Literature Review
Effect of obesity on EC tumorigenesis
With advances in tissue molecular research, we are now becoming increasingly aware that visceral fat functions as a complex endocrine organ. It is made up of adipocytes, macrophages, stromal, nerve and stem cells. The array of adipokines they secrete exerts a wide range of effects on endometrial cells, leading to increased proliferation, genetic mutations and eventually carcinogenesis (11, 15, 16).
Adipocytes, preadipocytes and mesenchymal stem cells within visceral fat are the main source of endogenous aromatase, which converts androgens to estrogen (17). In addition, sex hormone-binding globulin levels decrease with increasing adiposity, leading to an increase in the pool of bioactive estrogen (18). These factors contributes to estrogen-induced proliferation of endometrial cells, via the activation of the various signaling pathways. Estrogen metabolites are also thought to be mutagenic, causing DNA breaks and contributing to genetic instability, increasing the chance of carcinogenesis (19).
EC is strongly associated with metabolic syndrome and hyperinsulinemia, which in turn are strongly associated with obesity (20, 21). There is increased expression of insulin and IGF1 receptors observed in endometrial cells when there is endometrial hyperplasia, which increases the responsiveness of the cells to elevated levels of insulin and insulin-like growth factor 1 (IGF1) (22). This in turn leads to hyperactivity of MAPK and AKT signaling frequently seen in endometrial hyperplasia and EC. Hyperglycemia also serves to fuel the growth of metabolically tissues, including endometrial hyperplastic and cancer cells (23).
It is an increasingly well-established fact that obesity and metabolic syndrome is associated with a chronic inflammatory state. This is modulated by pro-inflammatory adipokines, such as leptin, tumor necrosis factor α and interleukin-6. Together with worsening insulin resistance and hyperinsulinemia, these inflammatory mediators increase the release of IGF1, leading to endometrial cellular proliferation(24). Because of the chronic inflammatory state, there is also increased cellular stress, leading to genetic instability and DNA damage. When endometrial cells with DNA mismatch repair defects accumulate deleterious genetic mutations, this leads to endometrial hyperplasia, atypia and eventually EC.
The interplay and synergistic effect of a hyper-estrogenic state, hyperinsulinemia and chronic inflammatory state predisposes obese women to an increased risk of developing EC much earlier, when they are of reproductive age.
Bariatric Surgery and Endometrial Cancer
BS has been shown to be the most durable and effective treatment for obesity (12) while improving the life expectancy and quality of life of obese patients (25). In addition, BS has also been shown to improve multiple aspects of metabolic health of obese patients, including diabetes control (decreased glycated hemoglobin levels, better glycemic control, decreased requirement for glucose-lowering medications), lipid control (decreased triglyceride levels, increased HDL levels) and microvascular complications (decreased urine albumin to creatinine ratio) (26, 27).
Patients who undergo BS have reduced overall cancer risk compared with controls (14, 28 – 30). There is also good evidence that obese patients who had BS have a reduced risk of developing endometrial cancer (14, 31 – 33). This is most likely from the improvement in the metabolic and insulin-resistance state from weight loss and other beneficial effects of BS. These common factors and pathways are also involved in the development of EC. Weight loss is associated with spontaneous clearance of serum and endometrial tissue biomarkers of endometrial cancer risks (34).
There is a paucity of data for using BS as part of the fertility sparing treatment. A prospective nonrandomized study conducted by Barr et. al. observed that weight loss improves the response rates in women with obesity and atypical hyperplasia or early EC undergoing fertility sparing treatment with intrauterine progestin. Patients who lost more than 10% of total body weight were nearly 4 times more likely to respond to intrauterine progestin than those who did not (OR 3.95 p=0.02). In this study, BS was offered as a treatment for obese patients and resulted in a greater and more sustainable weight loss compared to nonsurgical treatment (35).
Reproductive outcomes in patients undergoing fertility sparing treatment are promising, especially when Assisted Reproductive Techniques (ART) are used (36). However, obesity negatively affects fertility rates and lowers the chances of achieving a successful pregnancy, one of the long-term goals of fertility sparing treatment(37). Studies have indicated that BS improves fertility rates in obese female patients (38). Pregnancy is safe after BS and evidence shows lower risk of maternal complications like gestational diabetes and pre-eclampsia, compared to patients who are morbidly obese. There is mixed evidence regarding perinatal outcomes in patients who had undergone BS, with some studies showing possible association with reduced birth weight that may be due to nutritional growth restriction (39). As such, patients who have undergone BS should be advised to avoid conceiving for at least 12 months post-op, with adequate contraception during this period. When patients who have undergone BS conceive, they should have nutritional surveillance and be screened for macro- and micro-nutrient deficiencies regularly. They should also be instructed on strict compliance with nutritional supplementation during pregnancy(40).