Abstract

BACKGROUND

The relation between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD) remains unclear. In an attempt to provide high-quality evidence on the relation between PCOS and CVD, relevant literature for CVD risk markers [C-reactive protein (CRP), homocysteine (Hcy), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) [Lp(a)], advanced glycation end-products (AGEs), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and fibrinogen] in women with PCOS was reviewed and analyzed.

METHODS

A systematic search was conducted electronically using specific eligibility criteria. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed.

RESULTS

A total of 130 data sets were included in 11 different outcomes, involving 7174 and 5076 CVD markers in women with PCOS and controls, respectively. Women with PCOS demonstrated significantly elevated CRP [WMD (95% CI) 0.99 (0.77–1.21)], Hcy [2.25 (1.46–3.03)], PAI-1 antigen [16.96 (7.25–26.28)], PAI-1 activity [0.71 (0.18–1.23)], VEGF [1.72 (0.96–2.48)], ADMA [0.19 (0.08–0.3)], AGEs [3.91 (2.36–5.45)] and Lp(a) [0.81 (0.58–1.04)] concentrations compared with controls, yet with significant between-study heterogeneity. Borderline significance (not robust in the sensitivity analyses) was detected for TNF-α [0.75 (0.07–1.44)], ET-1 [1.06 (0.52–1.59)] and fibrinogen [0.20 (0.01–0.39)], whereas no difference was detected for IL-6 [0.71 (−0.16 to 1.59)].

CONCLUSIONS

Women with PCOS have increased serum concentrations of CVD risk markers compared with controls. Whether this apparent risk is translated into increased incidence of CVD in later life remains to be elucidated.

Introduction

Polycystic ovary syndrome (PCOS) affects 6–10% of women during their reproductive life (Wild et al., 2010; Goodarzi et al., 2011). Its complete phenotype is manifested by ovulatory dysfunction, hyperandrogenism and polycystic ovaries (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004; Wild et al., 2010). Although there are available data suggesting increased incidence of cardiovascular disease (CVD) in women with PCOS (Meyer et al., 2005; Lo et al., 2006), the relation between these two entities is far from being elucidated. This relation, especially if it is a causative one, could be explored through prospective cohort studies that would follow-up women with PCOS but without CVD and monitor them for the development of the latter. Given the experience in women treated with hormone replacement therapy as far as development of CVD is concerned (Rossouw et al., 2002), such studies are very difficult to conduct due to sample size, time and cost limitations. An alternate way would be case–control studies, in which women with established CVD would be questioned for PCOS-related parameters. Nevertheless, given the time delay between diagnosis of PCOS and development of CVD, the quality of PCOS-related data would inevitably be poor (Solomon et al., 2002).

The remaining, indirect way to explore the relation between PCOS and CVD is to conduct cross-sectional, case–control studies not on CVD per se but on risk factors for it. Thus, women with PCOS would be the case group and women without PCOS would be the control group, and the two groups would be compared as far a risk factor for CVD is concerned. Adopting such an approach, the question that emerges is ‘what can be considered as an established factor for CVD?’. Indeed, many conditions, mainly components of the metabolic syndrome, have been characterized as risk factors for CVD, such as impaired glucose tolerance/diabetes mellitus type 2, dyslipidemia, abdominal obesity and hypertension (Evangelista and McLaughlin, 2009). On top of these, and given the evidence that low-grade chronic inflammation provides the pathophysiology basis for atherosclerosis, new risk factors have been established, such as C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (Kaptoge et al., 2010; Nishida et al., 2010). Finally, a series of conditions related—in a direct or indirect way—to endothelial inflammation have provided additional risk factors for CVD, such as oxidative stress [homocysteine (Hcy), asymmetric dimethylarginine (ADMA), advanced glycation end-products (AGEs), endothelin-1 (ET-1)], disorders of the coagulation procedure [fibrinogen, plasminogen activator inhibitor-1 (PAI-1), lipoprotein (Lp)] and endothelium proliferation [vascular endothelial growth factor (VEGF)] (Homocysteine Studies Collaboration, 2002; Anderssohn et al., 2010).

Numerous studies have attempted to determine risk factors for CVD in women with PCOS and, despite a general conclusion of unfavorable (increased) serum concentrations in these women when compared with controls, their conclusions are far from being uniform. Given the large amount of the published evidence and the conflicting results, the aim of the present study was to systematically review the literature for cross-sectional case–control trials that have studied woman with PCOS for CVD risk factors, (namely CRP, IL-6, TNF-α, Hcy, ADMA, AGEs, fibrinogen, PAI-1, Lp(a), ET-1 and VEGF) and to meta-analyze the best evidence available, in an attempt to provide high-quality data on the linkage between PCOS and CVD.

