There are a number of risk factors for endometrial cancer. The most common form of endometrial cancer, endometrioid endometrial cancer, is often caused by stimulation of the endometrium by estrogen. Estrogen can come from a variety of sources including hormonal therapy (unopposed estrogen) and form obesity (fat cells produce estrogen that can stimulate the endometrium). In the United States, obesity is one of the common factors associated with the development of endometrial cancer. Compared to normal weight women, the incidence of endometrial cancer in overweight women is at least twice as high. Other hormonally related factors that slightly increase the risk of endometrial cancer include starting menstruation early, late menopause, and never having been pregnant.

Use of the drug tamoxifen has been associated with an increased risk of endometrial cancer. Tamoxifen is a drug utilized for the treatment and prevention of breast cancer. Overall, the risk of developing endometrial cancer while receiving tamoxifen is low and the benefits of using tamoxifen to prevent breast cancer usually outweigh the risks.

Endometrial cancer may be preceded by a precancerous condition known as endometrial hyperplasia. There are a number of different forms of endometrial hyperplasia, all of which are associated with a different risk of cancer. Complex atypical endometrial hyperplasia is the form of endometrial hyperplasia associated with the highest risk of cancer. Endometrial hyperplasia is typically treated either with surgery or with medications (progesterone).

Finally, although most cases of endometrial cancer are sporadic and not associated with genetics factors, in some women endometrial cancer may be inherited. The most common hereditary abnormality associated with endometrial cancer is Lynch syndrome. Lynch syndrome is a genetic abnormality caused by a defect in the genes that repair DNA. Women with Lynch syndrome not only have an increased risk for endometrial cancer, but also have an elevated risk of other cancers including colon cancer. Its important for women with a history suggestive of Lynch syndrome to undergo further evaluation and testing.