A number of studies have found a rising incidence of endometrial cancer in the United States. This rise in incidence might be due to an increase in the prevalence of one or more risk factors for endometrial cancer. As with all cancers, older women are more likely to develop endometrial cancer; the average age at the time of endometrial cancer diagnosis is 63 years. More specific risk factors include obesity, number of pregnancies, polycystic ovarian syndrome, artificial endometrial stimulation, and genetic risk factors. 

Obesity is an important risk factor for the development of endometrial cancer; this is especially so in postmenopausal women. Estrogen can be produced by adipocytes, which take androgen precursors from the bloodstream using an enzyme called aromatase or estrogen synthase and convert them to estrogen. This effect is more prominent in postmenopausal women. Intuitively, we can imagine that, in someone with a leaner body habitus, there might be less estrogen produced and metabolized in the adipose tissue to stimulate the lining of the endometrium and contribute to endometrial cancer risk. 

The interplay of risk factors is thought to be important, and you see the influences of both natural and iatrogenic hormonal changes. Oral contraceptives are thought to confer long-term protection against endometrial cancer. Additionally, multiparous women are known to have a lower risk of developing endometrial cancer than nulliparous women. Traditionally, the lack of ovulation and the shifting of sex hormonal balance, with decreased estrogen levels and increased progesterone levels during pregnancy, have been thought to be the major contributor to this decreased risk. Essentially, during pregnancy, the endometrium gets a break from the repeated and unopposed stimulation by estrogen that happens during each menstrual cycle. Thus, women who have not given birth and who do not use birth control pills are at an especially high risk compared with women who have given birth. 

Further, women with ovarian syndromes such as polycystic ovarian syndrome are also at an increased risk for endometrial cancer. Like endometrial cancer, polycystic ovarian syndrome is associated with dysfunction of the ovarian hormonal cycle, such that the ovary is churning out estrogen all the time, but an egg is not being released. As a result, progesterone is not being produced. The unopposed estrogen stimulates the endometrium, potentially leading to hyperplasia and, subsequently, endometrial cancer if the hyperplasia is not addressed. 

Next, a woman who is subjected to artificial (iatrogenic) endometrial stimulation with a hormone (typically estrogen) without opposing it with a progestogen can be at an increased risk for endometrial cancer. This can happen in patients who are taking selective estrogen receptor modulators, with the most commonly used agent being tamoxifen. Tamoxifen stimulates the endometrial lining and, if it is used for more than 2 years, increases the risk of endometrial cancer. 

Finally, there are genetic risk factors for the development of endometrial cancer. Perhaps the most well-known genetic risk factor is Lynch syndrome, which is caused by a genetic mutation in the DNA mismatch repair genes. When these genes are abnormal, a patient has a higher chance of developing a number of different malignancies, including both endometrial and colon cancers. Thus, screening and detection are important. According to the American Cancer Society, women with Lynch syndrome have up to a 70% chance (range of cumulative lifetime risk, 19%-71%) of having endometrial cancer at some point in their lifetime. Additionally, this syndrome may be associated with a highly immunogenic tumor environment, which can be targeted by specific and effective therapies such as immune checkpoint inhibitors. Another genetic abnormality that is very strongly associated with endometrial cancer risk is a PTEN mutation.