Materials and Methods

Search strategy

To identify eligible studies, the main search was conducted in the electronic databases MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) from inception through June 2010, using various combinations of Medical Subject Headings (MeSH) and non-MeSH terms. Search strings, using ADMA as an example, are given in Table I. The procedure was concluded by: (i) the perusal of the reference sections of all relevant studies, (ii) a manual search of key journals and abstracts from the major annual meetings in the field of Endocrinology and Obstetrics and Gynecology and (iii) contact with experts. The main search was completed independently by investigators (E.K., E.E., S.-A.M., G.M., A.P., S.S., A.M. and M.P.). Any discrepancy was solved by consultation of an investigator, not involved in the initial procedure (D.G.G.).

Table I

Search strings for ADMA, as an example.

MEDLINE 
[‘N,N-dimethylarginine ’(Substance Name) OR ‘asymmetric dimethylarginine’(All Fields) OR ‘ADMA’(All Fields)] AND [‘Polycystic Ovary Syndrome’(Mesh) OR ‘Hyperandrogenism’(Mesh)] AND ‘humans’(Mesh) 
EMBASE 
‘n(g),n(g) dimethylarginine'/exp OR ‘n(g),n(g) dimethylarginine’ OR ‘asymmetric dimethylarginine'/exp OR ‘asymmetric dimethylarginine’ OR ‘adma'/exp OR ‘adma’ AND (‘polycystic ovary syndrome'/exp OR ‘polycystic ovary syndrome’ OR ‘hyperandrogenism'/exp OR ‘hyperandrogenism’) AND (‘humans'/exp OR ‘humans’) 
MEDLINE 
[‘N,N-dimethylarginine ’(Substance Name) OR ‘asymmetric dimethylarginine’(All Fields) OR ‘ADMA’(All Fields)] AND [‘Polycystic Ovary Syndrome’(Mesh) OR ‘Hyperandrogenism’(Mesh)] AND ‘humans’(Mesh) 
EMBASE 
‘n(g),n(g) dimethylarginine'/exp OR ‘n(g),n(g) dimethylarginine’ OR ‘asymmetric dimethylarginine'/exp OR ‘asymmetric dimethylarginine’ OR ‘adma'/exp OR ‘adma’ AND (‘polycystic ovary syndrome'/exp OR ‘polycystic ovary syndrome’ OR ‘hyperandrogenism'/exp OR ‘hyperandrogenism’) AND (‘humans'/exp OR ‘humans’) 

Eligibility of relevant studies

Eligible for the systematic reviews were studies of any design, which reported CRP, Hcy, TNF-a, PAI, fibrinogen, IL-6, VEGF, ET-1, AGEs, Lp(a) and/or ADMA levels in women with PCOS compared with healthy controls. Women with PCOS were diagnosed consistently by either Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2004) criteria, National Institute of Health (Zawadski and Dunaif, 1992) criteria, oligomenorrhea with hyperandrogenemia or, very occasionally, other compatible criteria (Supplementary data).

Studies were excluded from the systematic reviews and the meta-analyses if the enrolled subjects had a disease other than PCOS, were on any kind of medication, were pregnant or were genetically related. Studies with no control group or control group including men were also excluded. Reviews, letters to the editor and studies published in language other than English were excluded as well.

Data extraction

Information from each study was extracted independently by two reviewers using a standardized data extraction form. Study general characteristics (author, journal, year of publication, design, ethnicity, study size and number of cases), characteristics of the PCOS and control groups (criteria, selection, age, BMI and smoking status), methodology (PCOS definition, measurements method) and outcomes were recorded (where available) and double-checked. When data were presented in subgroups, common standard deviation (SD) was calculated with the following formula: SDcommon2 = [(n1 – 1) × SD12 + (n2– 1) × SD22 + (m12 + m22 – 2 × m1× m2) × n1× n2/n1 + n2]/(n1+ n2 – 1), where n is the sample size, m the mean and SD the standard deviation. Where appropriate, the data set was completed through communication with the authors. Disagreement was resolved by consensus.

Statistical analysis

Weighted mean differences (WMDs) and 95% confidence intervals (CI) were calculated for each of the CVD risk factors for all eligible studies for the meta-analyses and combined using fixed or random effects model, where appropriate. Standardized mean difference (SMD) was used as a summary statistic, when different methodology was applied for the measurement of the index marker across studies. Heterogeneity between the results of different studies was examined by I2 test. To assess the extent of publication bias, Egger test was used. To ensure synthesis of the best available evidence, sensitivity analyses were performed excluding studies with: (i) significant differences in the mean BMI and/or age between groups, (ii) evidence of significant skewness in the distribution of index substance, as defined by a ratio of the mean to SD less than 1 (Altman and Bland, 1996) and (iii) t discordance among reviewers upon their eligibility was recorded. The effect of PCOS diagnostic criteria used (study-level characteristic) on the index test was investigated through restricted maximum likelihood-based random effects meta-regression analysis. Univariate meta-regression analyses were performed in the best available subset of studies to ensure interpretable results, when those studies were at least 10.

Meta-analysis and meta-regression were conducted using Stata/SE 9.0 for Windows (StataCorp LP, 4905 College Station, TX 77845, USA). The report of the study was complemented in adherence with the Meta-analysis Of Observational Studies in Epidemiology group standards for reporting meta-analysis of observational studies.

