Obesity is the strongest risk factor for endometrial cancer (EC). To inform targeted screening and prevention strategies, we assessed the impact of obesity and subsequent bariatric surgery‐induced weight loss on endometrial morphology and molecular pathways implicated in endometrial carcinogenesis. Blood and endometrial tissue were obtained from women with class III–IV obesity (body mass index ≥40 and ≥50 kg/m
2
, respectively) immediately prior to gastric bypass or sleeve gastrectomy, and at two and 12 months’ follow up. The endometrium underwent pathological examination and immunohistochemistry was used to quantify proliferation (Ki‐67), oncogenic signaling (PTEN, pAKT, pERK) and hormone receptor (ER, PR) expression status. Circulating biomarkers of insulin resistance, reproductive function and inflammation were also measured at each time point. Seventy‐two women underwent bariatric surgery. At 12 months, the mean change in total and excess body weight was −32.7 and −62.8%, respectively. Baseline endometrial biopsies revealed neoplastic change in 10 women (14%): four had EC, six had atypical hyperplasia (AH). After bariatric surgery, most cases of AH resolved (5/6) without intervention (3/6) or with intrauterine progestin (2/6). Biomarkers of endometrial proliferation (Ki‐67), oncogenic signaling (pAKT) and hormone receptor status (ER, PR) were significantly reduced, with restoration of glandular PTEN expression, at 2 and 12 months. There were reductions in circulating biomarkers of insulin resistance (HbA1c, HOMA‐IR) and inflammation (hsCRP, IL‐6), and increases in reproductive biomarkers (LH, FSH, SHBG). We found an unexpectedly high prevalence of occult neoplastic changes in the endometrium of women undergoing bariatric surgery. Their spontaneous reversal and accompanying down‐regulation of PI3K‐AKT–mTOR signaling with weight loss may have implications for screening, prevention and treatment of this disease.
Purpose of the ReviewTo assess the most recent high-quality evidence for endometrial cancer prevention strategies.Recent Findings
Obesity is an established risk factor for endometrial cancer.Weight cycling and weight gain in middle age are risk factors for endometrial cancer.Bariatric surgery reduces the risk of endometrial cancer by up to 81% in obese women who attain and maintain a normal weight.Combined oral contraceptives provide durable protection against endometrial cancer for 30 years or more.Ever use of the levonorgestrel intrauterine system (LNG-IUS) and inert intrauterine devices reduce endometrial cancer risk.The first oestrogen-based non-progestin HRT for non-hysterectomised women that contains estradiol and bazedoxifene has an effective protective effect on endometrium.Bisphosphonates reduce endometrial cancer risk.
SummaryWeight loss and LNG-IUS would seem to be an effective strategy for preventing the development of obesity-driven endometrial cancer in the highest risk women. Future research may identify other safe and effective chemoprevention interventions, such as aspirin, bisphosphonates or metformin.
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