Anna G Dagre MD1[*] and John Lekakis MD2, 1Vascular Laboratory and Endocrine Unit, Department of Clinical Therapeutics, Alexandra Hospital, University of Athens, Athens, Greece, 22nd Cardiology Department, Attikon Hospital, University of Athens, Athens, Greece, [*]23 Ikarias Street, 145 78, Ekali - Athens, Greece, E-mail: annadagre@hotmail.com

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in young women, affecting as many as 1 in 15 women of reproductive age [1 ]. PCOS is characterized by oligo-and/or anovulation, clinical and/or biochemical signs of hyperadrogenism and/or polycystic ovaries detected by ultrasound [2]. Lately there has been significant scientific interest for PCOS because of its speculated relationship with two major factors of morbidity and mortality: i) metabolic syndrome and ii) cardiovascular disease (CVD).

There is evidence to support that PCOS not only has a negative effect on fertility, but it is also a plurimetabolic syndrome associated with other endocrine disorders such as type 2 diabetes mellitus and insulin resistance as well as hypertension and dyslipidemia [3-6]. Furthermore, insulin resistance has been proposed as the key factor linking hypertension, impaired glucose tolerance, obesity, and lipid abnormalities with CVD in PCOS [7].

The proposed designation of PCOS is female cardiometabolic syndrome or "Syndrome XX" [8], a term that shows the potential risk for development of CVD that accompanies PCOS. Studies in young PCOS women have shown increased serum markers of premature atherosclerosis such as C-reactive protein (CRP) [9], homocysteine [10], and endothelin-1 [11]. In addition to serum markers, several indices of subclinical atherosclerosis such as endothelial dysfunction, carotid intima media thickness (IMT), coronary artery calcium (CAC), and arterial stiffness have been studied. Women with PCOS have been found to have endothelial dysfunction [12], greater IMT and CAC [13,14], and stiffer arteries than controls [15], suggesting early accelerated CVD.

However, certain aspects of PCOS are not so clear-cut. There is a confounding factor that interferes with all PCOS studies making interpretation of their results quite problematic: the definition of PCOS. PCOS by definition is a syndrome that means a set of signs or symptoms that occur together or in other words a combination of varying phenotypes. Even after the revised consensus on diagnostic criteria recently reported [2] the controversy regarding characteristics of PCOS still remains [16]. Lack of universally accepted diagnostic criteria for the syndrome makes comparison of studies assessing cardiovascular risk or metabolic abnormalities difficult [17].

On the other hand PCOS does not seem to be a CVD or a metabolic syndrome equivalent. Women suffering from metabolic syndrome do not seem to present signs of PCOS more often than the general female population [18]. Nor do all women with PCOS have metabolic syndrome considering that i) obesity is not a constant phenotype in PCOS [19] and ii) insulin resistance, assessed by invasive dynamic tests, is not documented in all women with PCOS [20,21]. Furthermore, insulin resistance cannot be translated clearly in a clinical setting as acknowledged guidelines or criteria are lacking [22].

The risk of premature CVD in PCOS is uncertain at present. Long-term outcome studies examining the prevalence of CVD among women with PCOS have failed to demonstrate a significantly increased risk of CV death [23, 24]. These results were somehow unexpected taking in account the observed alterations in serum markers [9-11] and subclinical indices of CVD [12-15 ] which had raised the calculated risk level of CV events in the PCOS population.

There are multiple potential reasons explaining lack of published data confirming increased CV events in this group. Due to the inconsistency in the definition of PCOS, it is hard to interpret the existing data as far as the long-term outcome of these women. This heterogeneity of diagnostic criteria is both confounding and confusing when assessing CVD in women with PCOS. The long lag time between diagnosis of PCOS and CV events, leads to inaccurate data. Furthermore, the young age of subjects in these cohort studies reduces their sensitivity to detect increased incidence of CV events.

Another possible explanation might be that women with PCOS are probably of "intermediate phenotype" regarding CV risk and that there is a pathophysiologic aspect of PCOS that counteracts the effects of hypertension, diabetes, hyperinsulinemia, or dyslipidemia on CVD.

We recently reported that elevated levels of dehydroepiandrosterone-sulfate (DHEA-S) improve endothelial dysfunction observed in PCOS women [25]. DHEA-S is the most abundant androgen produced by the adrenals and seems to directly induce endothelial nitric oxide synthesis through genomic and non-genomic mechanisms [26]. It also exerts several vascular protective effects such as prevention of platelets aggregation [27], reduction of cholesterol uptake [28], and decrease of vascular smooth muscle cell proliferation [29]. Our study, among others [30,31], indicates that increased DHEA-S levels, frequently encountered in PCOS, may offer a cardioprotective advantage that attenuates the effects of CV risk factors that accompany PCOS.

Furthermore, medical therapies applied in PCOS, such as the oral contraceptive pill, targeting a reduction in androgen levels may not be advantageous considering the suggested relationship between androgens and CV risk factors. It is also probable that the favorable effect in vasculature of insulin sensitizers may be mediated only through their effect on insulin resistance and not through the resulting amelioration in androgen levels. However, it is important to note that other investigators have not found association of androgen levels with CV function parameters [32,33]. Methodological aspects as well as patient selection criteria may contribute to that discrepancy. At present, the CV effects of androgens remain unclear; this is a topic to be clarified. PCOS is an intriguing group to address this issue since this population has a clustering of CV risk factors and is characterized by hyperadrogenism.

In conclusion, several metabolic and hormonal alterations have been recognized as possible contributing factors to the pathophysiology of CVD in PCOS. Additional research is required to clarify the following issues: a) the state of the CV system in PCOS women; b) enable identification of patients at risk; c) provide longitudinal follow up of PCOS cohorts into late decades of their lives; and finally d) determine the relative contribution of factors such as insulin resistance and androgen status, as well as the effects of interventions intending to modulate these factors in CV system of PCOS women.

While awaiting for answers in these questions through basic and clinical research, life-style changes with intent to reduce both type 2 diabetes and CVD risks in women with PCOS seem to be a logic proposal in everyday clinical practice.

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