Menopause, endometrial cancer and metabolic syndrome: links and treatments

MENOPAUSE AND ENDOMETRIAL CANCER Endometrial cancer (EC) is the most common gynecological malignancy in Europe and North America. The incidence of endometrial cancer is about 1 times higher in developed countries than developing countries. This could be due to an increased life expectancy, increased caloric intake, obesity, adjuvant Tamoxifen use for breast cancer, and a reduction in fertility rates. Endometrial cancer risk is found to be positively correlated with increasing age. Over 90% of the cases are diagnosed after the age of 50 years, therefore endometrial cancer is more common in post-menopausal women than in premenopausal women. Elevated serum estrogen level is associated with chronic anovulation, increasing the risk of developing endometrial cancer. Thus, women with Polycystic Ovary Syndrome (PCOS) and women with estrogen-secreting ovarian tumors. Insulin resistance and PCOS, both components of the metabolic syndrome, may play a central role in the pathogenesis of endometrial cancer. The risk of endometrial cancer becomes higher when obesity is associated with infertility or amenorrhea, as is the case for PCOS. Endometrial cancer risk increases by 1.2 fold for each 5 kilograms weight gain. Since obesity is also associated with insulin resistance and hyperinsulinemia the positive relationship with endometrial cancer riskbecomes even stronger. MENOPAUSE AND METABOLIC SYNDROME Metabolic syndrome (Mets) or Syndrome X has been studied since the early 80's and Syndrome X was initially coined by Gerald Reaven in 1988. It comprises of the following components: obesity, elevated blood pressure, hyperglycemia or insulin resistance and dyslipidemia. All these are important cardiovascular risk factors. In particular, obesity is considered to be the biggest contributor of cardiac dysfunction in postmenopausal women. The decrease in estrogen levels in menopausal women is associated with the loss of subcutaneous fat and an increase in abdominal fat. Human subcutaneous and visceral adipose tissues express both estrogen receptors (ER?? and ER??). ER?? plays a major role in the activity of adipocytes and sexual dimorphism of fat distribution. Estrogen exerted a direct positive effect on cardio vascular disease (CVD) risk in women, a benefit that was lost as women transitioned from a premenopausal to a postmenopausal state and experienced a loss of estrogen. Furthermore, the progressive androgenicity of the hormonal pattern exerts a direct negative effect on CVD risk. Testosterone is associated with insulin resistance, hyperinsulinemia, low HDL levels, high blood levels of glucose and triglycerides, and diabetes mellitus and from epidemiologic data showing that androgens are associated with inflammatory markers. Physiological changes during the menopausal transition, especially the alteration of reproductive endocrine function, might contribute to the risk of metabolic syndrome (MS). This is possibly but not totally related to increasing estrogenic deficiency. The prevalence of MS increases from 6.7% in the third decade to 43.5% in the seventh decade. The emergence of metabolic syndrome features may be a direct result of ovarian failure or, alternatively, an indirect result of the metabolic consequences of central fat redistribution with estrogen deficiency. METABOLIC SYNDROME AND ENDOMETRIAL CANCER Metabolic syndrome has emerged as a possible clinical condition that predisposes to malignant disease, in addition to weight and other metabolic risk factors such as insulin resistance, diabetes, hypertension, and dysglycemia. A central feature of the metabolic syndrome is obesity, which is expressed by an increased waist-hip ratio (WHR) or body mass index (BMI), which reflects an increase in adipose tissue. Circulating concentrations of estradiol in postmenopausal women are directly related to BMI. Estradiol can be formed from the conversion of androgens via the cytochrome P450 enzyme complex known as aromatase, which is present in adipocytes and adipocyte stromal tissue. Many breast and endometrial cancers are dependent on estradiol for tumor growth. Consequently obesity (BMI >30 kg/m2) predisposes to increased estrogen production and is associated with a twofold to fivefold increase in risk of endometrial cancer and a twofold increase in risk of breast cancer in postmenopausal women. Circulating estrogens are an important pathological mechanism linking obesity with breast and endometrial cancer development in postmenopausal women. Increased adiposity raises interleukin (IL)-6 and tumor necrosis factor (TNF)-a cytokines production in obese women that are potent inducers of aromatase activity and thus to production of estradiol, which is a potent growth factor for estrogen receptor-positive breast and endometrial cancers. Adipocytes, or fat cells, are not only a simple storage sites for triglycerides but a complex endocrine organ able to secrete hormones, cytokines, and other proteins with signaling properties (collectively termed "adipokines"). Adipokines are a diverse group of signaling molecules that play roles in such processes as appetite and energy balance, inflammation, insulin resistance/sensitivity, angiogenesis, lipid metabolism, cell proliferation, and atherosclerosis. Many of these functions are related to either the metabolic syndrome or cancer, and they may serve as a link between these two pathologies. There are more than 50 adipokines with diverse functions affecting glucose homeostasis, insulin sensitivity, angiogenesis, adipogenesis, inflammation, cellular proliferation, apoptosis, and differentiation. These cytokines secreted by adipocytes are known to promote insulin resistance and increase circulating triglycerides, features of the metabolic