Most of these risk factors are related to prolonged, unopposed estrogen stimulation of the endometrium. Nulliparous women have twoto threetimes the risk of parous women. Infertility and a history of irregular menses as a result of anovulatory cycles (prolonged exposure to estrogen without sufficient progesterone) increase risk. Natural menopause occurring after age 52 years increases the risk for endometrial cancer 2.4-fold compared with women who experienced menopause before 49 years of age, probably as a result of prolonged exposure of the uterus to progesterone-deficient menstrual cycles. The risk of endometrial cancer is increased 3 times in women who are 21 to 50 pounds overweight and 10 times in those more than 50 pounds overweight (resulting from excess estrone as a result of peripheral conversion of adrenallyderived androstenedione by aromatization in fat). The obesity epidemic in Western countries, together with growing rates of insulin resistance and “metabolic syndrome,” can be expected to increase the incidence of endometrial cancer in coming years.
Table 35.1 Risk Factors for Endometrial Cancer
Other factors leading to long-term estrogen exposure, such as polycystic ovary syndrome and functioning ovarian tumors, also are associated with an increased risk for endometrial cancer. Menopausal estrogen therapy without progestins increases the risk of endometrial cancer fourto eighttimes. This risk increases with higher doses and with more prolonged use and can be reduced to essentially baseline levels by the addition of progestin (8). The use of the antiestrogen tamoxifen for treatment of breast cancer is associated with a two-to threefold increased risk for the development of endometrial cancer, although this finding is confounded by the apparent greater risk of endometrial cancer in women who have breast cancer, with or without treatment with tamoxifen (9,10). Diabetes mellitus increases a women’s risk for endometrial cancer by 1.3 to 2.8 times. Women with Lynch II syndrome (previously referred to as hereditary nonpolyposis colorectal cancer syndrome, or HNPCC), a cancer susceptibility syndrome with germline mutations in mismatch repair genes MLH1, MSH2, and MSH6, have a 40% to 60% lifetime risk for endometrial and colon cancer (11). Other medical conditions, such as hypertension and hypothyroidism, are associated with endometrial cancer, but a causal relationship is not confirmed.
Endometrial hyperplasia represents a spectrum of morphologic and biologic alterations of the endometrial glands and stroma, ranging from an exaggerated physiologic state to carcinoma in situ. Clinically significant hyperplasias usually evolve within a background of proliferative endometrium as a result of protracted estrogen stimulation in the absence of progestin inﬂuence. Endometrial hyperplasias are important clinically because they may cause abnormal bleeding, be associated with estrogen-producing ovarian tumors, result from hormonal therapy, and precede or occur simultaneously with endometrial cancer.