CLINICAL, BIOCHEMICAL - MOLECULAR AND ETIOLOGICAL ASPECTS OF THE METABOLIC SYNDROME AFTER THE MENOPAUSE

The metabolic syndrome (METS) is a cluster of lipid and non-lipid factors that increase cardiovascular risk [1]. The National Cholesterol Educational Program and its Third Adult Treatment Panel (NCEP ATP-III) have established diagnostic criteria for the METS, which are met when three or more of the following are present: abdominal obesity, decreased highdensity lipoprotein cholesterol (HDL-C) levels and increased serum triglycerides (TG), fasting glucose and/or blood pressure levels [2]. A. Prevalence Prevalence of the METS is higher in women, especially those of Latin America ancestry [3], with an increased frequency observed in relation to age and the menopausal status. Indeed, during the menopausal transition there is an emergence of features related to the METS: obesity, dyslipidemia, diabetes, hyperinsulinism, hypertension and co-morbid conditions [4], possibly but not totally related to increasing estrogenic deficiency [5]. Rates may also vary according to the studied population from 22% [6] to 34% as determined in seven crosssectional studies of non-diabetic Europeans [7]. This syndrome increases cardiovascular morbidity and mortality and the risk of developing diabetes [8]. B. The effect of the menopause over female weight The prevalence of abdominal obesity is nearly double that of general obesity, with rates in North American women calculated for 2008 in 65.5% (aged 40-59 years) and 73.8% (60 years or more)[9]. It has been suggested that body mass index (BMI) but not menopausal status determines central adiposity in postmenopausal women. However, there is substantial evidence that the perimenopause is associated with a more rapid increase in fat mass and redistribution of fat to the abdomen, resulting in a transition from a gynoid to an android pattern of fat distribution and an increase in total body fat [10]. Moreover, postmenopausal women have greater amounts of intra-abdominal fat as compared to premenopausal ones, as determined with several radiological modalities [11]. Waist circumference represents both 5 subcutaneous and visceral adipose tissue depot size and correlates closely with the risk for cardiovascular disease. In women, it is also closely associated with dyslipidemia [12]. Abdominal fat is considered an endocrine organ as it has the capacity to secrete adipokines and other active substances closely related to metabolic diseases: insulin resistance, type 2 diabetes and the METS [13]. Both, the menopausal transition and aging, are associated with changes in adipose tissue metabolism, which contribute to the accumulation of body fat after menopause [14]. Deleterious changes in inflammatory markers and adipokines correlate strongly with increased visceral adiposity after the menopause [15]. Waist circumference significantly changes in relation to the time since final menstrual period. Moreover, significant increases in central abdominal fat have been reported from longitudinal studies in Caucasian and Asian women [16]. It has been observed that when non-obese premenopausal women are followed-up for several years, significant increases in total, percentage and truncal and visceral fat mass occur [16]. Women who later became peri or postmenopausal displayed a significant increase in visceral fat compared with baseline [16]. C. The impact of increased weight over menopausal symptoms Severity and prevalence of menopausal symptoms relate several factors. These include not only the hormonal changes imposed by the transition, but also psychosocial factors. As weight increased during the menopausal transition, so do menopausal symptoms. Obesity is an independent risk factor for more severe menopausal symptoms [17,18]. Reduction of weight, BMI and abdominal circumference have been associated with a significant reduction in vasomotor symptoms women who are overweight and obese [19]. The combination of dietary modification and exercise also has positive effects on health related quality of life (HRQOL) and psychological health, which may be greater than that from exercise or diet alone [20]. Improvements in weight, aerobic fitness and psychosocial factors may mediate some of the effects of these interventions on HRQOL [20]. Weight loss in 6 overweight and obese women improves psychological wellbeing, HRQOL, self-esteem and health practices [21]. In addition, dietary weight loss and exercise exert a positive effect over insulin resistance in postmenopausal women, which together with a decrease in menopausal symptoms may potentially decrease cardiovascular risk. D. The METS a state of pro-inflammation and endothelial dysfunction The METS is associated with increased inflammation, endothelial dysfunction, oxidative stress and abnormalities in both the macro- and microvasculature [22]. Adipocytes and adipose-tissue macrophages are involved in the production of IL-6, which is one of the main mediators of chronic inflammation [23]. Elevated IL-6 is an established risk factor for cardiovascular events in women after the menopause; thus, it is interesting to find that the presence of METS, rather than the menopause itself, relates to increased IL-6 levels. IL-6 serum levels are associated with visceral adipose tissue and can influence insulin levels [24]. On the other hand, it has been reported that IL-6 polymorphisms may play a role in the pathogenesis of the METS through the modulation of IL-6 levels [25]. F. Endothelial dysfunction during pregnancy as a model for future METS risk Preeclampsia is a leading cause of maternal mortality and morbidity worldwide [26]. Epidemiological data indicate that women complicated with preeclampsia are more likely to develop future cardiovascular disease (CVD). Population-based studies relate preeclampsia to an increased risk of later chronic hypertension (RR, 2.00 to 8.00) and cardiovascular morbidity/mortality (RR, 1.3 to 3.07), compared with normotensive pregnancy [27]. Women who develop preeclampsia before 36 weeks of gestation or have multiple hypertensive pregnancies are at highest risk (RR, 3.4 to 8.12). The underlying mechanism for the remote effects of preeclampsia is complex and probably multifactorial. Many risk factors are shared by CVD and preeclampsia, including endothelial dysfunction, obesity, hypertension, hyperglycemia, insulin resistance, and dyslipidemia. Therefore, it has been proposed that the METS may be a possible underlying mechanism common to CVD 7 and preeclampsia. Follow-up and counseling of women with a history of preeclampsia may offer a window of opportunity for prevention of future disease [27].