Results

The flow of studies from identification to systematic reviews and meta-analyses are presented in Table II. It was notable that a significant amount of between-study heterogeneity (I2 > 80%) was recorded in all analyses, unless otherwise specified.

Table II

Flow of studies from identification to systematic reviews and meta-analyses.

Studies CVD risk markers
 
 CRP Hcy TNF-α PAI-1 Fibrinogen IL-6 VEGF ADMA ET-1 AGEs Lp(a) 
Identified by the main search 410 369 167 181 33 49 23 29 24 82 10 
 Excluded as duplications 203 212 82 67 
 Excluded on a title-basis 55 76 31 45 12 10 42 
 Excluded on an abstract-basis 34 45 11 33 34 
Full-text was used 118 36 40 36 25 25 11 10 
 Excluded on a full text-basis 46 20 12 
Included in the systematic review 72 35 21 24 18 18 
 Excluded from the meta-analysis 24 11 
Included in the meta-analysis 48 24 13 16 13 10 
Studies CVD risk markers
 
 CRP Hcy TNF-α PAI-1 Fibrinogen IL-6 VEGF ADMA ET-1 AGEs Lp(a) 
Identified by the main search 410 369 167 181 33 49 23 29 24 82 10 
 Excluded as duplications 203 212 82 67 
 Excluded on a title-basis 55 76 31 45 12 10 42 
 Excluded on an abstract-basis 34 45 11 33 34 
Full-text was used 118 36 40 36 25 25 11 10 
 Excluded on a full text-basis 46 20 12 
Included in the systematic review 72 35 21 24 18 18 
 Excluded from the meta-analysis 24 11 
Included in the meta-analysis 48 24 13 16 13 10 

CRP, C-reactive protein; Hcy, homocysteine; TNF-α, tumor necrosis factor-alpha; PAI-1, plasminogen activator inhibitor-1 (antigen and/or activity); IL-6, interleukin-6; VEGF, vascular endothelial growth factor; ADMA, asymmetric dimethylarginine; ET-1, endothelin-1; AGEs, advanced glycation end-products; Lp(a), lipoprotein (a).

C-reactive protein

Selection of studies

There were 72 potentially eligible studies identified. Of these, 14 were excluded, since data were only available as medians or geometric means (Kelly et al., 2001; Tarkun et al., 2004a, b; Cho et al., 2005; Orio et al., 2005; Puder et al., 2005; Barutcuoglu et al., 2006; Engin-Ustun et al., 2006; Shroff et al., 2007; Glintborg et al., 2008; Thomann et al., 2008; Rajendran et al., 2009; Ruan and Dai, 2009; Makedos et al., 2010; Pamuk et al., 2010). After communication with the primary investigators, two studies (Cascella et al., 2006; Moran et al., 2009) were excluded to avoid data duplication. Moreover, eight studies were excluded since communication failed to clarify whether eligibility criteria were actually met (Erdogan et al., 2008; Kowalska et al., 2008; Arikan et al., 2009; Kaya et al., 2009a, 2010a; Oh et al., 2009; Oktem et al., 2009; Wu et al., 2009). In the sensitivity analysis, further studies were excluded due to differences between groups in the mean BMI (Mohlig et al., 2004; Gonzalez et al., 2005; Benson et al., 2008; Chen et al., 2009; Perez Calvo et al., 2009) or age (Boulman et al., 2004; Carmina et al., 2005; Moran et al., 2007; Alvarez-Blasco et al., 2009; Gonzalez et al., 2009; Martinez-Garcia et al., 2009; Tosi et al., 2009), evidence of significant skewness (Escobar-Morreale et al., 2003; Fenkci et al., 2003; Bickerton et al., 2005; Brinkworth et al., 2006; Diamanti-Kandarakis et al., 2006b, c, 2008b; Beckman et al., 2007; Costa et al., 2008; Jakubowska et al., 2008; Capoglu et al., 2009; Cetinkalp et al., 2009; Erdogan et al., 2009; Soares et al., 2009; Victor et al., 2009; Yang et al., 2009; Markou et al., 2010; Verit, 2010) or borderline eligibility (Karadeniz et al., 2008; Samy et al., 2009; Nikolajuk et al., 2010). Finally, 15 studies were considered as the best available evidence (Bahceci et al., 2004; Meyer et al., 2005; Orio et al., 2006; Topcu et al., 2006; Guzelmeric et al., 2007; Meden-Vrtovec et al., 2007; Nasiek et al., 2007; Cascella et al., 2008; Diamanti-Kandarakis et al., 2008c; Heutling et al., 2008; Gen et al., 2009; Thomson et al., 2009; Arikan et al., 2010; Kaya et al., 2010b; Moran et al., 2010).

