An excess of unopposed estrogen is a major risk factor for developing EC. Excess estrogen can be attributed to obesity (conversion of androstenedione to estrone in adipose tissue), anovulatory conditions (polycystic ovarian syndrome, which results in a deficiency of progesterone), and exogenous estrogen (estrogen hormone replacement therapy, or tamoxifen, a selective estrogen receptor modulator, which acts as an estrogen agonist in the uterus). Although associated with obesity, type 2 diabetes is also an independent risk factor for ECs, related to hyperinsulinemia. EC is also seen as part of Lynch syndrome (Hereditary non-polyposis colorectal cancer, HNPCC). This hereditary cancer syndrome is characterized by a very high lifetime risk of endometrial and colorectal cancers (both approximately 60%), as well as ovarian (lifetime risk of 10%), gastric, small bowel, ureter, and renal pelvis. This syndrome is caused by an inherited mutation in one of the DNA mismatch repair genes (mutations in MLH1, MSH2, MSH6, PMS2 account for 99% of all Lynch Syndrome), with the consequent tumours showing high microsatellite instability (MSI-H). These MSI-H tumours can be reliably identified by mismatch repair (MMR) protein immunohistochemistry, as described above.
With respect to prevention, weight loss in obese women and improving glycemic control in diabetic women may have the most potential for reducing risk in these specific populations. The use of combination oral contraceptives has been shown to decrease risk by 50% if used for 5 or more years (1). The addition of a progestin to estrogen replacement therapy counteracts the adverse effects of unopposed estrogen on the endometrium (2). Women who are identified as having Lynch Syndrome are advised to consider risk-reducing surgery (hysterectomy and bilateral salpingo-oophorectomy by the age of 40) to reduce their risk of endometrial and ovarian cancers (3). Screening for endometrial and ovarian cancer using endometrial biopsy, transvaginal ultrasound, and CA125 has not been proven to decrease the incidence or mortality from cancer in these high-risk women.
- Kelsey J, Whittemore AS. Epidemiology and primary prevention of cancers of the breast, endometrium and ovary: a brief review. Ann Epidemiology 1994;4:89-95.
- Miller AB. Planning cancer control strategies. Chronic Dis Can 1992;13:S1-S40.
- Schmeler KM et al, Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch Syndrome. N Engl J Med 2006;354(3):261-9.