syndrome. Inflammation has also been linked to many types of cancer, such as gastric, pancreatic, esophageal, liver, bladder, and colorectal cancers because it influences growth, apoptosis, and proliferation of tumor and stromal cells. TNF-a activates nuclear factor-KB, which increases production of NO, a substrate for Reactive Oxygen Species (ROS) formation and stimulates other inflammatory cytokines. ROS and inflammatory cytokines lead to insulin resistance and glucose intolerance. Thereby, increased circulating cytokines from adipocytes promote cancer progression by contributing to inflammation. Leptin is an adipocyte-specific hormone that serves as a metabolic signal to the brain that results in inhibition of appetite and increased basal metabolism to promote use of the stored energy (fat). Thus, circulating leptin levels are directly related to adiposity. However, obese patients develop resistance to leptin and consequently become hyperleptinemic and more susceptible to the components of the metabolic syndrome. In addition to its association with obesity and insulin resistance, increased plasma leptin levels are associated with prostate, colon, breast, and it is inversely correlated with breast, endometrial, and gastric cancer risk. Angiogenesis is the process of new blood vessel formation from pre-existing vasculature and is a critical process for tumor formation and metastasis. One of the most important proangiogenic factors secreted by adipocytes is Vascular Endothelial Growth Factor (VEGF). The adipocytokine Visfatin, has been linked to several inflammatory disease states and cancer. Thus, visfatin may be an obesity-induced adipocytokine involved in the development of MetS-related cancers. Adipokines influence insulin resistance by increasing or decreasing insulin sensitivity. Because insulin resistance is directly related to the metabolic syndrome and cancer development, adipokines may play a crucial role in linking these two diseases. The evidence for adipokines and proinflammatory cytokines derived from adipose tissue promoting carcinogenesis (either via promoting insulin resistance or directly influencing cancer cells) is considered intermediate. Previous epidemiological data, showed a strong association between endometrial cancer risk and obesity, as measured by both BMI and waist circumference. In particular, metabolic syndrome and hyperinsulinemia resulted associated with endometrial cancer. Among premenopausal women with metabolic syndrome, there is almost a twofold increased risk of endometrial cancer, largely due to increasing waist sizes. After menopause, this jumps to a 60–230% elevated risk of endometrial cancer in women with metabolic syndrome. PART II RESEARCH PROJECT N°1: EFFICACY OF MYOINOSITOL AND FLAVONOIDS IN POSTMENOPAUSAL WOMEN AFFECTED BY METABOLIC SYNDROME: A RANDOMIZED CROSSOVER STUDY. The aim of this study is to evaluate the efficacy of myo-inositol and soy isoflavones in reducing insulin resistance in postmenopausal patients with metabolic syndrome. Forty-two such patients were enrolled in the study and were randomized into two groups, G1 and G2. During the first year (time T0-T2), group G1 (21 patients) was administered myoinositol 2 g + soya isoflavones (genistein 200 mg) once daily while group G2 was treated with diet and exercise only. After one year, the treatments were crossed over: during the second year (time T2-T4), group G2 (21 patients) was administered myoinositol 2 g + soya isoflavones (genistein 200 mg) once daily, while group G1 stopped the pharmaceutical treatment and was treated with diet and exercise only. Patients were evaluated at baseline (T0) and every 6 months (T1-T4) for body mass index (BMI), abdominal circumference (CA), basal glucose (BG), triglycerides (TG), low density lipoprotein (LDL), and high-density lipoprotein (HDL). Myo-inositol in association with soy isoflavones produced a highly significant improvement in serum levels of BG and TG compared with the groups treated with diet and exercise only. There was no significant change in BMI in either group from T0 to T4. Supplementation with myo-inositol and soy isoflavones may be considered a reliable option in the treatment of metabolic syndrome in postmenopausal women. RESEARCH PROJECT N°2: THE ROLE OF NOVEL BIOMARKER HE4 IN ENDOMETRIAL CANCER: A CASE CONTROL PROSPECTIVE The aim of the study was to explore the clinical of serum human epididymis secretory protein E4 (HE4) and CA125 in endometrial carcinoma. From January 2010 to April 2012, serum specimens were collected from consecutive cases of endometrial carcinoma and from cases of uterus benign disease (control group). The CA125 normal value is considered less than 35 U/mL. Two HE4 cut-off are considered: less than 70 pmol/L and less than 150 pmol/L. The specificity analysis was performed using the Mann–Whitney test for the CA125 and HE4 series. The level of statistical significance is set at p <0.05. The sensitivity of CA125 in detecting endometrial cancer is 19.8%, whereas the sensitivity of HE4 is 59.4 and 35.6% for 70 and 150 pmol/L cutoff, respectively. Thus the specificity of HE4 is 100% (positive predictive value = 100%, negative predictive value = 71.52 and 61.31% considering the two HE4 cut-offs, respectively), whereas the CA125 specificity is 62.14% (positive predictive value 033.9%, negative predictive value 044.14%) in detection of endometrial cancer. Combining CA125 and HE4, the sensitivity to detect endometrial cancer is 60.4 and 34.6%, at HE4 cut off of 70 and 150 pmol/L, respectively, with a specificity of 100%. HE4 may be a new tool for preoperative evaluation and postoperative surveillance of endometrial cancer patients, with a positive predictive value = 100%. HE4 at cut-off of 70 pmol/L yields the best sensitivity and specificity.