Cardiovascular disease in the polycystic ovary syndrome new insights and perspectives

Prévia do material em texto

Atherosclerosis 185 (2006) 227–239
Review
Cardiovascular disease in the polycystic ovary syndrome:
New insights and perspectives
Andrea J. Cussonsa,c, Bronwyn G.A. Stuckeya,b,c, Gerald F. Wattsc,∗
a Keogh Institute for Medical Research, Nedlands, WA, Australia
b Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
c University of Western Australia, School of Medicine & Pharmacology, Royal Perth Hospital Unit, GPO Box X2213, Perth, WA 6847, Australia
Received 19 July 2005; received in revised form 29 September 2005; accepted 6 October 2005
Available online 28 November 2005
Abstract
The new millennium has brought intense focus of interest on the risk of cardiovascular disease in women. The polycystic ovary syndrome
(PCOS) is a common endocrine disorder in women characterised by hyperandrogenism and oligomenorrhoea. Most women with PCOS also
diabetes
diography,
employed
iovascular
rly insulin
nce to date,
en with
228
28
228
228
28
229
229
229
229
30
l nitric
s
exhibit features of the metabolic syndrome, including insulin resistance, obesity and dyslipidaemia. While the association with type 2
is well established, whether the incidence of cardiovascular disease is increased in women with PCOS remains unclear. Echocar
imaging of coronary and carotid arteries, and assessments of both endothelial function and arterial stiffness have recently been
to address this question. These studies have collectively demonstrated both structural and functional abnormalities of the card
system in PCOS. These alterations, however, appear to be related to the presence of individual cardiovascular risk factors, particula
resistance, rather than to the presence of PCOS and hyperandrogenaemia per se. However, given the inferential nature of the evide
more rigorous cohort studies of long-term cardiovascular outcomes and clinical trials of risk factor modification are required in wom
PCOS.
© 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Polycystic ovary syndrome; Cardiovascular function and structure; Cardiovascular risk; Insulin resistance
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Cardiovascular risk factors in PCOS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Biochemical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1. Insulin resistance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.2. Hyperandrogenaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1.3. Dyslipidaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.4. Other risk factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Clinical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Metabolic syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Cardiovascular epidemiology of PCOS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Abbreviations: BMI, body mass index; CIMT, carotid intima-medial thickness; DHEAS, dehydroepiandrosterone sulphate; ecNOS, endothelia
oxide synthase; FMD, flow mediated dilatation; HDL, high density lipoprotein; IVRT, isovolumetric relaxation time; LBF, leg blood flow; LDL, low denity
lipoprotein; LV, left ventricular; NIH, National Institutes for Health; NO, nitric oxide; PCO, polycystic ovaries; PCOS, polycystic ovary syndrome; PWV,
pulse wave velocity
∗ Corresponding author. Tel.: +61 8 9224 0240; fax: +61 8 9224 0246.
E-mail address: gfwatts@cyllene.uwa.edu.au (G.F. Watts).
0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.atherosclerosis.2005.10.007
228 A.J. Cussons et al. / Atherosclerosis 185 (2006) 227–239
4. Studies of subclinical cardiovascular disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
5. Functional studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
5.1. Ventricular function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
5.2. Arterial stiffness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
5.3. Endothelial function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
5.3.1. Conduit arteries: macrovascular endothelial function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
5.3.2. Resistance arteries: microvascular endothelial function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
6. Morphological studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
6.1. Carotid wall thickness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
6.2. Arterial calcification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
7. Conclusions and future perspectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Acknowledgement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
1. Introduction
Polycystic ovary syndrome (PCOS), characterised by
chronic anovulation and hyperandrogenism[1,2] is a com-
mon diagnosis made in up to 10% of women of reproductive
age[3]. Cardiovascular disease and type 2 diabetes are two
potential major long-term sequelae of this condition that
merit examination.
A summary of the most recent diagnostic criteria for
the diagnosis of PCOS is shown inTable 1. Application of
thesecriteria to diagnose PCOS also requires excluding other
c
f
C
n
r
p
c
c
t
e
P
r
o
of studies have in particular further elucidated the causal links
between PCOS and cardiovascular disease.
