Human Reproduction Update, Vol.17, No.6 pp.

741– 760, 2011

Advanced Access publication on May 30, 2011 doi:10.1093/humupd/dmr025

Meta-analysis of cardiovascular disease

risk markers in women with polycystic
ovary syndrome
Konstantinos A. Toulis , Dimitrios G. Goulis *, Gesthimani Mintziori ,
Evangelia Kintiraki , Evangelos Eukarpidis ,
Sophia-Anastasia Mouratoglou , Antigoni Pavlaki , Stavros Stergianos ,
Maria Poulasouchidou , Thrasivoulos G. Tzellos , Anastasios Makedos ,
Michael Chourdakis , and Basil C. Tarlatzis
Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki,
‘Papageorgiou’ General Hospital, Ring Road, 56403 Nea Efkapria, Thessaloniki, Greece

*Correspondence address. Tel: +30-2310-693131; Fax: +30-2310-991510; E-mail: [email protected]

Submitted on February 16, 2011; resubmitted on April 26, 2011; accepted on May 5, 2011

table of contents
...........................................................................................................................
† Introduction
† Materials and Methods
Search strategy
Eligibility of relevant studies
Data extraction
Statistical analysis
† Results
C-Reactive Protein
Homocysteine
Tumor Necrosis Factor-a
Plasminogen Activator Inhibitor-1
Fibrinogen
Interleukin -6
Vascular Endothelial Growth Factor
Asymmetric Dimethylarginine
Endothelin-1
Advanced Glycation End-products
Lipoprotein (a)
† Discussion

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-a), 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 dimethylargi-
nine (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% confi-
dence intervals (CIs) were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed.

& The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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742 Toulis et al.

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 sen-
sitivity analyses) was detected for TNF-a [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 (20.16 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.

Key words: polycystic ovary syndrome / cardiovascular disease / risk markers / meta-analysis

[fibrinogen, plasminogen activator inhibitor-1 (PAI-1), lipoprotein

Introduction (Lp)] and endothelium proliferation [vascular endothelial growth
Polycystic ovary syndrome (PCOS) affects 6 –10% of women during factor (VEGF)] (Homocysteine Studies Collaboration, 2002; Anders-
their reproductive life (Wild et al., 2010; Goodarzi et al., 2011). Its sohn et al., 2010).
complete phenotype is manifested by ovulatory dysfunction, hyperan- Numerous studies have attempted to determine risk factors for
drogenism and polycystic ovaries (Rotterdam ESHRE/ASRM- CVD in women with PCOS and, despite a general conclusion of unfa-
Sponsored PCOS Consensus Workshop Group, 2004; Wild et al., vorable (increased) serum concentrations in these women when com-
2010). Although there are available data suggesting increased inci- pared with controls, their conclusions are far from being uniform.
dence of cardiovascular disease (CVD) in women with PCOS Given the large amount of the published evidence and the conflicting
(Meyer et al., 2005; Lo et al., 2006), the relation between these results, the aim of the present study was to systematically review the
two entities is far from being elucidated. This relation, especially if it literature for cross-sectional case– control trials that have studied
is a causative one, could be explored through prospective cohort woman with PCOS for CVD risk factors, (namely CRP, IL-6,
studies that would follow-up women with PCOS but without CVD TNF-a, Hcy, ADMA, AGEs, fibrinogen, PAI-1, Lp(a), ET-1 and
and monitor them for the development of the latter. Given the experi- VEGF) and to meta-analyze the best evidence available, in an
ence in women treated with hormone replacement therapy as far as attempt to provide high-quality data on the linkage between PCOS
development of CVD is concerned (Rossouw et al., 2002), such and CVD.
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- Materials and Methods
related parameters. Nevertheless, given the time delay between diag-
nosis of PCOS and development of CVD, the quality of PCOS-related Search strategy
data would inevitably be poor (Solomon et al., 2002). To identify eligible studies, the main search was conducted in the elec-
The remaining, indirect way to explore the relation between PCOS tronic databases MEDLINE, EMBASE and Cochrane Central Register of
and CVD is to conduct cross-sectional, case –control studies not on Controlled Trials (CENTRAL) from inception through June 2010, using
CVD per se but on risk factors for it. Thus, women with PCOS various combinations of Medical Subject Headings (MeSH) and
would be the case group and women without PCOS would be the 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 refer-
control group, and the two groups would be compared as far a risk
ence sections of all relevant studies, (ii) a manual search of key journals and
factor for CVD is concerned. Adopting such an approach, the ques-
tion 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 Table I Search strings for ADMA, as an example.
CVD, such as impaired glucose tolerance/diabetes mellitus type 2,
dyslipidemia, abdominal obesity and hypertension (Evangelista and MEDLINE
McLaughlin, 2009). On top of these, and given the evidence that low- [‘N,N-dimethylarginine ’(Substance Name) OR ‘asymmetric
grade chronic inflammation provides the pathophysiology basis for dimethylarginine’(All Fields) OR ‘ADMA’(All Fields)] AND [‘Polycystic
Ovary Syndrome’(Mesh) OR ‘Hyperandrogenism’(Mesh)] AND
atherosclerosis, new risk factors have been established, such as
‘humans’(Mesh)
C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis
EMBASE
factor-alpha (TNF-a) (Kaptoge et al., 2010; Nishida et al., 2010).
‘n(g),n(g) dimethylarginine’/exp OR ‘n(g),n(g) dimethylarginine’ OR
Finally, a series of conditions related—in a direct or indirect way—
‘asymmetric dimethylarginine’/exp OR ‘asymmetric dimethylarginine’ OR
to endothelial inflammation have provided additional risk factors for ‘adma’/exp OR ‘adma’ AND (‘polycystic ovary syndrome’/exp OR
CVD, such as oxidative stress [homocysteine (Hcy), asymmetric ‘polycystic ovary syndrome’ OR ‘hyperandrogenism’/exp OR
dimethylarginine (ADMA), advanced glycation end-products (AGEs), ‘hyperandrogenism’) AND (‘humans’/exp OR ‘humans’)
endothelin-1 (ET-1)], disorders of the coagulation procedure
CVD risk markers in PCOS 743

