Introduction: The 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. Methods: 118 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. Results: 80 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. Conclusions: Such 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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:756803 |
| Date | January 2016 |
| Creators | Mackintosh, Michelle |
| Contributors | Crosbie, Emma |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/the-impact-of-obesity-and-weight-loss-on-the-malignant-potential-of-endometrium(99ba5e72-6a91-4812-a97e-67648d105b9f).html |
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