2. Cardiovascular risk factors in PCOS
2.1. Biochemical
2.1.1. Insulin resistance
Insulin resistance is thought to play a role in the pathogen-
esis of PCOS, and is often exacerbated by co-existent obesity
sed
om-
nci-
er-
li-
dro-
d in
e
auses of the phenotype, including pituitary and adrenal dys-
unction. It should be noted that compared with the Rotterdam
riteria, the National Institutes for Health (NIH) Criteria do
ot include the detection of polycystic ovaries on ultrasonog-
aphy. This may have important implications for the sample
opulation and for generalizing the findings of the cardiovas-
ular studies referred to in this review.
Although PCOS is increasingly recognised as being asso-
iated with a clustering of cardiovascular risk factors[4–6],
here is no definitive evidence for increased cardiovascular
vents in PCOS. Nor is there, evidently, data showing that
COS alone imparts increased risk independent of associated
isk factors. The present article aims to review the spectrum
[7]. Both lean and obese women with PCOS have increa
rates of insulin resistance and type 2 diabetes mellitus c
pared with body mass index (BMI) matched controls[7–9].
Both PCOS and obesity have synergistic effects on the i
dence and severity of insulin resistance.
There is also a strong positive correlation between hyp
androgenaemia and insulin resistance in PCOS[10]. This
may chiefly reflect the stimulatory effect of hyperinsu
naemia on ovarian androgen production[11], although hyper-
androgenaemia may also contribute to insulin resistance[12].
This may also underlie the association between hyperan
genaemia and impaired vascular function in PCOS reporte
some studies[13–15]. However, although insulin resistanc
f cardiovascular risk factors, the cardiovascular epidemi-
ical
ular
set
per se has been associated with endothelial dysfunction and
increased cardiovascular risk[16,17], there is no consistent
e rdio-
v e
s
2
ular
d roids
w ogens
a
H tion
b sease
[ ine
t devel-
o d that
a t-
vidence that hyperandrogenaemia is a risk factor for ca
ascular disease in women[18], and this is borne out by th
tudies of subclinical disease in PCOS reviewed later.
.1.2. Hyperandrogenaemia
The gender difference in susceptibility to cardiovasc
isease has been attributed to the difference in sex ste
ith oestrogen being seen as cardioprotective and andr
s a possible exacerbating cardiovascular risk factor[19].
owever, no study in men has shown a positive correla
etween circulating androgens and cardiovascular di
18]. In women without PCOS, the few studies that exam
he association between endogenous androgens and the
pment of cardiovascular disease have not demonstrate
ndrogen status plays a significant role[20]. In pre- and pos
ology and especially the most recent studies of subclin
cardiovascular disease in PCOS, examining cardiovasc
structure and function. Whilst not definitive, these latter
Table 1
Diagnostic criteria for PCOS
1990 NIHa
Criteria (2)
2003 Rotterdam
Criteria (1) (2 out
of 3 required)
Anovulation + +
Hyperandrogenism (clinical +/or
biochemical)
+ +
Polycystic ovaries on ultrasound
(Exclusion of other aetiologies
required for diagnosis of
PCOS using either criteria)
− +
a National Institutes for Health.
A.J. Cussons et al. / Atherosclerosis 185 (2006) 227–239 229
menopausal women carotid intima-medial thickness (CIMT)
has been shown to be inversely correlated with endogenous
dehydroepiandrosterone sulphate (DHEAS) and testosterone
[21].
Studies of endogenous androgen deprivation in men or
testosterone administration to women in gender reassignment
have failed to show an effect of either on cardiovascular mor-
bidity or mortality[22]. However, in an experimental model,
testosterone administration to female primates was associated
with increased atherogenesis, independent of lipid effects
[23]. Similar experiments in animal models of PCOS have
not been reported to date.
It seems that despite the acknowledged consistent gender
imbalance in the prevalence of cardiovascular disease, non-
hormonal, genetic and environmental risk factors may play a
greater role than that of androgens.