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

Studies CVD risk markers

..............................................................................................................................................
CRP Hcy TNF-a 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 4 7 1 5 7 6 0
Excluded on a title-basis 55 76 31 45 2 12 6 10 0 42 0
Excluded on an abstract-basis 34 45 11 33 2 5 5 5 7 34 2
Full-text was used 118 36 40 36 25 25 11 9 10 6 8
Excluded on a full text-basis 46 1 20 12 7 7 3 1 3 2 4
Included in the systematic review 72 35 21 24 18 18 8 8 7 4 4
Excluded from the meta-analysis 24 11 8 8 5 8 4 3 0 1 0
Included in the meta-analysis 48 24 13 16 13 10 4 5 7 3 4

CRP, C-reactive protein; Hcy, homocysteine; TNF-a, 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).

Figure 1 C-reactive protein serum concentrations in women with PCOS and controls.
744 Toulis et al.

Figure 2 Homocysteine serum concentrations in women with PCOS and controls.

abstracts from the major annual meetings in the field of Endocrinology and Studies were excluded from the systematic reviews and the
Obstetrics and Gynecology and (iii) contact with experts. The main search meta-analyses if the enrolled subjects had a disease other than PCOS,
was completed independently by investigators (E.K., E.E., S.-A.M., G.M., were on any kind of medication, were pregnant or were genetically
A.P., S.S., A.M. and M.P.). Any discrepancy was solved by consultation related. Studies with no control group or control group including men
of an investigator, not involved in the initial procedure (D.G.G.). were also excluded. Reviews, letters to the editor and studies published
in language other than English were excluded as well.
Eligibility of relevant studies
Eligible for the systematic reviews were studies of any design, which Data extraction
reported CRP, Hcy, TNF-a, PAI, fibrinogen, IL-6, VEGF, ET-1, AGEs, Information from each study was extracted independently by two
Lp(a) and/or ADMA levels in women with PCOS compared with reviewers using a standardized data extraction form. Study general charac-
healthy controls. Women with PCOS were diagnosed consistently by teristics (author, journal, year of publication, design, ethnicity, study size
either Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop and number of cases), characteristics of the PCOS and control groups (cri-
Group (2004) criteria, National Institute of Health (Zawadski and Dunaif, teria, selection, age, BMI and smoking status), methodology (PCOS defi-
1992) criteria, oligomenorrhea with hyperandrogenemia or, very occasion- nition, measurements method) and outcomes were recorded (where
ally, other compatible criteria (Supplementary data). available) and double-checked. When data were presented in subgroups,
CVD risk markers in PCOS 745

