Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes mellitus but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is associated most strongly with endometrial cancer incidence and death. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease.
Obesity is a well-established risk factor for the development of multiple types of cancer, cancer-related death, and all-cause death. Among all cancers, increasing body mass index (BMI) and obesity are associated most strongly with endometrial cancer incidence and death. In a recent metaanalysis of 19 reviews and prospective studies, Renehan et al found that each increase in BMI of 5 kg/m 2 significantly increased a woman’s risk of the development of endometrial cancer (relative risk, 1.59; 95% confidence interval [CI], 1.50–1.68). In the Million Women Study conducted in the United Kingdom, the investigators found that increasing BMI was associated with increased incidence of endometrial cancer (trend in relative risk per 10-units, 2.89; 95% CI, 2.62–3.18). Endometrial cancer death is also impacted adversely by obesity. Calle et al, in a prospective study of >495,000 women who were observed for 16 years, showed a significantly increased risk of death in obese women with endometrial cancer. Even more striking was the trend that was associated with increasing BMI; the relative risk of uterine cancer-related death for women who were considered obese (BMI, 30-34.9 kg/m 2 ) was 2.53; for morbidly obese women (BMI >40 kg/m 2 ), the relative risk was 6.25. Not only does obesity impact cancer-related death, but through its association with other medical co-morbidities (such as diabetes mellitus and hypertension), it adversely impacts all-cause death. In a retrospective review of 380 patients with early endometrial cancer, the Gynecologic Oncology Group found that morbid obesity was associated with a higher mortality rate (hazard ratio, 2.77; 95% CI, 1.21–6.36) from causes other than endometrial cancer or disease recurrence. Further complicating matters, there is limited public knowledge of the relationship between obesity and cancer risk. A recent survey indicated that up to 58% of women were not aware that obesity increased endometrial cancer risk.
Although it has been presumed that excess estrogen because of the peripheral conversion of androstenedione to estrone accounts for the increased risk of endometrial cancer in obese women, new studies implicate other mechanisms by which obesity promotes endometrial cancer. This review will discuss the current understanding of what factors underlie the association of obesity and endometrial cancer and what strategies are available for both prevention and treatment ( Figure 1 ) .
Obesity and hormone imbalance
Estrogen is a known endometrial growth factor. Although the ovaries are the primary source of estrogen in premenopausal women, peripheral tissues, which include adipose tissue, become the primary sources of circulating estrogen in postmenopausal women. Androgens are converted to estrone and estradiol by the enzyme aromatase in adipose tissue. Aromatase is produced by mesenchymal stromal cells, which include adipocyte stem cells, and to a lesser degree by mature adipocytes themselves. Aromatase levels increase as a function of age and obesity and are reflected by an increase in circulating estrogen levels with increasing BMI in postmenopausal women. Cauley et al demonstrated >40% increases in both circulating estrone and estradiol in obese (BMI, >30 kg/m 2 ) vs normal (BMI, <27 kg/m 2 ) postmenopausal women. Furthermore, concentrations of estrogens in adipose tissue have been measured at levels several fold above that observed in plasma. Therefore, visceral adipose tissue represents not only a source of estrogen but also provides an ideal milieu for the growth of metastatic, estrogen-sensitive endometrial cancer. Furthermore, serum hormone–binding globulin levels decrease with increasing adiposity. This glycoprotein binds both estrogen and testosterone and inhibits their activity. Therefore, irrespective of de novo synthesis, obesity can influence biologically active levels of these hormones.
Estrogen promotes the growth of endometrial cancer cells by both direct and indirect regulation of gene transcription. The binding to cytoplasmic estrogen receptors alpha and beta leads to recruitment of transcriptional cofactors and the direct activation of a wide variety of estrogen responsive genes. Estrogen receptors can also bind in an estrogen-dependent and -independent manner to other transcription factors and enhance gene transcription through alternative response elements. It is also apparent that estrogen itself exerts rapid, nongenomic effects that are associated with a variety of cytoplasmic kinase signaling cascades. 17β-estradiol treatment activates both the phosphoinositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, which are associated with cellular proliferation and are frequently hyperactivated in cancers. The direct association between estrogen receptors and cell surface receptors, including insulin-like growth factor 1 receptor (IGF-1R) and epidermal growth factor receptor, represents a mechanism that directly links estrogen to the downstream kinase cascades that promote cell growth and tumor progression.
In normal premenstrual endometrium, progesterone counters estrogen-driven proliferation and induces glandular differentiation and decidualization of the endometrial stroma. Conditions that are accompanied by prolonged progesterone deficiencies therefore promote endometrial proliferation and increase the risk of endometrial hyperplasia and its progression to endometrial cancer. For example, nulliparity, irregular menses, and extended postmenopausal hormone replacement therapy with unopposed estrogen are associated with increased endometrial cancer risk. In premenopausal obese women, lack of progesterone because of anovulation, such as that observed in polycystic ovarian syndrome (PCOS), is also likely to contribute to endometrial cancer risk.
PCOS is a heterogeneous disorder that affects 6-8% of women and that is characterized by androgen excess and menstrual abnormalities because of ovulatory dysfunction and is often associated with polycystic ovarian morphologic condition. Obesity is found in approximately 30-70% of women with PCOS. A principle element of this disorder is the presence of insulin resistance, which is worsened by obesity. A recent Australian case-control study of women under the age of 50 years has shown that women with PCOS had a 4-fold greater risk of endometrial cancer compared with women without PCOS. When adjusted for BMI, PCOS remained an independent risk factor and was associated with a >2-fold increased risk for endometrial cancer.
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