Main analysis

A total of 48 studies, involving 4765 women (2835 with PCOS and 1930 controls), were eligible for the meta-analysis. Women with PCOS demonstrated significantly elevated CRP serum concentrations when compared with controls, yet with significant between-study heterogeneity [48 studies, random effects WMD (95% CI) = 0.99 (0.77–1.21)]. This finding was similar, even when studies with estimation of regular CRP or high sensitivity CRP (hs-CRP) concentrations were analyzed separately (Fig. 1). Small-study effect (publication bias) was found to be marginally insignificant (Egger test, P = 0.052). In the sensitivity analysis, the difference in CRP concentrations between women with PCOS and controls remained robust (15 studies, random effects WMD (95% CI) = 1.07 (0.76–1.39)]. It was notable that sensitivity analysis resulted in a substantial decrease in heterogeneity detected in the subset of hs-CRP studies (I2 = 43%). Meta-regression failed to provide evidence of a significant effect of PCOS criteria on CRP concentrations (P = 0.203).

Figure 1

C-reactive protein serum concentrations in women with PCOS and controls.

Figure 1

C-reactive protein serum concentrations in women with PCOS and controls.

Homocysteine

Selection of studies

There were 35 potentially eligible studies identified. Five of them were excluded, since relevant data were not extractable, being available only as medians (Palep-Singh et al., 2007, 2008; Makedos et al., 2010; Pamuk et al., 2010) or only in abstract (Luque-Ramirez et al., 2009). Six studies were excluded because it was impossible to rule out data duplication (Kaya et al., 2009a, b, c, 2010b, c, d). In the sensitivity analysis, further studies were excluded due to differences between groups in the mean BMI (Yarali et al., 2001; Vrbikova et al., 2002) or age (Schachter et al., 2003) and borderline eligibility (Bayraktar et al., 2004; Cetinkalp et al., 2009). Finally, 19 studies were considered as the best available evidence (Orio et al., 2003; Boulman et al., 2004; Kilic-Okman et al., 2004; Wijeyaratne et al., 2004; Bickerton et al., 2005; Yilmaz et al., 2005a, b, 2008; Topcu et al., 2006; Sahin et al., 2007; Atamer et al., 2008; Battaglia et al., 2008; Arikan et al., 2009; Mancini et al., 2009; Oktem et al., 2009; Soares et al., 2009; Fulghesu et al., 2010; Kaya et al., 2010a; Markou et al., 2010; Nafiye et al., 2010).

Main analysis

A total of 24 studies, involving 2191 women (1209 with PCOS and 982 controls), were eligible for the meta-analysis. Women with PCOS demonstrated significantly elevated Hcy serum concentrations when compared with controls, yet with significant between-study heterogeneity [random effects WMD (95% CI) = 2.25 (1.46–3.03)] (Fig. 2). No evidence of publication bias was detected (Egger test, P = 0.171). In the sensitivity analysis, the difference in Hcy concentrations between women with PCOS and controls remained robust [19 studies, random effects WMD (95% CI) = 1.87 (1.04–2.70)]. Meta-regression failed to provide evidence of a significant effect of PCOS criteria on Hcy concentrations (P = 0.633).

Figure 2

Homocysteine serum concentrations in women with PCOS and controls.

Figure 2

Homocysteine serum concentrations in women with PCOS and controls.

Tumor necrosis factor-α

Selection of studies

There were 21 potentially eligible studies identified. Seven of them were excluded, since data were not available in an extractable format (Amato et al., 2003; Omu et al., 2003; Puder et al., 2005, 2006; Shroff et al., 2007; Knebel et al., 2008; Thomann et al., 2008). One study was excluded because it did not fulfill standard quality requirements (Ravishankar Ram et al., 2005). In the sensitivity analysis, further studies were excluded due to differences between groups in mean age (Vgontzas et al., 2006; Moran et al., 2007) and skewness in the distribution of TNF-α concentrations (Sayin et al., 2003; Jakubowska et al., 2008). Finally, nine studies were considered as the best available evidence (Escobar-Morreale et al., 2001; Escobar-Morreale et al., 2003; Tarkun et al., 2006; Olszanecka-Glinianowicz et al., 2007; Arikan et al., 2009; Samy et al., 2009; Soares et al., 2009; Victor et al., 2009).

Main analysis

A total of 13 studies, involving 871 women (475 with PCOS and 396 controls), were finally eligible for the meta-analysis. Women with PCOS demonstrated elevated TNF-α serum concentrations of borderline significance when compared with controls, yet with significant between-study heterogeneity [random effects WMD (95% CI) = 0.75 (0.07–1.44)] (Fig. 3). No evidence of publication bias was detected (Egger test, P = 0.430). In the sensitivity analysis, the difference in TNF-α concentrations between women with PCOS and controls was found similar [nine studies, random effects WMD (95% CI) = 0.85 (0.10–1.59)].

Figure 3

TNF-α serum concentrations in women with PCOS and controls.

Figure 3

TNF-α serum concentrations in women with PCOS and controls.

Plasminogen activator inhibitor-1

There were 20 potentially eligible studies identified. Four of them reported serum concentrations of both PAI-1 antigen and PAI-1 activity, nine reported only the former and seven only the latter.