Figure 3 TNF-a serum concentrations in women with PCOS and controls.

common standard deviation (SD) was calculated with the following meta-regression analysis. Univariate meta-regression analyses were per-
formula: SD2common ¼ [(n1 – 1) × SD21 + (n2 – 1) × SD22 + (m21 + m22 – formed in the best available subset of studies to ensure interpretable
2 × m1 × m2) × n1 × n2/n1 + n2]/(n1 + n2 – 1), where n is the sample results, when those studies were at least 10.
size, m the mean and SD the standard deviation. Where appropriate, Meta-analysis and meta-regression were conducted using Stata/SE 9.0
the data set was completed through communication with the authors. for Windows (StataCorp LP, 4905 College Station, TX 77845, USA).
Disagreement was resolved by consensus. 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.
Statistical analysis
Weighted mean differences (WMDs) and 95% confidence intervals (CI)
were calculated for each of the CVD risk factors for all eligible studies Results
for the meta-analyses and combined using fixed or random effects The flow of studies from identification to systematic reviews and
model, where appropriate. Standardized mean difference (SMD) was
meta-analyses are presented in Table II. It was notable that a signifi-
used as a summary statistic, when different methodology was applied
cant amount of between-study heterogeneity (I 2 . 80%) was
for the measurement of the index marker across studies. Heterogeneity
between the results of different studies was examined by I 2 test. To recorded in all analyses, unless otherwise specified.
assess the extent of publication bias, Egger test was used. To ensure syn-
thesis of the best available evidence, sensitivity analyses were performed C-reactive protein
excluding studies with: (i) significant differences in the mean BMI and/or
Selection of studies
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 There were 72 potentially eligible studies identified. Of these, 14
(Altman and Bland, 1996) and (iii) t discordance among reviewers upon were excluded, since data were only available as medians or geo-
their eligibility was recorded. The effect of PCOS diagnostic criteria metric means (Kelly et al., 2001; Tarkun et al., 2004a, b; Cho
used (study-level characteristic) on the index test was investigated et al., 2005; Orio et al., 2005; Puder et al., 2005; Barutcuoglu
through restricted maximum likelihood-based random effects et al., 2006; Engin-Ustun et al., 2006; Shroff et al., 2007; Glintborg
746 Toulis et al.

et al., 2008; Thomann et al., 2008; Rajendran et al., 2009; Ruan and et al., 2008; Capoglu et al., 2009; Cetinkalp et al., 2009; Erdogan
Dai, 2009; Makedos et al., 2010; Pamuk et al., 2010). After com- et al., 2009; Soares et al., 2009; Victor et al., 2009; Yang et al.,
munication with the primary investigators, two studies (Cascella 2009; Markou et al., 2010; Verit, 2010) or borderline eligibility
et al., 2006; Moran et al., 2009) were excluded to avoid data dupli- (Karadeniz et al., 2008; Samy et al., 2009; Nikolajuk et al., 2010).
cation. Moreover, eight studies were excluded since communication Finally, 15 studies were considered as the best available evidence
failed to clarify whether eligibility criteria were actually met (Bahceci et al., 2004; Meyer et al., 2005; Orio et al., 2006;
(Erdogan et al., 2008; Kowalska et al., 2008; Arikan et al., 2009; Topcu et al., 2006; Guzelmeric et al., 2007; Meden-Vrtovec
Kaya et al., 2009a, 2010a; Oh et al., 2009; Oktem et al., 2009; et al., 2007; Nasiek et al., 2007; Cascella et al., 2008; Diamanti-
Wu et al., 2009). In the sensitivity analysis, further studies were Kandarakis et al., 2008c; Heutling et al., 2008; Gen et al., 2009;
excluded due to differences between groups in the mean BMI Thomson et al., 2009; Arikan et al., 2010; Kaya et al., 2010b;
(Mohlig et al., 2004; Gonzalez et al., 2005; Benson et al., 2008; Moran et al., 2010).
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., Main analysis
2009; Tosi et al., 2009), evidence of significant skewness (Escobar- A total of 48 studies, involving 4765 women (2835 with PCOS and
Morreale et al., 2003; Fenkci et al., 2003; Bickerton et al., 2005; 1930 controls), were eligible for the meta-analysis. Women with
Brinkworth et al., 2006; Diamanti-Kandarakis et al., 2006b, c, PCOS demonstrated significantly elevated CRP serum concentrations
2008b; Beckman et al., 2007; Costa et al., 2008; Jakubowska when compared with controls, yet with significant between-study

