At this moment there is no single and universally accepted definition for PCOS. This is probably the pivotal reason why published studies on PCOS cannot be easily reanalyzed in order to provide a conclusive assessment of the CVR or CVD in this group of patients. Nevertheless, several lines of evidence (11-15) indicate alterations in intermediate endpoints for CVR in women with PCOS and provide evidence for an association between CVR factors in PCOS and CVD (Table 1). Most studies
Recognized CVR factors Atherosclerosis; coronary artery disease; myocardial infarction; athero genic lipid profile (iTC, iLDL, TtG, or ¿HDL) Emerging/Novel CVR factors TCRP; TWBC (lymphocytes and monocytes)
Direct measurement of subclinical CVD LVH and diastolic dysfunction; TiMT; endothelial dysfunction (¿FMD,
TeT-1); impaired fibrinolysis (TpAI-1) Increased clinical CVD No increased mortality from CVD documented to date in PCOS; how ever, insulin resistance is a frequent cause of increased CVR and CVD
TC, total cholesterol; LDL, low-density lipoprotein; TG, triglycerides; HDL, high-density lipoproteins; LVH, left ventricular hypertrophy; IMT, intima media thickness; CRP, C-reactive protein; WBC, white blood cell count; FMD, flow-mediated dilation; ET-1, endothelin-1; PAI-1, plasminogen activator inhibitor-1.
on CVD in PCOS used criteria adopted at the 1990 National Institute of Child Health and Human Development (NICHD) conference to diagnose PCOS (16). Patients with PCOS diagnosed by the NICHD criteria, which include androgen excess as a sine qua non, should have a risk for CVD significantly higher in comparison with patients with PCOS who have their diagnosis made according to European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine criteria (17), which allow for normal androgen levels in women with oligo- or amenorrhea and anatomically polycystic ovaries. In fact, a crucial contributing factor to CVD in PCOS may be hyperandrogenemia.
Decreased sex hormone-binding globulin (SHBG), which is typical in PCOS and increases bioavailable testosterone, may be considered a surrogate marker of IR such that lower levels of SHBG are related to a greater degree of IR (18). Therefore, IR may in part indirectly contribute to CVR in PCOS by amplifying androgen excess. In addition to this possible selection bias, large-scale clinical trials evaluating the morbidity and mortality for CVD in women with PCOS are lacking. No long-term data of well-characterized women with PCOS are present in the literature, and the link of PCOS to primary cardiovascular events, such as stroke or myocardial infarction (MI), remains to be demonstrated.
Epidemiological studies on isolated signs and stigmata of PCOS have produced mixed results. Some preliminary studies suggest a slight increase in cardiovascular events in women with PCOS. For example, an uncalculated but significantly increased risk of atherosclerosis (19) and a sevenfold increased risk of CVD (20) have been reported in subjects with PCOS. Notably, the risk of coronary artery disease and MI has been reported to be increased in patients with PCOS compared with regularly cycling women (13) even if mortality from circulatory disease does not seem to be increased. However, overall, the small size and limited number of these epidemiological studies have been inadequate to confirm an association between PCOS and CVD, especially because both are common conditions in women.
Moreover, as a consequence of IR, patients with PCOS often have an abnormal lipid profile and increased incidence of CVR factors (21). As noted earlier, IR has been associated with elevated triglyceride levels, increased levels of LDL, and decreased levels of HDL (7,8). Therefore, different confounding factors may co-exist in patients with PCOS, such as obesity, arterial HTN, impaired glucose tolerance (IGT), and/or type 2 diabetes mellitus, hyperinsulinemia, dyslipidemia, and coagulation disorders. Each of these factors could independently increase the risk for CVD in these subjects, making it difficult to quantify the increased CVR conferred by PCOS per se vs associated comorbidities. Interestingly, recent data have demonstrated a correlative and causative relationship between IR and inflammation (22). In light of the role of IR in PCOS, and of the increased CVR of affected women, a relationship between inflammation and hormonal-metabolic features in women with PCOS has also been suggested (23).
Women with PCOS appear to have significantly increased C-reactive protein (CRP) concentrations (24), a marker of low-grade chronic inflammation and predictor of coronary heart disease and cardiovascular events, and indicated an independent inverse relationship between CRP and insulin insensitivity. The leukocyte count has been reported to be significantly higher in women with PCOS compared with healthy women, although frank leukocytosis was absent from both groups. Furthermore, in the leukocyte differential count, a significant increase in lymphocytes and monocytes was observed in women with PCOS with regard to controls (23), as might be expected considering that they play a key role in the pathophysiological mechanism of atherosclerosis. Although these findings are provocative, further studies are needed for confirmation.
The metabolic syndrome (MBS), as defined by The National Cholesterol Education Program Adult Treatment Panel, a condition of increased CVR thought to be linked to IR and visceral obesity, is more prevalent in PCOS than in the general female population. In a recent study by Apridonidze et al. (25), the prevalence of the MBS in young women with PCOS was 43%. MBS contributes to an increased risk for CVD, and the presumed increased IR of women with PCOS with MBS should confer increased risk for glucose intolerance (25). IR, as previously mentioned, is probably not the only major risk factor for the occurrence of CVD in PCOS, but may represent the most important and pathogenic feature of MBS.