PAI-1 antigen

Selection of studies

Three out of 13 potentially eligible studies were excluded, since data were only available as geometric means or inter-quartile ranges (Sills et al., 2003; Baillargeon and Carpentier, 2007a, b; Tan et al., 2009). One study was excluded because communication failed to clarify whether eligibility criteria were actually met (Lin and Yongmei, 2008) and another one was excluded after contact with the primary investigator (Gonzalez et al., 2009). In the sensitivity analyses, further studies were excluded due to differences between groups in mean BMI (Velazquez et al., 1997; Carmassi et al., 2005) or age (Lindholm et al., 2010).

Main analysis

A total of eight studies (Velazquez et al., 1997; Paradisi et al., 2003; Diamanti-Kandarakis et al., 2004; Tarkun et al., 2004a, b; Carmassi et al., 2005; Lin et al., 2009; Oral et al., 2009; Lindholm et al., 2010), involving 883 women (529 with PCOS and 354 controls), were eligible for the meta-analysis. Women with PCOS demonstrated significantly elevated PAI-1 antigen serum concentrations when compared with controls, yet with significant between-study heterogeneity [random effects WMD (95% CI) = 16.96 (7.65–26.28)] (Fig. 4a). No evidence of publication bias was detected (Egger test, P = 0.73). In the sensitivity analysis, the difference in PAI-1 antigen concentrations between women with PCOS and controls remained robust [five studies, random effects WMD (95% CI) = 16.49 (4.87–28.11)].

Figure 4

Plasminogen activator inhibitor-1 antigen (a) and activity (b) serum concentrations in women with PCOS and controls.

Figure 4

Plasminogen activator inhibitor-1 antigen (a) and activity (b) serum concentrations in women with PCOS and controls.

PAI-1 activity

Selection of studies

Three out of 11 potentially eligible studies were excluded, since data were not extractable (Sills et al., 2003; Orio et al., 2004a, b; Tan et al., 2009). In the sensitivity analyses, further studies were excluded due to differences between groups in mean BMI (Slopien et al., 2006) or age (Atiomo et al., 2000; Yarali et al., 2001; Lindholm et al., 2010).

Main analysis

A total of eight studies (Atiomo et al., 1998, 2000; Yarali et al., 2001; Tarkun et al., 2004a, b; Slopien et al., 2006; Cascella et al., 2008; Moran et al., 2009; Lindholm et al., 2010), involving 868 women (548 with PCOS and 320 controls), were eligible for the meta-analysis. Women with PCOS demonstrated significantly elevated PAI-1 activity serum concentrations when compared with controls, yet with significant between-study heterogeneity [random effects SMD (95% CI) = 0.71 (0.18–1.23] (Fig. 4b). No evidence of publication bias was detected (Egger test, P = 0.76). In the sensitivity analysis, the difference in PAI-1 activity concentrations between women with PCOS and controls remained robust [four studies, random effects SMD (95% CI) = 1.33 (0.62–2.04)].

Fibrinogen

Selection of studies

There were 18 potentially eligible studies identified. Five of them were excluded, since necessary data were not extractable (Atiomo et al., 2000; Nacul et al., 2007; Nasiek et al., 2007; Mohamadin et al., 2010; Pamuk et al., 2010). In sensitivity analysis, further studies were excluded due to differences between groups in the mean BMI (Atiomo et al., 1998; Bickerton et al., 2005) or age (Yarali et al., 2001; Kelly et al., 2002). Finally, nine studies were considered as the best available evidence (Yildiz et al., 2002; Slopien et al., 2006; Baillargeon and Carpentier, 2007a, b; Karakurt et al., 2008; Erdogan et al., 2009; Kebapcilar et al., 2009; Luque-Ramirez et al., 2009; Mancini et al., 2009; Lenarcik et al., 2010).

Main analysis

A total of 13 studies, involving 925 women (507 with PCOS and 418 controls), were finally eligible for the meta-analysis. Women with PCOS demonstrated a borderline significant elevation in fibrinogen concentrations when compared with controls, yet with significant between-study heterogeneity [random effects WMD (95% CI) = 0.20 (0.01–0.39)] (Fig. 5). No evidence of publication bias was detected (Egger test, P = 0.689). In the sensitivity analyses, no significant difference in fibrinogen levels was detected between women with PCOS and controls [nine studies, random effects WMD (95% CI) = 0.19 (−0.12 to 0.51)].

Figure 5

Fibrinogen serum concentrations in women with PCOS and controls.

Figure 5

Fibrinogen serum concentrations in women with PCOS and controls.

Interleukin -6

Selection of studies

There were 18 potentially eligible studies identified. Six of them were excluded, since necessary data were not extractable (Amato et al., 2003; Mohlig et al., 2004; Shroff et al., 2007; Benson et al., 2008; Glintborg et al., 2008; Benson et al., 2009). Two studies were excluded, since communication failed to clarify whether eligibility criteria were actually met (Ravishankar Ram et al., 2005; Jakubowska et al., 2008). In the sensitivity analyses, further studies were excluded due to differences between groups in the mean BMI (Vgontzas et al., 2006; Kaya et al., 2010d) or age (Escobar-Morreale et al., 2003; Moran et al., 2007; Gonzalez et al., 2009) and skewness in the distribution of IL-6 concentrations (Soares et al., 2009). The remaining four studies were considered as the best available evidence (Olszanecka-Glinianowicz et al., 2007; Gen et al., 2009; Samy et al., 2009; Nikolajuk et al., 2010).