Figure 4 Plasminogen activator inhibitor-1 antigen (a) and activity (b) serum concentrations in women with PCOS and controls.
CVD risk markers in PCOS 747

Figure 4 Continued.

heterogeneity [48 studies, random effects WMD (95% CI) ¼ 0.99 data duplication (Kaya et al., 2009a, b, c, 2010b, c, d). In the sensitivity
(0.77–1.21)]. This finding was similar, even when studies with esti- analysis, further studies were excluded due to differences between
mation of regular CRP or high sensitivity CRP (hs-CRP) concentrations groups in the mean BMI (Yarali et al., 2001; Vrbikova et al., 2002)
were analyzed separately (Fig. 1). Small-study effect (publication bias) or age (Schachter et al., 2003) and borderline eligibility (Bayraktar
was found to be marginally insignificant (Egger test, P ¼ 0.052). In the et al., 2004; Cetinkalp et al., 2009). Finally, 19 studies were considered
sensitivity analysis, the difference in CRP concentrations between as the best available evidence (Orio et al., 2003; Boulman et al., 2004;
women with PCOS and controls remained robust (15 studies, Kilic-Okman et al., 2004; Wijeyaratne et al., 2004; Bickerton et al.,
random effects WMD (95% CI) ¼ 1.07 (0.76– 1.39)]. It was notable 2005; Yilmaz et al., 2005a, b, 2008; Topcu et al., 2006; Sahin et al.,
that sensitivity analysis resulted in a substantial decrease in heterogen- 2007; Atamer et al., 2008; Battaglia et al., 2008; Arikan et al., 2009;
eity detected in the subset of hs-CRP studies (I 2 ¼ 43%). Mancini et al., 2009; Oktem et al., 2009; Soares et al., 2009;
Meta-regression failed to provide evidence of a significant effect of Fulghesu et al., 2010; Kaya et al., 2010a; Markou et al., 2010; Nafiye
PCOS criteria on CRP concentrations (P ¼ 0.203). et al., 2010).

Main analysis
Homocysteine A total of 24 studies, involving 2191 women (1209 with PCOS and
Selection of studies 982 controls), were eligible for the meta-analysis. Women with
There were 35 potentially eligible studies identified. Five of them were PCOS demonstrated significantly elevated Hcy serum concentrations
excluded, since relevant data were not extractable, being available only when compared with controls, yet with significant between-study het-
as medians (Palep-Singh et al., 2007, 2008; Makedos et al., 2010; erogeneity [random effects WMD (95% CI) ¼ 2.25 (1.46–3.03)]
Pamuk et al., 2010) or only in abstract (Luque-Ramirez et al., 2009). (Fig. 2). No evidence of publication bias was detected (Egger test,
Six studies were excluded because it was impossible to rule out P ¼ 0.171). In the sensitivity analysis, the difference in Hcy
748 Toulis et al.

Figure 5 Fibrinogen serum concentrations in women with PCOS and controls.

concentrations between women with PCOS and controls remained et al., 2007; Arikan et al., 2009; Samy et al., 2009; Soares et al.,
robust [19 studies, random effects WMD (95% CI) ¼ 1.87 (1.04– 2009; Victor et al., 2009).
2.70)]. Meta-regression failed to provide evidence of a significant
effect of PCOS criteria on Hcy concentrations (P ¼ 0.633).