It is well established that the presence of MBS correlates with CVD risk (26); the finding of a markedly high prevalence of MBS even in young women with PCOS lends credence to previous reports of increased atherosclerosis and a sevenfold increased risk of CVD in women with PCOS (20). Because MBS is associated with an increased risk for cardiovascular morbidity and mortality and the prevalence of MBS is significantly higher in PCOS women, it is reasonable to conclude that all women with PCOS, regardless of age and body mass index (BMI), should be screened for the individual components of MBS, other CVR factors, and CVD.
As noted above, in addition to classic CVR factors, other factors such as homocysteine, LVH, and oxidative stress seem to be independently associated with an increase in CVR (9). Whereas data on homocysteine levels in women with PCOS are inconclusive and conflicting (27,28), an early and IR-related impairment of endothelial structure and function (12), as well as diastolic dysfunction and LVH (11), have been demonstrated in young normal-weight women with PCOS. Both IR and hyperandrogenism have been widely accepted as risk factors for increased intima-media thickness, a potential marker of risk for CVD, which has also been shown to be present in women with PCOS (12,19,29).
Impaired fibrinolysis, one of the more important cofactors in the development of fatal ischemic heart disease in women, has also been demonstrated in PCOS (30). Specifically, a significant increase in serum PAI-1 activity (31) has been reported. This increase was positively related to IR, but independent of obesity (31).
Finally, as documented from several studies, type 2 diabetes is present in 5-10% of women with PCOS, whereas IGT is found in 30-40% (32,33). IGT is a major risk factor for type 2 diabetes mellitus and a strong independent risk factor for CVD. Hyperinsulinemia from IR or IGT, with or without diabetes, probably plays a pivotal role in the acceleration of macrovascular disease in women with PCOS(21). Moreover, 50-60% of women with PCOS are obese (34), and obesity could further worsen the metabolic pattern and even the CVR of this group of patients.
Does the putative increase in CVD in PCOS translate into increased mortality in PCOS women? One important study addressing this question reported no increased CVD mortality in PCOS (2,35). The first report of the study (2) showed no increased mortality from cardiovascular-related causes, although there was an increased number of deaths following complications of diabetes in the PCOS group. The second (35) reported no increased long-term coronary heart disease mortality in the PCOS group, although there was evidence of increased stroke-related mortality even after adjustment for BMI.
It appears that PCOS may accelerate the development of an adverse CVR profile or even signs of subclinical atherosclerosis. Interestingly, IR is frequently cited as the cause of an increased risk for
CVD among women with PCOS, even if no measure of insulin sensitivity is included in current diagnostic criteria (36). Finally, phenotypic variability has been reported to influence the findings of abnormal metabolic and CVR parameters in the general population of hyperandrogenic women (35). For example, the prevalence of metabolic and cardiovascular abnormalities was highest in women who fulfilled the "classical" criteria for PCOS (which includes androgen excess and chronic oligo-amenorrhea), followed by normal ovulatory women with PCOS (i.e., with androgen excess and anatomically polycystic ovaries) and then women with idiopathic hyperandrogenism (37). This is a crucial point because it demonstrates the difficulty of defining the true CVR and putative CVD of PCOS, since the lack of a validated definition results in PCOS currently consisting of a heterogeneous group of affected women. In the future, all evaluations of the CVR should not only specify the criteria used in establishing the diagnosis, but should also take into consideration the different pheno-types of this complex disorder.
Whereas consistent and well-characterized phenotypes of reproductive and metabolic abnormalities have been demonstrated in PCOS, suggesting an increased risk for CVD in the disorder, prospective studies and clinical trials from large-scale studies with long-term follow-up are lacking. Few studies of PCOS have selected mortality (cardiovascular or otherwise) as their endpoint, and at present these limited studies do not indicate an increased mortality for CVD in PCOS. Several parameters denoting increased CVR, such as lipoprotein abnormalities, HTN, LVH, endothelial dysfunction, and low-grade chronic inflammation, have been described in PCOS women, even at an early age, although in small sample studies. Therefore, larger prospective trials with long-term follow-up are needed to more accurately define the CVR and the putative subsequent CVD of PCOS.
An early diagnosis of PCOS could provide an important opportunity to begin primary prevention of CVD. There are multiple and several surrogate variables in PCOS, including anthropometric and biochemical parameters, but the ability of these variables to predict primary clinical endpoints (such as cardiovascular mortality) remains to be determined, and represent a major problem when designing trials to assess CVR in PCOS women.
CVD is arguably the most important clinical endpoint in PCOS studies evaluating CVR, but few studies have addressed this endpoint. Future multicenter studies in women with PCOS should focus on CVD as the primary clinical endpoint.
The therapeutic effects of diet, physical exercise (i.e., lifestyle modifications), oral contraceptives, and insulin-sensitizing drugs (metformin, thiazolidinediones, etc.) on CVR factors should be carefully investigated in future studies of PCOS.
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