associated with a return to regular menstrual cycles in a high proportion of women with previous menstrual irregularities.[21] The Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death (SPLENDID) study was a retrospective, observational, matched cohort study of patients with obesity who underwent contemporary bariatric surgery (i.e., Roux-en-Y gastric bypass or sleeve gastrectomy) or received usual care (no bariatric surgery).[22] Median follow-up was 6.1 years. The primary end point was the first occurrence of 1 of 13 predefined obesity-associated cancers. Secondary endpoints included incidence of all types of cancer and cancer-related mortality.[22] In the adjusted Cox models that evaluated incidence of individual cancer types, only endometrial cancer remained significant (adjusted HR, 0.47; 95% CI, 0.27–0.83). There were limitations to this study, which included selection bias and different rates of cancer screening behaviors between the study arms, stemming from the observational nature of the study. In addition, there was the low number of incident cancers and a limited follow-up time.

Physical Activity

A meta-analysis combined data from prospective studies of recreational activity (nine studies) and occupational activity (five studies) to determine whether activity is associated with endometrial cancer.[23] The highest category of recreational activity was associated with an RR of endometrial cancer of 0.73 (95% CI, 0.58–0.93), compared with lowest category. The RR of endometrial cancer for the highest category of occupational physical activity, based on job classification, was 0.75 (95% CI, 0.68–0.83), compared with the lowest category. Further investigation using the metabolic equivalent of task (MET) and combining data from case-control and cohort studies revealed a decrease in endometrial cancer risk with activity up to 50 MET-hours per week (up to 15 hours/week).[24]

Smoking

Ever-smokers who smoked at least 20 cigarettes per day have a decreased risk of endometrial cancer, with greatest risk reductions seen in postmenopausal women and in current smokers. This effect has been seen in observational cohort, prospective cohort, and case-control studies and was summarized in a meta-analysis.[25,26] However, such a decrease does not begin to compensate for the many well-documented harms of smoking. These harms are most evident in the increased risk of cardiovascular diseases and other cancers, to the extent that smokers have at least a 10-year decrease in overall life expectancy, compared with nonsmokers.[27]

In contrast, Mendelian randomization analyses have not shown a causal relationship between smoking and decreased endometrial cancer risk in the U.K. Biobank and European Prospective Investigation into Cancer and Nutrition (EPIC) patient cohorts, questioning the strength of this association that was seen in the study's observational analyses.[26]

References
  1. Dossus L, Allen N, Kaaks R, et al.: Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 127 (2): 442-51, 2010. [PUBMED Abstract]
  2. Jordan SJ, Na R, Weiderpass E, et al.: Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium. Int J Cancer 148 (9): 2068-2078, 2021. [PUBMED Abstract]
  3. Jordan SJ, Na R, Johnatty SE, et al.: Breastfeeding and Endometrial Cancer Risk: An Analysis From the Epidemiology of Endometrial Cancer Consortium. Obstet Gynecol 129 (6): 1059-1067, 2017. [PUBMED Abstract]
  4. Regidor PA: Clinical relevance in present day hormonal contraception. Horm Mol Biol Clin Investig 37 (1): , 2018. [PUBMED Abstract]
  5. Iversen L, Sivasubramaniam S, Lee AJ, et al.: Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners' Oral Contraception Study. Am J Obstet Gynecol 216 (6): 580.e1-580.e9, 2017. [PUBMED Abstract]
  6. Michels KA, Pfeiffer RM, Brinton LA, et al.: Modification of the Associations Between Duration of Oral Contraceptive Use and Ovarian, Endometrial, Breast, and Colorectal Cancers. JAMA Oncol 4 (4): 516-521, 2018. [PUBMED Abstract]
  7. 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 16 (9): 1061-70, 2015. [PUBMED Abstract]
  8. Orbo A, Vereide A, Arnes M, et al.: Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial. BJOG 121 (4): 477-86, 2014. [PUBMED Abstract]
  9. Kim MK, Seong SJ, Kim JW, et al.: Management of Endometrial Hyperplasia With a Levonorgestrel-Releasing Intrauterine System: A Korean Gynecologic-Oncology Group Study. Int J Gynecol Cancer 26 (4): 711-5, 2016. [PUBMED Abstract]
  10. Pal N, Broaddus RR, Urbauer DL, et al.: Treatment of Low-Risk Endometrial Cancer and Complex Atypical Hyperplasia With the Levonorgestrel-Releasing Intrauterine Device. Obstet Gynecol 131 (1): 109-116, 2018. [PUBMED Abstract]
  11. Jareid M, Thalabard JC, Aarflot M, et al.: Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study. Gynecol Oncol 149 (1): 127-132, 2018. [PUBMED Abstract]
  12. Soini T, Hurskainen R, Grénman S, et al.: Cancer risk in women using the levonorgestrel-releasing intrauterine system in Finland. Obstet Gynecol 124 (2 Pt 1): 292-9, 2014. [PUBMED Abstract]
  13. Parker ED, Folsom AR: Intentional weight loss and incidence of obesity-related cancers: the Iowa Women's Health Study. Int J Obes Relat Metab Disord 27 (12): 1447-52, 2003. [PUBMED Abstract]
  14. Luo J, Chlebowski RT, Hendryx M, et al.: Intentional Weight Loss and Endometrial Cancer Risk. J Clin Oncol 35 (11): 1189-1193, 2017. [PUBMED Abstract]
  15. Sjöström L, Gummesson A, Sjöström CD, et al.: Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol 10 (7): 653-62, 2009. [PUBMED Abstract]
  16. Anveden Å, Taube M, Peltonen M, et al.: Long-term incidence of female-specific cancer after bariatric surgery or usual care in the Swedish Obese Subjects Study. Gynecol Oncol 145 (2): 224-229, 2017. [PUBMED Abstract]
  17. Schauer DP, Feigelson HS, Koebnick C, et al.: Bariatric Surgery and the Risk of Cancer in a Large Multisite Cohort. Ann Surg 269 (1): 95-101, 2019. [PUBMED Abstract]
  18. Winder AA, Kularatna M, MacCormick AD: Does Bariatric Surgery Affect the Incidence of Endometrial Cancer Development? A Systematic Review. Obes Surg 28 (5): 1433-1440, 2018. [PUBMED Abstract]
  19. Aravani A, Downing A, Thomas JD, et al.: Obesity surgery and risk of colorectal and other obesity-related cancers: An English population-based cohort study. Cancer Epidemiol 53: 99-104, 2018. [PUBMED Abstract]
  20. Sarwer DB, Spitzer JC, Wadden TA, et al.: Changes in sexual functioning and sex hormone levels in women following bariatric surgery. JAMA Surg 149 (1): 26-33, 2014. [PUBMED Abstract]
  21. Butterworth J, Deguara J, Borg CM: Bariatric Surgery, Polycystic Ovary Syndrome, and Infertility. J Obes 2016: 1871594, 2016. [PUBMED Abstract]
  22. Aminian A, Wilson R, Al-Kurd A, et al.: Association of Bariatric Surgery With Cancer Risk and Mortality in Adults With Obesity. JAMA 327 (24): 2423-2433, 2022. [PUBMED Abstract]
  23. Moore SC, Gierach GL, Schatzkin A, et al.: Physical activity, sedentary behaviours, and the prevention of endometrial cancer. Br J Cancer 103 (7): 933-8, 2010. [PUBMED Abstract]
  24. Keum N, Ju W, Lee DH, et al.: Leisure-time physical activity and endometrial cancer risk: dose-response meta-analysis of epidemiological studies. Int J Cancer 135 (3): 682-94, 2014. [PUBMED Abstract]
  25. Zhou B, Yang L, Sun Q, et al.: Cigarette smoking and the risk of endometrial cancer: a meta-analysis. Am J Med 121 (6): 501-508.e3, 2008. [PUBMED Abstract]
  26. Dimou N, Omiyale W, Biessy C, et al.: Cigarette Smoking and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses. Cancer Epidemiol Biomarkers Prev 31 (9): 1839-1848, 2022. [PUBMED Abstract]
  27. Centers for Disease Control and Prevention: Smoking and Tobacco Use. Atlanta, Ga: Centers for Disease Control and Prevention, Office on Smoking and Health, 2015. Available Online. Last accessed December 18, 2023.