Main analysis
A total of 13 studies, involving 871 women (475 with PCOS and 396
Tumor necrosis factor-a controls), were finally eligible for the meta-analysis. Women with
Selection of studies PCOS demonstrated elevated TNF-a serum concentrations of bor-
There were 21 potentially eligible studies identified. Seven of them derline significance when compared with controls, yet with significant
were excluded, since data were not available in an extractable between-study heterogeneity [random effects WMD (95% CI) ¼ 0.75
format (Amato et al., 2003; Omu et al., 2003; Puder et al., 2005, (0.07–1.44)] (Fig. 3). No evidence of publication bias was detected
2006; Shroff et al., 2007; Knebel et al., 2008; Thomann et al., 2008). (Egger test, P ¼ 0.430). In the sensitivity analysis, the difference in
One study was excluded because it did not fulfill standard quality TNF-a concentrations between women with PCOS and controls
requirements (Ravishankar Ram et al., 2005). In the sensitivity analysis, was found similar [nine studies, random effects WMD (95% CI) ¼
further studies were excluded due to differences between groups in 0.85 (0.10–1.59)].
mean age (Vgontzas et al., 2006; Moran et al., 2007) and skewness
in the distribution of TNF-a concentrations (Sayin et al., 2003; Jaku- Plasminogen activator inhibitor-1
bowska et al., 2008). Finally, nine studies were considered as the There were 20 potentially eligible studies identified. Four of them
best available evidence (Escobar-Morreale et al., 2001; Escobar- reported serum concentrations of both PAI-1 antigen and PAI-1
Morreale et al., 2003; Tarkun et al., 2006; Olszanecka-Glinianowicz activity, nine reported only the former and seven only the latter.
CVD risk markers in PCOS 749

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

PAI-1 antigen PAI-1 antigen concentrations between women with PCOS and con-
Selection of studies. Three out of 13 potentially eligible studies were trols remained robust [five studies, random effects WMD (95%
excluded, since data were only available as geometric means or inter- CI) ¼ 16.49 (4.87–28.11)].
quartile ranges (Sills et al., 2003; Baillargeon and Carpentier, 2007a, b;
Tan et al., 2009). One study was excluded because communication PAI-1 activity
failed to clarify whether eligibility criteria were actually met (Lin and Selection of studies. Three out of 11 potentially eligible studies were
Yongmei, 2008) and another one was excluded after contact with excluded, since data were not extractable (Sills et al., 2003; Orio
the primary investigator (Gonzalez et al., 2009). In the sensitivity ana- et al., 2004a, b; Tan et al., 2009). In the sensitivity analyses, further
lyses, further studies were excluded due to differences between studies were excluded due to differences between groups in mean
groups in mean BMI (Velazquez et al., 1997; Carmassi et al., 2005) BMI (Slopien et al., 2006) or age (Atiomo et al., 2000; Yarali et al.,
or age (Lindholm et al., 2010). 2001; Lindholm et al., 2010).

Main analysis. A total of eight studies (Velazquez et al., 1997; Paradisi Main analysis. A total of eight studies (Atiomo et al., 1998, 2000; Yarali
et al., 2003; Diamanti-Kandarakis et al., 2004; Tarkun et al., 2004a, b; et al., 2001; Tarkun et al., 2004a, b; Slopien et al., 2006; Cascella et al.,
Carmassi et al., 2005; Lin et al., 2009; Oral et al., 2009; Lindholm et al., 2008; Moran et al., 2009; Lindholm et al., 2010), involving 868 women
2010), involving 883 women (529 with PCOS and 354 controls), were (548 with PCOS and 320 controls), were eligible for the meta-analysis.
eligible for the meta-analysis. Women with PCOS demonstrated sig- Women with PCOS demonstrated significantly elevated PAI-1 activity
nificantly elevated PAI-1 antigen serum concentrations when com- serum concentrations when compared with controls, yet with signifi-
pared with controls, yet with significant between-study cant between-study heterogeneity [random effects SMD (95% CI) ¼
heterogeneity [random effects WMD (95% CI) ¼ 16.96 (7.65– 0.71 (0.18–1.23] (Fig. 4b). No evidence of publication bias was
26.28)] (Fig. 4a). No evidence of publication bias was detected detected (Egger test, P ¼ 0.76). In the sensitivity analysis, the differ-
(Egger test, P ¼ 0.73). In the sensitivity analysis, the difference in ence in PAI-1 activity concentrations between women with PCOS
750 Toulis et al.

