As noted, the incidence of endometrial cancer is increasing substantially. Advancing age is an important risk factor for endometrial cancer and likely accounting for some of this increase as the population ages. Most tumors occur during the sixth and seventh decades. While fewer than 5% occur before age 40 years, 25% of all endometrial adenocarcinomas occur in premenopausal women. The risk is increased among first-degree relatives of patients with endometrial cancer. Epidemiologic studies have also shown an association with cancers of the breast and colon. The cumulative incidence of endometrial cancer by age 70 years is as high as 40% to 50% among women with hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome II, compared with 3% in the general population. Women who present with endometrial cancer before age 50 years and have a family history of another HNPCC-associated cancer (colon, ovary, stomach, small bowel, renal pelvis, or ureter) may opt for genetic testing to ascertain their risks and those of family members.

Obesity, diabetes, and metabolic syndrome are leading risk factors for the development of endometrial cancer. Case-control studies have demonstrated a high prevalence of obesity and glucose intolerance among patients with this cancer. The Women’s Health Initiative determined that obese women with a BMI greater than 33 had a 67% increased risk of endometrial cancer. Up to 40% of patients with endometrial cancer in some studies have diabetes mellitus. Among diabetic women, the odds ratio for development of endometrial cancer was observed to be 1.7. Surveillance Epidemiology and End Result (SEER) registries from 1973 through 1988 demonstrated that women with endometrial cancer were most likely to die from cardiovascular disease, reflecting the high prevalence of cardiac risk factors in this cohort.

Estrogens, either endogenous or exogenous, play a principal role. The histologic precursor of endometrial cancer is atypical endometrial hyperplasia. Among women with atypical endometrial hyperplasia undergoing hysterectomy, 42.6% demonstrated endometrial carcinoma in the hysterectomy specimen. A number of clinical syndromes that include ovarian estrogen excess have been associated with the increased risk of endometrial cancer. Postmenopausal women with estrogen-secreting tumors have been reported to have a 10% to 24% incidence of endometrial cancer. There is also a high incidence of cancer in patients with polycystic ovary syndrome (PCOS); 19% to 25% of young women with endometrial carcinoma have underlying Stein-Leventhal syndrome. However, in women with PCOS, obesity appears to be the dominant risk factor. It is likely that less well-defined abnormalities of estrogen control explain the association of endometrial cancer with menstrual abnormalities and infertility. Approximately half of all women with endometrial carcinoma and 20% to 30% of married women with endometrial carcinoma are nulliparous.

The principal estrogen in postmenopausal women is estrone, which is peripherally converted from androstenedione produced in the adrenal glands. Peripheral conversion of androstenedione to estrone has been shown to be increased in patients with endometrial cancer, and estrone-to-estradiol ratios are higher. Peripheral conversion by adipose cells may be the explanatory link between obesity and endometrial cancer.

Available evidence suggests that postmenopausal estrogen therapy (but not estrogen plus progesterone hormone replacement therapy) substantially increases the risk of endometrial cancer. Rates of endometrial cancer among estrogen users ranged from 4 to 14 times those among control patients. Several studies demonstrated a dose-response relationship, in that the use of estrogen for longer periods of time was associated with greater risk. Women who take tamoxifen as adjuvant therapy for breast cancer or for chemoprevention are also at increased risk for endometrial cancer. A meta-analysis of adjuvant therapy trials found a relative risk of 4.1 among tamoxifen users compared with women taking placebos. Case-control data suggested a 50% decrease in risk among women who have used combination birth control pills for a minimum of 12 months, with the protective effect lasting from 8 to 15 years. Women with BRCA1 and BRCA2 genes have a higher risk of endometrial cancer, but only if they have taken tamoxifen for previous breast cancer or for chemoprevention.