2.1.3. Dyslipidaemia
Dyslipidaemia may be the most common metabolic abnor-
mality in PCOS, with a prevalence of up to 70% by the
National Cholesterol Education Program criteria[4,8]. PCOS
is classically associated with an atherogenic lipoprotein pro-
file, characterised by elevated triglyceride-rich lipoproteins,
accumulation of small dense low density lipoprotein (LDL)
and depressed high density lipoprotein (HDL). All these
changes are closely related to insulin resistance, although
e by
s d
q ount
f inde-
p this
n
2
non-
t ulin
r those
i
p
e -
t OS
i
2
age
m and
w ries
g com-
m d
w sion,
i acti-
v ity,
a cant
a data
a cen-
tral fat, contributes to the development of impaired glucose
tolerance and type 2 diabetes[9]. The association between
central obesity and cardiovascular disease in PCOS may be
partly related to low plasma adiponectin levels, although this
hypothesis has not yet been critically tested[39]. There have
also been reports of a higher prevalence of obstructive sleep
apnoea in women with PCOS compared with age and weight
matched controls[40,41], which is likely to be related to coex-
isting factors such as central obesity and insulin resistance.
Smoking is a major risk factor for cardiovascular disease, but
information on its prevalence and significance in women with
PCOS is sparse.
Whether the prevalence of hypertension is increased in
women with PCOS is unclear. Studies, including those utilis-
ing 24-h ambulatory blood pressure monitoring techniques,
have reported conflicting results[30,42–44]. The lack of sig-
nificant association with hypertension is surprising given the
close link between PCOS and the metabolic syndrome. Per-
tinent studies have, however, utilised variable definitions of
PCOS and employed a wide variety of techniques to assess
blood pressure.
In summary, there is evidence that multiple biochemi-
cal and clinical cardiovascular risk factors are increased in
women with PCOS. It is, however, unclear whether this
translates to increased rates of cardiovascular events, and
specifically whether PCOS and hyperandrogenaemia have an
e sting
f
2
own
t ease,
a ce,
c lbu-
m e is
p ly to
r sulin
r ndro-
g
p tors
w e
o e is
g indi-
c emia
i nifes-
t and
i –40-
y h
P dia-
b
be
a bolic
s of
c ay
b dard
levated androgens may contribute to small HDL size
timulating hepatic lipase activity[24]. The aforementione
ualitative changes in lipoprotein metabolism could acc
or an increased risk of cardiovascular disease in PCOS
endent of changes in total or LDL cholesterol levels, but
otion remains to be demonstrated.
.1.4. Other risk factors
Several studies have demonstrated abnormalities in
raditional markers of cardiovascular risk related to ins
esistance and obesity in PCOS. The majority, such as
nvolving C-reactive protein[25–27], adiponectin[28,29],
lasminogen activator-1[30], Von Willebrand factor[31],
ndothelin-1[32], homocysteine[33] and markers of oxida
ive stress[34], have shown that their association with PC
s dependent upon co-existent obesity.
.2. Clinical
Women with PCOS are generally more obese than
atched controls, and have an elevation of both BMI
aist/hip ratio[35]. The expression of obesity in PCOS va
eographically, the obese phenotype being particularly
on in the United States of America[3]. Obesity is associate
ith risk factors for atherosclerosis, such as hyperten
nsulin resistance, dyslipidaemia and increased platelet
ation [36–38]. An android or central pattern of obes
s evidenced by an elevated waist/hip ratio, is a signifi
nd independent cardiovascular risk factor. Longitudinal
lso show that weight gain, especially accumulation of
ffect on cardiovascular risk independentof these coexi
actors.
.3. Metabolic syndrome
The metabolic syndrome is a clustering of factors kn
o increase the risk of diabetes and cardiovascular dis
nd typically includes a combination of insulin resistan
entral obesity, dyslipidaemia, hypertension and microa
inuria[45,46]. The prevalence of the metabolic syndrom
robably increased in subjects with PCOS, and this is like
epresent the interaction of a genetic predisposition to in
esistance, dyslipidaemia and hypertension with hypera
enaemia in the setting of visceral obesity[47–49]. This may
artly account for the clustering of cardiovascular risk fac
ithin families of women with PCOS[50]. The prevalenc
f the individual components of the metabolic syndrom
reater than the fully established syndrome in PCOS. As
ated above, hypertension is less common than dyslipida
n PCOS. The prevalence of type 2 diabetes, another ma
ation of the metabolic syndrome, is increased in PCOS
ncreases with age, being reported in up to 21% of 35
ear-old women with PCOS[5]. South Asian women wit
COS are particularly prone to insulin resistance and
etes[51].