Figure 7 VEGF serum concentrations in women with PCOS and controls.

and controls remained robust [four studies, random effects SMD (95% 0.20 (0.01–0.39)] (Fig. 5). No evidence of publication bias was
CI) ¼ 1.33 (0.62–2.04)]. detected (Egger test, P ¼ 0.689). In the sensitivity analyses, no signifi-
cant difference in fibrinogen levels was detected between women with
Fibrinogen PCOS and controls [nine studies, random effects WMD (95% CI) ¼
Selection of studies 0.19 (20.12 to 0.51)].
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., Interleukin -6
2010; Pamuk et al., 2010). In sensitivity analysis, further studies Selection of studies
were excluded due to differences between groups in the mean BMI There were 18 potentially eligible studies identified. Six of them were
(Atiomo et al., 1998; Bickerton et al., 2005) or age (Yarali et al., excluded, since necessary data were not extractable (Amato et al.,
2001; Kelly et al., 2002). Finally, nine studies were considered as the 2003; Mohlig et al., 2004; Shroff et al., 2007; Benson et al., 2008; Glint-
best available evidence (Yildiz et al., 2002; Slopien et al., 2006; Baillar- borg et al., 2008; Benson et al., 2009). Two studies were excluded,
geon and Carpentier, 2007a, b; Karakurt et al., 2008; Erdogan et al., since communication failed to clarify whether eligibility criteria were
2009; Kebapcilar et al., 2009; Luque-Ramirez et al., 2009; Mancini actually met (Ravishankar Ram et al., 2005; Jakubowska et al.,
et al., 2009; Lenarcik et al., 2010). 2008). In the sensitivity analyses, further studies were excluded due
to differences between groups in the mean BMI (Vgontzas et al.,
Main analysis 2006; Kaya et al., 2010d) or age (Escobar-Morreale et al., 2003;
A total of 13 studies, involving 925 women (507 with PCOS and 418 Moran et al., 2007; Gonzalez et al., 2009) and skewness in the distri-
controls), were finally eligible for the meta-analysis. Women with bution of IL-6 concentrations (Soares et al., 2009). The remaining four
PCOS demonstrated a borderline significant elevation in fibrinogen studies were considered as the best available evidence (Olszanecka-
concentrations when compared with controls, yet with significant Glinianowicz et al., 2007; Gen et al., 2009; Samy et al., 2009; Nikolajuk
between-study heterogeneity [random effects WMD (95% CI) ¼ et al., 2010).
CVD risk markers in PCOS 751

Figure 8 ADMA serum concentrations in women with PCOS and controls.

Main analysis considered as the best available evidence (Abd El Aal et al., 2005;
A total of 10 studies, involving 815 women (454 with PCOS and 361 Artini et al., 2009).
controls), were finally eligible for the meta-analysis. Women with
PCOS had no significant difference in IL-6 levels compared with con- Main analysis
trols, yet with significant between-study heterogeneity [random effects Meta-analysis included four studies, involving 206 women (111 with
WMD (95% CI) ¼ 0.71 (20.16 to 1.59)] (Fig. 6). No evidence of PCOS and 95 controls). Women with PCOS demonstrated signifi-
publication bias was detected (Egger test, P ¼ 0.110). In the sensitivity cantly higher VEGF concentrations compared with controls, yet with
analysis, the difference in IL-6 levels between women with PCOS and significant between-study heterogeneity [random effects WMD (95%
controls remained non-significant [four studies, random effects WMD CI) ¼ 1.72 (0.96–2.48)] (Fig. 7). No evidence of publication bias
(95% CI) ¼ 0.14 (21.42 to 1.69)]. was detected (Egger test, P ¼ 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%
Vascular endothelial growth factor CI) ¼ 2.27 (1.94– 2.59); I 2 ¼ 8%].
Selection of studies
Eight potentially eligible studies were identified. Two of them were Asymmetric dimethylarginine
excluded since necessary data were not extractable (Ng et al., 2005; Selection of studies
Sova et al., 2010). Two studies were excluded since communication Eight potentially eligible studies were identified. Two of them were
failed to clarify whether eligibility criteria were actually met (Artini excluded, since necessary data were not extractable (Mohamadin
et al., 2006). In the sensitivity analysis, further studies were excluded et al., 2010; Pamuk et al., 2010). One study was excluded, because
due to differences between groups in the mean BMI (Agrawal et al., it is still awaiting assessment (Charitidou et al., 2008). In the sensitivity
1998; Tulandi et al., 2000). The remaining two studies were analysis, further studies were excluded due to differences between
752 Toulis et al.

