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Endometrial Cancer Prevention (PDQ®)–Health Professional Version

Who Is at Risk?

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 with a first-degree relative with endometrial cancer.

Overview

Note: Separate PDQ summaries on Endometrial Cancer Screening; Endometrial Cancer Treatment; Genetics of Breast and Gynecologic Cancers; and Uterine Sarcoma Treatment are also available.

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] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

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, and the risk increases with duration of use.

  • 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] A similar SERM, raloxifene, does not have this association.[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.

Factors With Adequate Evidence for a Decreased Risk of Endometrial Cancer

Increasing parity 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, 0.65; 95% confidence interval [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 with breastfeeding more 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.[21,22] 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.[23,24] Dumping syndrome and metabolic and nutritional derangements from malabsorption may also occur.[25]

Physical activity: Benefits

Based on solid evidence, increased physical exercise is associated with a decreased risk of endometrial cancer.[26,27]

Magnitude of Effect: Regular exercise may be associated with a 38% to 46% relative decrease in risk, although a trend in risk reduction with increasing 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.[28]

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).[28]

  • 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 years fewer than nonsmokers.[29]

Intervention With Adequate Evidence of No Association With Endometrial Cancer

Fruits, vegetables, and vitamins

There is adequate evidence of no association between endometrial cancer and diet or vitamin intake.[30-34]

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.
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. 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]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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 August 9, 2019.
  30. International Agency for Research On Cancer: IARC Handbooks of Cancer Prevention. Volume 8: Fruit and Vegetables. Lyon, France: International Agency for Research On Cancer, 2003.
  31. 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. Washington, DC: World Cancer Research Fund, American Institute for Cancer Research, 2006.
  32. 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]
  33. 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]
  34. 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]

Description of Evidence

Incidence and Mortality

Endometrial cancer is the most common invasive gynecologic cancer in U.S. women, with an estimated 61,880 new cases expected to occur in 2019.[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 12,160 women will die of endometrial cancer in 2019. From 2006 to 2015, incidence rates of endometrial cancer increased by 1% per year in white women and by 2% per year in African American women. From 2007 to 2016, death rates for endometrial cancer increased by about 2% per year in both white women and African American women.[1] Higher mortality from endometrial cancer in African Americans compared with white women is only partly attributable to lower socioeconomic issues that impair access to care.[3,4]

Compared with white Americans, endometrial cancer incidence is lower in Japanese Americans (relative risk [RR], 0.6; 95% confidence interval [CI], 0.46–0.83) and Latinas (RR, 0.63; 95% CI, 0.46–0.87), but not African Americans (RR, 0.76; 95% CI, 0.53–1.08) or native Hawaiians (RR, 0.92; 95% CI, 0.58–1.46).[5]

Endometrial cancer risk is associated with endogenous and exogenous factors associated with estrogen effects.[6-8] 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%.[9] (Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for additional information on inherited risk.)

Factors With Adequate Evidence for an Increased Risk of Endometrial Cancer

Endogenous estrogen

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 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.[10] 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.[8] Polycystic ovary syndrome has been associated with a threefold increased risk of endometrial cancer in a meta-analysis.[11]

Postmenopausal estrogen therapy

An association between postmenopausal estrogen replacement therapy and endometrial cancer was reported in 1975 [12] and confirmed soon after.[13,14] 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),[15-18] and a persistent effect lasting more than 10 years after 1 year of use.[19] When these findings were publicized, prescriptions for estrogen declined sharply, followed rapidly by a drop in endometrial cancer incidence.[20]

Postmenopausal estrogen was long recognized to be associated with the risk of endometrial hyperplasia, often a precursor of endometrial cancer.[21] In addition, progestational agents were known to be effective in the treatment of uterine neoplasms.[22-24] Consequently, combined estrogen-progesterone postmenopausal hormone therapy (HT) has been shown to avoid the endometrial cancer risk associated with unopposed estrogen and actually reduce the risk by 35%.[25] 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% 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.[26,27] The absolute excess risk for breast cancer attributable to estrogen/progestin in the randomized trial of combination estrogen and progestin therapy versus no hormone replacement in the Women’s Health Initiative (WHI) study was 8 more invasive breast cancers per 10,000 person-years.[27]

Selective estrogen receptor modulators (SERMs): Tamoxifen and raloxifene

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.[28] Since then, confirmation of the association has been provided by randomized clinical trials using tamoxifen for breast cancer treatment and prevention [29-32] 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 receiving tamoxifen versus 0.68 cases per 1,000 women for those on placebo. Significantly increased risks were restricted to women 50 years or older at study entry. Of the 53 invasive cancers associated with tamoxifen use, 52 were stage I.[33] Tamoxifen use has also been shown to be associated with high-risk histologic 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 histologic subtypes remains low.[34]

