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 ovarian syndrome, postmenopausal estrogen therapy, obesity with adult weight gain, and tamoxifen use. Women with hereditary nonpolyposis colorectal cancer syndrome have an increased risk of endometrial cancer, as do women with a first-degree relative with endometrial cancer.
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.     (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Based on solid evidence, increased parity and duration of lactation are associated with a decreased risk of endometrial cancer. 
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. This benefit lasts at least 15 years after cessation. 
Based on solid evidence, current use of oral contraceptives is associated with an increased risk of blood clots, stroke, and myocardial infarction, especially among women who smoke cigarettes and who are older than 35 years.
Based on solid evidence, cigarette smoking is associated with a decreased risk of endometrial cancer. 
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. 
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. 
Endometrial cancer is the most common invasive gynecologic cancer in U.S. women, with an estimated 61,380 new cases expected to occur in 2017.  This disease primarily affects postmenopausal women at an average age of 60 years at diagnosis.  In the United States, it is estimated that approximately 10,920 women will die of endometrial cancer in 2017. From 2004 to 2013, incidence rates of endometrial cancer have increased by 1% per year in white women and by 3% per year in African American women. From 2005 to 2014, death rates for endometrial cancer increased by about 1% per year in white women and by 2% per year in African American women. 
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 in Latinas (RR, 0.63; 95% CI, 0.46–0.87), but not in African Americans (RR, 0.76; 95% CI, 0.53–1.08) or in native Hawaiians (RR, 0.92; 95% CI, 0.58–1.46).  Higher mortality from endometrial cancer in African Americans is at least partly attributable to lower socioeconomic issues that impair access to care. 
Endometrial cancer risk is associated with endogenous and exogenous factors associated with estrogen effects.    Thus, risk factors for endometrial cancer include reproductive factors such as nulliparity, early menarche, and late menopause, obesity, polycystic ovarian syndrome, postmenopausal estrogen use and tamoxifen use.
Women with hereditary nonpolyposis colorectal cancer syndrome have a lifetime risk of endometrial cancer of up to 60%.  (Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for additional information on inherited risk.)
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. Other factors associated with increased risk, such as obesity and polycystic ovarian syndrome, may also be related to increased estrogen exposure. 
An association between postmenopausal estrogen replacement therapy and endometrial cancer was reported in 1975  and confirmed soon after.   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),     and a persistent effect lasting more than 10 years after 1 year of use.  When these findings were publicized, prescriptions for estrogen declined sharply, followed rapidly by a drop in endometrial cancer incidence. 
Postmenopausal estrogen was long recognized to be associated with the risk of endometrial hyperplasia, often a precursor of endometrial cancer.  In addition, progestational agents were known to be effective in the treatment of uterine neoplasms.    Consequently, combined estrogen-progesterone postmenopausal hormone therapy (HT) was proposed to avoid the endometrial cancer risk associated with unopposed estrogen.   Unfortunately, the combined therapy increases the risk of breast cancer, so it is not recommended to treat menopausal symptoms.
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.  Since then, confirmation of the association has been provided by randomized clinical trials using tamoxifen for breast cancer treatment and prevention     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 2.3 cases per 1,000 women for those receiving tamoxifen versus 0.91 cases per 1,000 women for those on placebo. Women older than 50 years experienced the largest effect. Of the 51 invasive cancers diagnosed in this trial, 50 were stage I. 
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).  A population-based study of 547 women with endometrial cancer and 1,410 controls was done in Philadelphia, Pennsylvania. Of the cases, 18 (3.3%) had taken raloxifene and 34 (6.2%) had taken tamoxifen (odds ratio [OR], 3.0; 95% CI, 1.3–6.9). 
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.  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.  Obesity has been associated with several factors known to increase the risk of endometrial cancer, including upper-body or central adiposity, polycystic ovarian syndrome, and physical inactivity.  
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. 
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.    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.     An increased risk is observed across all measures of adiposity, such as BMI, waist circumference, waist-to-hip ratio, and weight gain. 
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.  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. 
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.  In an umbrella analysis of studies of the association between type 1 diabetes and cancer, endometrial cancer was one of only a few sites with robust evidence of an association. 
Women with inherited conditions such as Lynch syndrome, Cowden syndrome, and polycystic ovarian 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.  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). 
This familial risk may result from inherited genetic predisposition and other common factors that exist is families, such as shared culture or learned behaviors.
Decreased risk of endometrial cancer is associated with parity and lactation, perhaps by inhibiting ovulation. A case-control study conducted in Mexico City, among low-risk women, indicates a 58% to 72% reduction in risk of endometrial cancer associated with increasing duration of lactation. A significant trend was seen for duration of lactation and for the number of children breastfed.  A population-based case-control study, comparing Wisconsin women who breastfed for at least 2 weeks versus those who did not, was negative (OR, 0.90; 95% CI, 0.72–1.13). Increasing duration of lactation was not associated with a decrease in disease risk, but breastfeeding within the past three decades was associated with reduced risk (OR, 0.58; 95% CI, 0.36–0.96), as was the first breastfeeding after age 30 years (95% CI, 0.28–0.90).  The European Prospective Investigation into Cancer and Nutrition observed a decreased risk associated with parity compared with nulliparous women (hazard ratio, 0.65; 95% CI, 0.54–0.77) with a trend of decreasing risk with increasing number of full-term pregnancies (P < .0001). While breastfeeding for more than 18 months was associated with a decreased risk, the association attenuated and was no longer statistically significant after adjusting for the numbers of full-term pregnancies. 
Oral contraceptive usage confers a long-term reduction in the risk of endometrial cancer. 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.  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. 
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.  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 activities in the range up to 50 MET hours per week (up to 15 hours/week). 
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.  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. 
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,  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 Women’s Health Initiative (WHI) cohort  whose weight measured at baseline and 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 (and thus prone to measurement error) 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 weight loss is protective for endometrial cancer.
Studies of the association between endometrial cancer and diet, phytoestrogens, soy, and vitamin D have been negative.      Multivitamin use has little or no influence on the risk of common cancers, including endometrial cancer, or on total mortality in postmenopausal women. 
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.
Added text about an analysis of 36,793 women from the Women's Health Initiative cohort whose weight was measured at baseline and 3-year follow-up and was combined with self-reported intentionally of weight loss that showed an association between intentional weight loss of 10 pounds or more and lower endometrial cancer incidence (cited Luo et al. as reference 58).
Added text to state that both of these analyses share substantial limitations; 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 weight loss is protective for endometrial cancer.
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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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