Figure 9 ET-1 serum concentrations in women with PCOS and controls.

groups in the mean BMI (Demirel et al., 2007; Rajendran et al., 2009). because of evidence of significant skewness (Diamanti-Kandarakis
The remaining three studies were considered as the best available evi- et al., 2001; Meden-Vrtovec et al., 2007).
dence (Heutling et al., 2008; Ozgurtas et al., 2008; Moran et al., 2009).

Main analysis
Main analysis Meta-analysis included seven studies, involving 576 women (366 with
Meta-analysis included five studies, involving 406 women (275 with PCOS and 210 controls). Women with PCOS demonstrated signifi-
PCOS and 131 controls). Women with PCOS demonstrated signifi- cantly elevated ET-1 concentrations when compared with controls,
cantly elevated ADMA levels compared with women without PCOS, yet with significant between-study heterogeneity [seven studies,
yet with significant between-study heterogeneity [random effects random effects WMD (95% CI) ¼ 1.05 (0.52–1.59)] (Fig. 9). No evi-
WMD (95% CI) ¼ 0.19 (0.08–0.30)] (Fig. 8). No evidence of publi- dence of publication bias was detected (Egger test, P ¼ 0.170).
cation bias was detected (Egger test, P ¼ 0.401). In the sensitivity ana- However, in the sensitivity analyses involving studies considered as
lyses, the difference in ADMA levels between women with PCOS and the best available evidence, the difference in ET-1 concentrations
those without PCOS remained robust [three studies, random effects between women with PCOS and controls was found to be non-
WMD (95% CI) ¼ 0.28 (0.06–0.50)]. significant [four studies, random effects WMD (95% CI) ¼ 0.65
(20.01 to 1.31)].
Endothelin-1
Selection of studies Advanced glycation end product
After excluding studies with potential sample overlap, seven poten- Selection of studies
tially eligible studies were identified (Diamanti-Kandarakis et al., Four potentially eligible studies from the same group were identified.
2001, 2005, 2006b; Orio et al., 2004a, b; Meden-Vrtovec et al., One of them was excluded, since data were only available as medians
2007; Charitidou et al., 2008; Palomba et al., 2010). In the sensitivity (Diamanti-Kandarakis et al., 2008a). In the sensitivity analysis, one
analysis, one study was excluded due to differences between groups in study was excluded due to differences between groups in the mean
the mean age (Charitidou et al., 2008), and two studies were excluded BMI (Diamanti-Kandarakis et al., 2006a). The remaining two studies
CVD risk markers in PCOS 753

Figure 10 Advanced glycation end product serum concentrations in women with PCOS and controls.

were considered as the best available evidence (Diamanti-Kandarakis when compared with controls, with no between-study heterogeneity
et al., 2007, 2009). Confirmation was provided by authors regarding [four studies, random effects SMD (95% CI) ¼ 0.81 (0.58–1.04); I 2 ¼
non-violation of independent samples. 0%] (Fig. 11). No evidence of publication bias was detected (Egger
test, P ¼ 0.188). No meaningful sensitivity analysis could be
Main analysis performed.
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 Discussion
controls, yet with significant between-study heterogeneity [three The aim of the present study was to systematically review the litera-
studies, random effects WMD (95% CI) ¼ 3.91 (2.36 – 5.45)] ture for cross-sectional, case –control trials that have studied CVD
(Fig. 10). No evidence of publication bias was detected (Egger risk markers in woman with PCOS (CRP, Hcy, TNF-a, PAI-1, Lp(a),
test, P ¼ 0.401). In the sensitivity analyses, the difference in AGEs, VEGF, IL-6, ADMA, ET-1 and fibrinogen) and to meta-analyze
AGEs concentrations between women with PCOS and controls the best evidence available, in an attempt to provide high-quality data
remained robust [two studies, random effects WMD (95% CI) ¼ on the linkage between PCOS and CVD. There were 130 data sets
3.35 (1.23 – 5.86)]. included in 11 different outcomes, involving a total of 7174 CVD
markers in women with PCOS and 5076 markers in controls.
Lipoprotein(a) Women with PCOS demonstrated significantly elevated CRP, Hcy,
Four potentially eligible studies were identified (Yilmaz et al., 2005a, b; PAI-1 antigen, PAI-1 activity, VEGF, ADMA, AGEs and Lp(a) levels
Bahceci et al., 2007; Berneis et al., 2009; Rizzo et al., 2009). Women when compared with controls, yet with significant between-study het-
with PCOS demonstrated significantly elevated Lp(a) concentrations erogeneity. Borderline significance was detected for TNF-a, ET-1 and
754 Toulis et al.