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 (RR, 0.8; 95% CI, 0.2–2.7).[35] A population-based case-control study of 547 women with endometrial cancer and 1,410 controls reported a reduction of risk for endometrial cancer with raloxifene use (OR, 0.50; 95% CI, 0.29–0.85) and confirmed an increased risk associated with tamoxifen use.[36]

Obesity, weight gain, metabolic syndrome, and diabetes

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 obese women as a result of aromatization of androstenedione in adipose tissue, which increases the production of estrogen.[37] 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.[38] 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.[39,40]

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.[41]

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.[42-44] 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.[45-48] An increased risk is observed across all measures of adiposity, such as BMI, waist circumference, waist-to-hip ratio, and weight gain.[49]

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.[50] 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.[51]

A meta-analysis examining the association between metabolic syndrome and endometrial cancer 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.[52] 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.[53] However, data from the WHI suggest that the association between diabetes and endometrial cancer is largely mediated through the risk of obesity.[54]

Genetic predisposition

Women with inherited conditions such as Lynch syndrome, Cowden syndrome, and polycystic ovary syndrome have an increased risk of endometrial cancer. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer for more information.) However, in addition to inherited syndromes with highly penetrant genes, having a family history of endometrial cancer in a first-degree relative also is associated with an increased risk of cancer.[55] 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%).[55]

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

Factors With Adequate Evidence for a Decreased Risk of Endometrial Cancer

Increasing parity 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 (HR, 0.65; 95% CI, 0.54–0.77) with a trend of decreasing risk with increasing number of full-term pregnancies (P < .0001).[10] Pooled data from 17 studies participating in the Epidemiology of Endometrial Cancer Consortium suggest that among parous women—after adjusting for age, parity, use of oral contraception and duration of use, BMI, and education level—there was an 11% reduction in risk of endometrial cancer for those who had reported breastfeeding (pooled OR, 0.89; 95% CI, 0.81–0.98).[56] The risk reduction associated with increasing total duration of breastfeeding was not linear. While 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), 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).[56]

Hormonal contraceptives

Oral contraceptives were first approved by the U.S. Food and Drug Administration in 1960, and for many years 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).[57]

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.[58] 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.[59] A meta-analysis combining data from 36 epidemiological studies including 27,276 women observed a risk reduction of 0.76 (95% CI, 0.73–0.78) for every 5 years of use. The lower risk persisted for more than 30 years after the last use of oral contraceptives.[58,60] Ten years of oral contraceptive use was associated with an absolute risk reduction of endometrial cancer before age 75 from 2.3 to 1.3 per 100 women, among women from highly developed countries.[60]

Emerging data suggest that use of levonorgestrel-releasing intrauterine systems (LNG-IUS) are associated with a statistically significant reduction in the risk of developing endometrial cancer. Use of LNG-IUS are an effective treatment for endometrial hyperplasia, which in some cases is a precursor to endometrial cancer and early-stage low-risk endometrial cancer.[61-63]. 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 RR of endometrial cancer was 0.22 (95% CI, 0.13–0.40) for ever-users of LNG-IUS.[64] 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.[65] 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 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,[66] 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, an analysis of 36,793 women from the WHI cohort [67] whose weight measured at baseline and at 3-year follow-up was combined with self-reported intentionality of weight loss 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, resulting 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.[68] Emerging evidence suggests an association between bariatric surgery and a decreased risk of endometrial cancer.[69-71] In a prospective cohort study from Sweden, 1,420 obese women who underwent bariatric surgery and 1,447 matched controls who underwent conventional obesity treatment were followed for a median of 18.1 years.[69] 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 endpoint 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.[70] 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).[71] 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 for endometrial cancer after bariatric surgery compared with obese controls.[72] 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.[73] Bariatric surgery has also been associated with a return to regular menstrual cycles in a high proportion of women with previous menstrual irregularities.[74]

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 association with endometrial cancer.[75] The highest versus the lowest category of recreational activity was associated with an RR for endometrial cancer of 0.73 (95% CI, 0.58–0.93); the RR of endometrial cancer for the highest versus lowest category of occupational physical activity, based on job classification, was 0.75 (95% CI, 0.68–0.83.) 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).[50]

Smoking

Ever-smokers of at least 20 cigarettes per day have a decreased risk of endometrial cancer, with greater risk reduction in postmenopausal women and in current smokers. This effect has been seen in prospective cohort and case-control studies and was summarized in a meta-analysis.[76] The many well-documented harms of smoking 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 life expectancy, compared with nonsmokers.[77]

Interventions With Inadequate Evidence of an Association With Endometrial Cancer

Fruits, vegetables, and vitamins

Studies of the association between endometrial cancer and diet, phytoestrogens, soy, and vitamin D have been negative.[78-83] Multivitamin use has little or no influence on the risk of common cancers, including endometrial cancer, or on total mortality in postmenopausal women.[84]

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Changes to This Summary (09/10/2019)

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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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