Focusing on individual and traditional risk factors may
s important as establishing the diagnosis of the meta
yndrome in young women to predict their future risk
ardiovascular disease[52]. Hence, cardiovascular risk m
e underestimated in women with PCOS if the stan
230 A.J. Cussons et al. / Atherosclerosis 185 (2006) 227–239
composite diagnosis of the metabolic syndrome, rather than
its individual components, is utilised to guide clinical inter-
vention. The validity of employing the National Cholesterol
Education Program Adult Treatment Panel III and World
Health Organisation criteria to make the diagnosis of the
metabolic syndrome in general has recently been strongly
challenged[53], and it is likely that similar arguments
could also apply to its use in the setting of PCOS. The new
International Diabetes Federation definition of the metabolic
syndrome may, however, address some but not all of these
concerns[54].
3. Cardiovascular epidemiology of PCOS
Although cardiovascular risk factors are more prevalent
in women with PCOS, definitive evidence for an increased
incidence of cardiovascular disease is lacking. Based on the
calculated risk factor profile, Dahlgren et al. predicted a rel-
ative risk of myocardial infarction of 7.4 in a small group
of women (n = 33) with histopathological evidence of poly-
cystic ovaries (PCO) compared with aged-matched controls
[43]. However, a retrospective cohort study from the United
Kingdom found that while women (n = 345) with a history of
PCOS, diagnosed primarily from ovarian morphology, had
more cardiovascular risk factors, including diabetes, hyper-
c tality
a iffer
f
fi of a
n vas-
c less,
t cular
d and
2 ear
f
P cular
e ally
a
P efer-
e
, the
m ,439
w ular
m with a
h ad
i eart
d llow-
u the
B obe-
s ased
c as-
c sian
t pre-
d
r
In general, epidemiological studies of women with PCOS
have been hampered by small sample sizes, relatively short
periods of follow-up, use of highly selected clinic popula-
tions and potential confounding due to effects of treatments
at baseline and changing clinical phenotype over time.
4. Studies of subclinical cardiovascular disease
By contrast to the sparse epidemiological data, several
studies of markers of subclinical disease have recently elu-
cidated the relationship between PCOS and cardiovascular
disease. These studies, which focus on the arterial wall and
the myocardium, are summarized inTables 2 and 3and are
discussed below.
5. Functional studies
5.1. Ventricular function
Left ventricular (LV) diastolic dysfunction is an early man-
ifestation of diabetic cardiomyopathy[57], and has been
shown to identify hypertensive patients at increased risk
of cardiovascular events[58]. Its aetiology is multifactorial
and relates to coronary artery disease, hypertension, auto-
n ulin
r
S my-
o colla-
g
with
P elax-
a n,
a hed
c t
d RT
w were
c t cor-
r
e the
h car-
d etes
m he
m r the
e have
h lood
fl ow-
e ased
m ulin
r
5
oci-
a ssure
holesterolaemia, hypertension and obesity, their mor
nd morbidity from coronary heart disease did not d
rom age-matched controls (n = 1060)[55]. This surprising
nding could be ascribed to ascertainment bias, to use
on-standard definition of PCOS, or possibly to a cardio
ular protective effect of hyperandrogenaemia. Neverthe
he odds ratios for developing diabetes and cerebrovas
isease in this study were increased significantly at 2.3
.8, respectively, even after adjusting for BMI. A 10 y
ollow-up case-control study (n = 126 versusn = 142) from
ittsburgh showed that the odds ratio of a cardiovas
vent in Caucasian women with PCOS, defined princip
s hyperandrogenic chronic anovulation, was 5.91[35]. The
COS group were, however, more overweight than the r
nce population.
Although a definitive diagnosis of PCOS was not used
uch larger Nurses’ Health Study reported that of 82
omen 15% reported usually irregular or very irreg
enses between the age of 20 and 35 years. Those
istory of menstrual irregularity or chronic anovulation h
ncreased relative risk of fatal and non-fatal coronary h
isease of 1.25 and 1.67, respectively, after a 14-year fo
p [56]. That these risks were diminished after adjusting
MI is consistent with the notion, suggested earlier, that
ity and insulin resistance may chiefly mediate the incre
oronary risk in women with PCOS. The risk of cardiov
ular disease in PCOS may be greater with Southern A
han Caucasian women owing to the former’s heightened
isposition to insulin resistance and diabetes[51], but this
emains to be demonstrated.
omic neuropathy, microangiopathy, dyslipidaemia, ins
esistance, endothelial dysfunction and oxidative stress[59].
pecific myocardial mechanisms include altered cardio
cyte substrate metabolism and bioenergetics, altered
en metabolism, inflammation and fibrosis[60].
