IntroductionThe incidence of endometrial cancer is rising steeply, with the obesity epidemic believed to be the cause. Women with a BMI > 42kg/m2 have a 9-fold increase in their relative risk of endometrial cancer. Few studies have investigated the endometrial effects of obesity or weight loss. I hypothesised that morbidly obese women had a high prevalence of undiagnosed endometrial cancer and pre-cancer, and that major weight loss would result in measurable systemic and endometrial effects. Methods118 morbidly obese women undergoing weight loss surgery or non-surgical weight management were recruited into a prospective cohort study. Blood and endometrial samples were taken at baseline, 2 and 12 months.Results80 women have undergone baseline assessment (mean age 44 years, median BMI 52kg/m2). Menstrual and reproductive dysfunction was common (15% pre-menopausal amenorrhoea, 31% oligomenorrhoea) and less than one third reported regular menstrual cycles. Four cases of endometrial cancer and six of atypical endometrial hyperplasia were detected at baseline (prevalence 12.5%, 95% CI 6.2-21.8), and women with abnormal endometrium had significantly higher HbA1c and pAKT levels. Undiagnosed diabetes was found in 6%, and overall more than 38% were diabetic and up to 40% more had raised HOMA-IR levels.Significant serial improvements were seen in insulin resistance, adipokines, inflammation and androgens after bariatric surgery. In endometrium significant reductions were seen in Ki-67, pAKT, ER and PR expression. In samples matched for cycle timing and not affected by exogenous hormone treatment Ki-67 reduced by 11% and 17% at 2 and 12 months post-surgery. AEH resolved with weight loss alone in 3/6 patients and with weight loss and LNG-IUS in 2/6 women. Ki-67 expression correlated weakly with pAKT, serum oestradiol, HOMA-IR, FAI and adipokines.ConclusionsSuch a high prevalence of endometrial cancer and pre-cancer in morbidly obese women supports targeted screening in this high-risk group and highlights the importance of diagnosing and managing insulin resistance. Reduction in proliferation appears to be mediated by the PI3K/AKT pathway and through changes in insulin resistance, reproductive hormones and inflammation. Ki-67 may have a use as a marker of the 'high-risk' endometrium or in the future surveillance of endometrial abnormality being managed by fertility-sparing means.