Interventions With Inadequate Evidence of an Association With Endometrial Cancer

Fruits, Vegetables, and Vitamins

Studies have not found an association between endometrial cancer and diet, phytoestrogens, soy, and vitamin D.[1-6] Multivitamin use has little or no influence on the risk of common cancers, including endometrial cancer, or on total mortality in postmenopausal women.[7]

Hair Products, Including Dyes, Bleach, Highlights, Straighteners, and Permanents

One retrospective analysis of the Sister Study addressed a possible association between these hair products and uterine cancers, including endometrial cancers. A limitation to this study was a lack of properly adjusted analysis for multiple comparisons, thus making the significance of the findings hard to interpret.[8]

References
  1. International Agency for Research On Cancer: IARC Handbooks of Cancer Prevention. Volume 8: Fruit and Vegetables. International Agency for Research On Cancer, 2003.
  2. Bandera EV, Kushi LH, Gifkins DM, et al.: WCRF Systematic Literature Review: The Association Between Food, Nutrition, and Physical Activity and the Risk of Endometrial Cancer and Underlying Mechanisms. World Cancer Research Fund, American Institute for Cancer Research, 2006.
  3. Horn-Ross PL, John EM, Canchola AJ, et al.: Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst 95 (15): 1158-64, 2003. [PUBMED Abstract]
  4. Xu WH, Zheng W, Xiang YB, et al.: Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case-control study. BMJ 328 (7451): 1285, 2004. [PUBMED Abstract]
  5. Zeleniuch-Jacquotte A, Gallicchio L, Hartmuller V, et al.: Circulating 25-hydroxyvitamin D and risk of endometrial cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol 172 (1): 36-46, 2010. [PUBMED Abstract]
  6. Liu JJ, Bertrand KA, Karageorgi S, et al.: Prospective analysis of vitamin D and endometrial cancer risk. Ann Oncol 24 (3): 687-92, 2013. [PUBMED Abstract]
  7. Neuhouser ML, Wassertheil-Smoller S, Thomson C, et al.: Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts. Arch Intern Med 169 (3): 294-304, 2009. [PUBMED Abstract]
  8. Chang CJ, O'Brien KM, Keil AP, et al.: Use of Straighteners and Other Hair Products and Incident Uterine Cancer. J Natl Cancer Inst 114 (12): 1636-1645, 2022. [PUBMED Abstract]

Latest Updates to This Summary (03/15/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence and Mortality

Updated statistics with estimated new cases and deaths for 2024 (cited American Cancer Society as reference 1). Also revised text to state that over the past decade, incidence rates of endometrial cancer increased by about 1% per year in White women and by 2% to 3% per year in women of all other racial and ethnic groups. Since the mid-2000s, death rates for endometrial cancer increased by 1.7% per year.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about endometrial cancer prevention. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

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Levels of Evidence

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PDQ® Screening and Prevention Editorial Board. PDQ Endometrial Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/uterine/hp/endometrial-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389477]

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