prevalence of obesity among affected women (37). A higher prevalence of MBS has also been found in PCOS-affected adolescents in comparison to age and BMI-matched control groups (96,97). There is intriguing evidence that this increased risk may be conferred not only by insulin resistance but also by hyperandrogenemia (93,98), in agreement with the higher bioavailable testosterone levels of postmenopausal women with rather than without MBS (99). The components of the MBS, namely obesity, dyslipidemia, insulin resistance and less commonly, hypertension, may be important determinants of overall, long-term health in PCOS patients (48,100).
Dyslipidemia is a primary target for therapeutic intervention in patients with MBS and CVD (101). A multitude of studies have shown elevated levels of total, LDL and VLDL cholesterol and triglycerides, as well as low HDL cholesterol in PCOS patients in excess of values expected from their obesity (102-108). Furthermore, total and LDL cholesterol were increased in hyperandrogenemic and PCOS-affected sisters and mothers of PCOS patients, consistent with a heritable trait (36,37).
Results concerning hypertension and PCOS are conflicting. While several studies have reported a higher prevalence of hypertension in PCOS patients (109-111), others have not (3). In 24-h ambulatory Holter-monitoring, women with PCOS had higher systolic blood pressure in comparison with BMI-, body fat-, and insulin sensitivity-matched controls in a study from Sweden (112), but not in a study from Canada (113).
Low-grade chronic inflammation is involved in the pathogenesis of the MBS and atherosclerosis (114). Hyperinsulinemia is associated with low-grade inflammation, which can be demonstrated by the elevation of C-reactive protein (CRP). CRP is an independent predictor for the development of T2DM (115) and a prognostic factor for cardiovascular events (116). Studies from Israel (117) and Turkey (118) found higher CRP levels in PCOS patients compared to controls, while a German study found a correlation of CRP levels with BMI unrelated to the presence of PCOS (119). Cytokines, which stimulate hepatic CRP production via induction of tumor necrosis factor-a (TNF-a), have also been correlated with MBS and CVD (114). In PCOS patients, Escobar-Moreale et al. found elevated interleukin-18 levels, which correlated with total testosterone and several indexes of global and visceral adiposity and with insulin resistance (120), while interleukin-6 was correlated with obesity rather than PCOS (119,121). An elevated white blood cell count has been proposed as a marker of subclinical inflammation and predictor of future cardiovascular events (114). This putative marker of CVR has recently been shown to correlate with other risk factors in PCOS patients (122). While elevated homocysteine levels appear to be correlated to CVD, therapeutic intervention with folate and B-vitamin substitution did not reduce morbidity or mortality in the HOPE-2 trial (123). Several studies have reported elevated homocysteine levels in PCOS, with a positive correlation with the degree of insulin resistance (124-126). Endothelin-1, a marker of vascular dysfunction, was found to be elevated in PCOS patients and could be reduced by metformin treatment both in lean (127) and obese patients (128).
Two studies have linked insulin resistance to endothelial dysfunction in PCOS patients by showing diminished vasodilatation to methacholine infusion (129) or reduced pulse wave velocity (130). However, a study using ultrasound to examine brachial arterial diameters as marker for vasodilatation found no difference between women with and without PCOS (131). In PCOS women older than 45 years, increased carotid intima media thickness (132,133) and coronary calcification on electron beam computed tomography (6) as surrogate markers of CVD have been reported. Recently, increased intima media thickness has also been reported for younger PCOS patients and was found to correlate with age, BMI, insulin resistance, dyslipidemia and family history of CVD and T2DM (134).
Concurrent with the increased prevalence of PCOS with obesity, the prevalence of the MBS is substantially higher in women with PCOS, ranging in the U.S. from 33% to more than 50% (93). However, in some other countries, the prevalence of the MBS in patients with PCOS is lower than that observed in the U.S. (3,54), most likely due to differences in body weight, environmental factors and food composition (Fig. 3). In contrast to the 1990 NIH criteria, which predict a higher prevalence of the MBS in PCOS patients, the use of PCO as a screening parameter does not identify PCOS patients at increased risk for the MBS (Fig. 4) (95).
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