**4. The relationship between endometrial cancer and obesity**

Obesity is known to increase the risk of endometrial cancer in women [40, 41]. Approximately 57% of endometrial cancers in the United States are thought to be attributable to being overweight and obese. The incidence of endometrial cancer increases as body mass index (BMI) increases [42]. More importantly, obesity and overweight can increase the likelihood of dying from cancer. A review of the literature states that most of the associations between adiposity indices and endometrial cancer are supported by strong or highly suggestive evidence. A review (IARC) from a comprehensive meta-analysis of weight, physical activity, and cancer incidence by the International Agency for Research on Cancer demonstrated that it is the cause of 39% of endometrial cancer cases [43].

The cause and effect relationship between obesity and endometrial cancer can be explained by 3 mechanisms; first; in obese patients, the adrenal glands secrete more androgen precursors for conversion to estrogen in peripheral tissues. An androgen, androstenedione, (A) is converted to estrone (E1) mainly in peripheral adipose tissue, and this conversion is increased in adipose tissue of obese patients. Plasma SHBG levels that bind estradiol (E2) are reduced in obese subjects and therefore higher-than-normal amounts of serum estradiol are present in the circulation, thereby increasing the estrogenic stimulus in target tissues [44]. Proinflammatory cytokines such as tumor necrosis factor-a in obesity are associated with low plasma SHBG levels [45]. Obese patients also have changes in the concentration of insulin-like growth factors and their binding proteins and insulin resistance, all of which may contribute to an increased risk of endometrial cancer in these patients [46]. The triad of obesity, insulin resistance, and adipokine aberrations is linked to cancer [47], since adipokines impair insulin signaling and contribute to insulin resistance [48]. Other mechanisms in pathophysiology are subclinical chronic low-grade inflammation, oxidative stress, and sex hormone biosynthesis [6]. Adipokine-mediated chronic inflammation and cellular stress cause genetic instability and DNA damage [42]. All of these mechanisms lead to endometrial hyperplasia and cancer. Despite all these conditions, obese patients who do not have metabolic problems seem to have an increased risk of endometrial cancer [49].

The mechanisms underlying the relationship between obesity and endometrial cancer have not been fully defined. However, estrogens and proinflammatory adipokines are known to stimulate cell proliferation in endometrial carcinoma. In addition to stimulating cell proliferation, estrogen also has mutagenic properties. Genotoxic metabolites of estrogen react with DNA and contribute to DNA breaks and genetic instability [50]. Although the role of estrogen metabolites in the pathogenesis of breast cancer is well defined, their role in the context of endometrial cancer has not been fully understood. However, defects in DNA mismatch repair genes were detected in one-third of endometrial cancer cases. Visceral fat is a complex endocrine organ composed of adipocytes, preadipocytes, macrophages, stromal, nerve, and stem cells [42]. Adipokines secreted by these cells increase endometrial proliferation and promote tumor formation [51], even mesenchymal stem cells support tumor growth and progression [52, 53].

Cyclic secretion of ovarian estrogen and estrogen-induced cyclic secretion of insulin-like growth factor 1 (IGF1) in premenopausal women stimulates endometrial proliferation [54, 55]. In postmenopausal women, especially adipose tissue

is the main site of estrogen synthesis [56]. Aromatase enzyme, which provides estrogen synthesis from androgens, is mainly found in adipose tissue [57]. As body adiposity increases, the amount and activity of aromatase increases [58]. Steroid hormone synthesis from cholesterol and estrogen synthesis from androgens by aromatase enzyme is shown in **Figure 1**.

In a pooled analysis of individual patient data from 10 cohort and 14 case–control studies, including more than 14,000 endometrial cancer cases and more than 35,000 controls, for type I endometrial cancer, by body mass index (BMI): overweight (BMI) 25.0 to <30.0 kg/m<sup>2</sup> ) OR 1.5, OR 2.5 (30.0 to <35.0 kg/m<sup>2</sup> ) for class 1 obesity, OR 4.5 for class 2 obesity (35.0 to 39.9 kg/m<sup>2</sup> ) and calculated as 7.1 for class 3 obesity (≥40.0 kg/m2 ). For type 2 endometrial cancer, the ORs were calculated as 1.2 for overweight, 1.7 for class 1 obesity, 2.2 for class 2 obesity, and 3.1 for class 3 obesity [59]. Higher BMI is associated with the development of endometrial cancer at a younger age (<45 years old) [60]. In another meta-analysis, body mass index and waist-to-hip ratio were associated with increased cancer risk in premenopausal women (RR 1.49 per 5 kg/m<sup>2</sup> ; CI 1.39–1.61) and for total endometrial cancer (RR 1.21 per 0.1 unit; CI 1.13–1.29), respectively [61].

Severely obese patients (BMI ≥40 kg/m2 ) who develop endometrial cancer are more likely to have a less aggressive histological subtype (endometrioid 87% vs. serous or clear cell 75%) compared to patients with BMI <30 kg/m2 [62]. Therefore, patients with severe obesity are more likely to present with stage I disease (77 versus 61%) or low-grade histology (44% vs. 24%), but severe obesity is associated with an increased risk of death in endometrial cancer patients [63, 64]. After being diagnosed with endometrial cancer, being obese indicates worse outcomes. Obesity has a negative effect on all-cause mortality. A retrospective study found that morbidly obese women with early-stage disease had higher mortality rates compared with women with a normal body mass index, accounting for 67% of these deaths. It has been determined that there are obesity-related causes unrelated to cancer [65]. Increased mortality may be due to sustained stimulation of metastatic cells by endogenous estrogen or may result from obesity-related conditions such as diabetes or cardiovascular disease [66, 67].

#### *Obesity and Endometrial Cancer DOI: http://dx.doi.org/10.5772/intechopen.99827*

After obese women are diagnosed with endometrial cancer, clinical management strategies can be complex. As the operations of obese patients are technically more difficult it takes a longer time than normal-weight individuals. Since these patients also have many co-morbid medical problems, both perioperative and postoperative complication rates are increased. Even though the patients have early-stage cancer, they may not be able to be operated on due to concomitant systemic diseases such as cardiovascular and diabetes mellitus, and they may have to undergo primary radiotherapy. Robotic surgery may provide an advantage over conventional laparoscopy in such patients [68, 69].

Meta-analyses show that increased physical activity reduces the risk of endometrial cancer [70–72]. Exercise may provide moderate protection against endometrial cancer [73]. Physical activity benefits by reducing obesity and making positive changes in immune function, endogenous sexual and metabolic hormone levels, and growth factors [74]. Losing weight through lifestyle changes such as diet and physical activity or bariatric surgery can reduce obesity. Bariatric surgery has been associated with a 50% to 80% reduction in the occurrence of endometrial cancer in a meta-analysis of controlled trials [75, 76]. Obesity-related hormonal and metabolic disorders and drugs aimed at correcting insulin resistance can also be used as a prevention strategy. Losing weight has health benefits beyond protecting the endometrium. Preventing or treating obesity can provide significant lifelong health benefits. Public health interventions may be beneficial to reduce the incidence of endometrial cancer in the community. Obese patients should receive counseling about health risks, lifestyle changes, obesity treatment options, and risk factor reduction.