Main analysis

A total of 10 studies, involving 815 women (454 with PCOS and 361 controls), were finally eligible for the meta-analysis. Women with PCOS had no significant difference in IL-6 levels compared with controls, yet with significant between-study heterogeneity [random effects WMD (95% CI) = 0.71 (−0.16 to 1.59)] (Fig. 6). No evidence of publication bias was detected (Egger test, P = 0.110). In the sensitivity analysis, the difference in IL-6 levels between women with PCOS and controls remained non-significant [four studies, random effects WMD (95% CI) = 0.14 (−1.42 to 1.69)].

Figure 6

IL-6 serum concentrations in women with PCOS and controls.

Figure 6

IL-6 serum concentrations in women with PCOS and controls.

Vascular endothelial growth factor

Selection of studies

Eight potentially eligible studies were identified. Two of them were excluded since necessary data were not extractable (Ng et al., 2005; Sova et al., 2010). Two studies were excluded since communication failed to clarify whether eligibility criteria were actually met (Artini et al., 2006). In the sensitivity analysis, further studies were excluded due to differences between groups in the mean BMI (Agrawal et al., 1998; Tulandi et al., 2000). The remaining two studies were considered as the best available evidence (Abd El Aal et al., 2005; Artini et al., 2009).

Main analysis

Meta-analysis included four studies, involving 206 women (111 with PCOS and 95 controls). Women with PCOS demonstrated significantly higher VEGF concentrations compared with controls, yet with significant between-study heterogeneity [random effects WMD (95% CI) = 1.72 (0.96–2.48)] (Fig. 7). No evidence of publication bias was detected (Egger test, P = 0.751). In the sensitivity analysis, the difference in VEGF concentrations between women with PCOS and controls remained robust [two studies, random effects WMD (95% CI) = 2.27 (1.94–2.59); I2 = 8%].

Figure 7

VEGF serum concentrations in women with PCOS and controls.

Figure 7

VEGF serum concentrations in women with PCOS and controls.

Asymmetric dimethylarginine

Selection of studies

Eight potentially eligible studies were identified. Two of them were excluded, since necessary data were not extractable (Mohamadin et al., 2010; Pamuk et al., 2010). One study was excluded, because it is still awaiting assessment (Charitidou et al., 2008). In the sensitivity analysis, further studies were excluded due to differences between groups in the mean BMI (Demirel et al., 2007; Rajendran et al., 2009). The remaining three studies were considered as the best available evidence (Heutling et al., 2008; Ozgurtas et al., 2008; Moran et al., 2009).

Main analysis

Meta-analysis included five studies, involving 406 women (275 with PCOS and 131 controls). Women with PCOS demonstrated significantly elevated ADMA levels compared with women without PCOS, yet with significant between-study heterogeneity [random effects WMD (95% CI) = 0.19 (0.08–0.30)] (Fig. 8). No evidence of publication bias was detected (Egger test, P = 0.401). In the sensitivity analyses, the difference in ADMA levels between women with PCOS and those without PCOS remained robust [three studies, random effects WMD (95% CI) = 0.28 (0.06–0.50)].

Figure 8

ADMA serum concentrations in women with PCOS and controls.

Figure 8

ADMA serum concentrations in women with PCOS and controls.

Endothelin-1

Selection of studies

After excluding studies with potential sample overlap, seven potentially eligible studies were identified (Diamanti-Kandarakis et al., 2001, 2005, 2006b; Orio et al., 2004a, b; Meden-Vrtovec et al., 2007; Charitidou et al., 2008; Palomba et al., 2010). In the sensitivity analysis, one study was excluded due to differences between groups in the mean age (Charitidou et al., 2008), and two studies were excluded because of evidence of significant skewness (Diamanti-Kandarakis et al., 2001; Meden-Vrtovec et al., 2007).

Main analysis

Meta-analysis included seven studies, involving 576 women (366 with PCOS and 210 controls). Women with PCOS demonstrated significantly elevated ET-1 concentrations when compared with controls, yet with significant between-study heterogeneity [seven studies, random effects WMD (95% CI) = 1.05 (0.52–1.59)] (Fig. 9). No evidence of publication bias was detected (Egger test, P = 0.170). However, in the sensitivity analyses involving studies considered as the best available evidence, the difference in ET-1 concentrations between women with PCOS and controls was found to be non-significant [four studies, random effects WMD (95% CI) = 0.65 (−0.01 to 1.31)].

Figure 9

ET-1 serum concentrations in women with PCOS and controls.

Figure 9

ET-1 serum concentrations in women with PCOS and controls.