Figure 11 Lipoprotein(a) serum concentrations in women with PCOS and controls.

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

CVD risk WMD Selected published evidence Reference

markers
.............................................................................................................................................................................................
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 Pearson et al. (2003)
.3 mg/l; these values correspond to approximate tertiles in the general population
Women who developed CHD: 3.10 (1.30–7.50) mg/l; matched controls: 2.20 (1.00–5.10) mg/l. Data Pai et al. (2004)
as median (IQR)
Hcy (mmol/l) 2.25 Independently of Framingham risk factors, each increase in Hcy concentrations of 5 mmol/l increases the Humphrey et al.
risk of CHD events by 20% (2008)
PAI-1 activity 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.
(U/ml) (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 Danesh et al. (2005)
(95% CI 2.24–2.60) g/l and for stroke 2.06 (95% CI 1.83– 2.33) g/l
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. Pai et al. (2004)
Data as median (IQR)
ADMA (mmol/l) 0.19 Patients who developed CVD: 0.70 (0.60 –0.82) mmol/l; controls: 0.63 (0.53– 0.74) mmol/l. Data as Schnabel et al.
median (IQR) (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-a, 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.

fibrinogen, whereas no significance was detected for IL-6. Thus, inflammation (Hcy, ADMA, AGEs), but to disorders of the coagulation
according to these results, PCOS is related not only to low-grade procedure [PAI-1, Lp(a)] and endothelium proliferation (VEGF) as
chronic inflammation (CRP) and, more specifically endothelial well.
CVD risk markers in PCOS 755

In a recent meta-analysis, Escobar-Morreale et al. performed a interpretation, writing and final approval of the manuscript; seven
review and meta-analysis of the studies evaluating the status of M.Sc. or Ph.D. students collected and assembled the data and
serum inflammatory markers in women with PCOS (Escobar- approved the final version of the manuscript as follows: E. Kintiraki
Morreale et al., 2010). Despite the many differences between the (CRP), S.-A. Mouratoglou (Hcy), G. Mintziori (TNF-a), E. Eukarpidis
two meta-analyses (the number of searched electronic databases, (fibrinogen, IL-6, VEGF), A. Pavlaki (PAI-1), S. Stergianos [AGEs,
the number of investigated risk markers, PCOS definition, Lp(a)], M. Poulasouchidou (ADMA) and A. Makedos (ET-1).
meta-analysis technique and outcomes), the results are very similar
as far as the three common indices are concerned (CRP, TNF-a
and IL-6). In addition, in both studies, the results are independent of
Acknowledgements
the presence and degree of obesity, as groups not matched for BMI We are very grateful to the authors of the original publications who
(as well as age, in our meta-analysis) were either excluded or were kindly provided additional information or clarifications of their
the subject of sensitivity analysis. publications.
If we accept the statement that women with PCOS have increased
serum concentrations of CVD risk markers when compared with con-
trols, the question that arises is ‘Are these increases of the same
Conflict of interest
degree as that observed in patients with established CVD?’. Unfortu- All authors have completed the Unified Competing Interest form and
nately, there is no direct or, even, indirect way to make such compari- declare (i) no support from any organization for the submitted work,
sons, mainly due to different baseline characteristics between women (ii) no financial relationships with any organizations that might have an
with PCOS and patients with CVD (sex, age, concomitant diseases) as interest in the submitted work in the previous 3 years and (iii) no
well as different study methodologies. A rough clinical interpretation of other relationships or activities that could appear to have influenced
the results of this study based on selected published evidence is the submitted work.
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
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