Advanced glycation end product

Selection of studies

Four potentially eligible studies from the same group were identified. One of them was excluded, since data were only available as medians (Diamanti-Kandarakis et al., 2008a). In the sensitivity analysis, one study was excluded due to differences between groups in the mean BMI (Diamanti-Kandarakis et al., 2006a). The remaining two studies were considered as the best available evidence (Diamanti-Kandarakis et al., 2007, 2009). Confirmation was provided by authors regarding non-violation of independent samples.

Main analysis

Meta-analysis included three studies, involving 165 women (103 with PCOS and 62 controls). Women with PCOS demonstrated significantly elevated AGEs concentrations when compared with controls, yet with significant between-study heterogeneity [three studies, random effects WMD (95% CI) = 3.91 (2.36–5.45)] (Fig. 10). No evidence of publication bias was detected (Egger test, P = 0.401). In the sensitivity analyses, the difference in AGEs concentrations between women with PCOS and controls remained robust [two studies, random effects WMD (95% CI) = 3.35 (1.23–5.86)].

Figure 10

Advanced glycation end product serum concentrations in women with PCOS and controls.

Figure 10

Advanced glycation end product serum concentrations in women with PCOS and controls.

Lipoprotein(a)

Four potentially eligible studies were identified (Yilmaz et al., 2005a, b; Bahceci et al., 2007; Berneis et al., 2009; Rizzo et al., 2009). Women with PCOS demonstrated significantly elevated Lp(a) concentrations when compared with controls, with no between-study heterogeneity [four studies, random effects SMD (95% CI) = 0.81 (0.58–1.04); I2 = 0%] (Fig. 11). No evidence of publication bias was detected (Egger test, P = 0.188). No meaningful sensitivity analysis could be performed.

Figure 11

Lipoprotein(a) serum concentrations in women with PCOS and controls.

Figure 11

Lipoprotein(a) serum concentrations in women with PCOS and controls.

Discussion

The aim of the present study was to systematically review the literature for cross-sectional, case–control trials that have studied CVD risk markers in woman with PCOS (CRP, Hcy, TNF-α, PAI-1, Lp(a), AGEs, VEGF, IL-6, ADMA, ET-1 and fibrinogen) and to meta-analyze the best evidence available, in an attempt to provide high-quality data on the linkage between PCOS and CVD. There were 130 data sets included in 11 different outcomes, involving a total of 7174 CVD markers in women with PCOS and 5076 markers in controls. Women with PCOS demonstrated significantly elevated CRP, Hcy, PAI-1 antigen, PAI-1 activity, VEGF, ADMA, AGEs and Lp(a) levels when compared with controls, yet with significant between-study heterogeneity. Borderline significance was detected for TNF-α, ET-1 and fibrinogen, whereas no significance was detected for IL-6. Thus, according to these results, PCOS is related not only to low-grade chronic inflammation (CRP) and, more specifically endothelial inflammation (Hcy, ADMA, AGEs), but to disorders of the coagulation procedure [PAI-1, Lp(a)] and endothelium proliferation (VEGF) as well.

In a recent meta-analysis, Escobar-Morreale et al. performed a review and meta-analysis of the studies evaluating the status of serum inflammatory markers in women with PCOS (Escobar-Morreale et al., 2010). Despite the many differences between the two meta-analyses (the number of searched electronic databases, the number of investigated risk markers, PCOS definition, meta-analysis technique and outcomes), the results are very similar as far as the three common indices are concerned (CRP, TNF-α and IL-6). In addition, in both studies, the results are independent of the presence and degree of obesity, as groups not matched for BMI (as well as age, in our meta-analysis) were either excluded or were the subject of sensitivity analysis.

If we accept the statement that women with PCOS have increased serum concentrations of CVD risk markers when compared with controls, the question that arises is ‘Are these increases of the same degree as that observed in patients with established CVD?’. Unfortunately, there is no direct or, even, indirect way to make such comparisons, mainly due to different baseline characteristics between women with PCOS and patients with CVD (sex, age, concomitant diseases) as well as different study methodologies. A rough clinical interpretation of the results of this study based on selected published evidence is attempted in Table III. A general comment would be that the increases in serum concentrations of CVD risk markers found in this study are not negligible, being on a magnitude similar to those in patients with established CVD.

Table III

Clinical interpretation of the results of this study based on selected evidence.

CVD risk markers WMD Selected published evidence Reference 
hs-CRP (mg/l) 0.99 For the determination of CVD risk, low, average and high risk values were defined as <1, 1–3 and >3 mg/l; these values correspond to approximate tertiles in the general population Pearson et al. (2003
  Women who developed CHD: 3.10 (1.30–7.50) mg/l; matched controls: 2.20 (1.00–5.10) mg/l. Data as median (IQR) Pai et al. (2004
Hcy (μmol/l) 2.25 Independently of Framingham risk factors, each increase in Hcy concentrations of 5 µmol/l increases the risk of CHD events by ∼20% Humphrey et al. (2008
PAI-1 activity (U/ml) 0.70 Patients who developed CHD: 13.1 ± 8.2 U/ml; controls: 10.8 ± 8.3 U/ml. Data as mean ± SD Juhan-Vague et al. (1996
Fibrinogen (g/l) 0.20 The age- and sex-adjusted hazard ratio per 1 g/l increase in fibrinogen concentration for CHD was 2.42 (95% CI 2.24–2.60) g/l and for stroke 2.06 (95% CI 1.83–2.33) g/l Danesh et al. (2005
IL-6 (pg/ml) 0.71 Women who developed CHD: 1.99 (1.30–3.05) pg/ml; matched controls: 1.65 (1.15–2.65) pg/ml. Data as median (IQR) Pai et al. (2004
ADMA (μmol/l) 0.19 Patients who developed CVD: 0.70 (0.60–0.82) μmol/l; controls: 0.63 (0.53–0.74) μmol/l. Data as median (IQR) Schnabel et al. (2005
CVD risk markers WMD Selected published evidence Reference 
hs-CRP (mg/l) 0.99 For the determination of CVD risk, low, average and high risk values were defined as <1, 1–3 and >3 mg/l; these values correspond to approximate tertiles in the general population Pearson et al. (2003
  Women who developed CHD: 3.10 (1.30–7.50) mg/l; matched controls: 2.20 (1.00–5.10) mg/l. Data as median (IQR) Pai et al. (2004
Hcy (μmol/l) 2.25 Independently of Framingham risk factors, each increase in Hcy concentrations of 5 µmol/l increases the risk of CHD events by ∼20% Humphrey et al. (2008
PAI-1 activity (U/ml) 0.70 Patients who developed CHD: 13.1 ± 8.2 U/ml; controls: 10.8 ± 8.3 U/ml. Data as mean ± SD Juhan-Vague et al. (1996
Fibrinogen (g/l) 0.20 The age- and sex-adjusted hazard ratio per 1 g/l increase in fibrinogen concentration for CHD was 2.42 (95% CI 2.24–2.60) g/l and for stroke 2.06 (95% CI 1.83–2.33) g/l Danesh et al. (2005
IL-6 (pg/ml) 0.71 Women who developed CHD: 1.99 (1.30–3.05) pg/ml; matched controls: 1.65 (1.15–2.65) pg/ml. Data as median (IQR) Pai et al. (2004
ADMA (μmol/l) 0.19 Patients who developed CVD: 0.70 (0.60–0.82) μmol/l; controls: 0.63 (0.53–0.74) μmol/l. Data as median (IQR) Schnabel et al. (2005

CVD, cardio-vascular disease; CHD, coronary heart disease; WMD, weighted mean difference (this study); IQR, interquartile range; CI, confidence interval; CRP, C-reactive protein; Hcy, homocysteine; TNF-α, tumor necrosis factor-alpha; PAI-1, plasminogen activator inhibitor-1 (antigen and/or activity); IL-6, interleukin-6; VEGF, vascular endothelial growth factor; ADMA, asymmetric dimethylarginine; AGEs, advanced glycation end-products.

The present meta-analysis has a series of limitations, such as confounding variables (e.g. age, BMI, smoking status, concomitant subclinical inflammatory diseases), lack of uniformity (e.g. PCOS diagnostic criteria, assay methodology of index marker) and exclusion of studies written in languages other than English. In addition, it was not possible to take into account different PCOS phenotypes. As a consequence, the high degree of heterogeneity in all outcomes of CVD markers is not surprising, adding difficulties in the interpretation of the results and limitations in the strength of evidence provided by the present meta-analysis. In an attempt to further explore heterogeneity, univariate meta-regression analyses were undertaken, using PCOS diagnostic criteria as potential effect modifier, in the best available subset of studies for CRP and Hcy. The observed lack of effect should be interpreted as failure to document any potential existing effect of PCOS criteria (and consequently, PCOS phenotypes) on the CVD markers rather than as evidence of no effect, since meta-regression analyses may have low statistical power and are strictly observational in nature (Toulis et al., 2009).

In conclusion, women with PCOS have increased serum concentrations of CVD risk markers when compared with controls. Whether this apparent risk is translated into increased incidence of CVD in later life remains to be elucidated.

Supplementary data

Supplementary data are available at http://humupd.oxfordjournals.org/.

Authors’ roles

K.A.T., G.M., T.G.T. and M.C.: data analysis, writing and final approval of the manuscript; D.G.G. and B.C.T.: conception and design, data interpretation, writing and final approval of the manuscript; seven M.Sc. or Ph.D. students collected and assembled the data and approved the final version of the manuscript as follows: E. Kintiraki (CRP), S.-A. Mouratoglou (Hcy), G. Mintziori (TNF-α), E. Eukarpidis (fibrinogen, IL-6, VEGF), A. Pavlaki (PAI-1), S. Stergianos [AGEs, Lp(a)], M. Poulasouchidou (ADMA) and A. Makedos (ET-1).

Conflict of interest

All authors have completed the Unified Competing Interest form and declare (i) no support from any organization for the submitted work, (ii) no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and (iii) no other relationships or activities that could appear to have influenced the submitted work.

Acknowledgements

We are very grateful to the authors of the original publications who kindly provided additional information or clarifications of their publications.

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Supplementary data