In a case-control, echocardiographic study, women
COS were found to have an increased isovolumetric r
tion time (IVRT), an index of early LV diastolic dysfunctio
nd lower ejection fraction compared with weight matc
ontrols[61] (Tiras et al.,Table 2a column 1). A significan
irect relationship between plasma insulin levels and IV
as demonstrated in the PCOS group. These findings
onsistent with another report showing an independen
elation between hyperinsulinaemia and LV mass[62] (Orio
t al.,Table 2a column 2). The existing studies support
ypothesis that insulin resistance may contribute to myo
ial dysfunction in PCOS. Women with PCOS and diab
ellitus could exhibit diastolic dysfunction owing to t
echanisms referred to earlier, which may account fo
chocardiographic findings reported to date. No studies
itherto investigated the effect of PCOS on coronary b
ow or myocardial substrate utilisation. One would, h
ver, predict impaired coronary flow reserve and decre
yocardial glucose utilisation in PCOS related to ins
esistance and type 2 diabetes[63].
.2. Arterial stiffness
Arterial stiffness of the peripheral circulation is ass
ted with increased systolic blood pressure, pulse pre
A
.J.C
ussons
etal./A
therosclerosis
185
(2006)
227–239
231
Table 2
Summary of studies of cardiovascular function in PCOS
Part a: Author Tiras et al. (1999)[61] Orio et al. (2004)[62] Kelly et al. (2002)[66] Lakhani et al. (2002)[67] Mather et al. (2000)[14] Orio et al. (2004)[71]
Definition of PCOS Clinical and biochemical
hyperandrogenism,
oligomenorrhoea, and
PCO on US
1990 NIH criteria Biochemical hyperandrogenism
and ovulatory dysfunction
PCO on ultrasound, plus
hirsutism or menstrual
irregularity
Oligomenorrhoea plus
clinical and biochemical
evidence of
hyperandrogenism
1990 NIH criteria
Study design 35 PCOS 30 PCOS 19 PCOS 20 PCOS 18 PCOS 30 PCOS
35 controls 30 controls 12 controls 20 PCO 19 controls 30 controls case-control
Case-control Case-control Case-control 20 controls Case-control Case-control
Technique employed Echocardiography Echocardiography Pulse wave velocity, myography Carotid ultrasoundFlow mediated dilatation
of brachial artery
Flow mediated dilatation
of brachial artery
Outcome in PCOS Diastolic dysfunction Increased LV mass,
decreased LV ejection
fraction and diastolic
filling
Abnormal arterial stiffness and
endothelial function
Increased arterial stiffness
in PCOS and PCO
Normal endothelial
function
Abnormal endothelial
function
Factors associated with
outcome in PCOS
Basal and total insulin
levels
BMI, insulin resistance ? ? ? Insulin resistance
Independent association
with PCOS?
? No ? Yes No No
Part b: Author Kravariti et al. (2005)[72] Tarkun et al. (2004)[15] Diamanti-Kandarakis et al.
(2005)[73]
Paradisi et al. (2001)[13] Bickerton et al. (2005)
[81]
Carmassi et al. (2005)[82]
Definition of PCOS 2003 Rotterdam criteria 2003 Rotterdam criteria 1990 NIH criteria Menstrual irregularity and
clinical and biochemical
hyperandrogenism
Menstrual irregularity,
biochemical
hyperandrogenism, PCO
on ultrasound, and
gonadotrophin
abnormalities
1990 NIH criteria
Study design 62 PCOS 37 PCOS 20 PCOS 12 PCOS 11 PCOS 16 PCOS
17 Control 25 controls 20 control 13 controls 12 controls 6 controls
Case-control Case-control Case-control and intervention Case-control Case-control Case-control
Technique employed Flow mediated dilatation
of brachial artery
Flow mediated dilatation
of brachial artery
Flow mediated dilatation of
brachial artery
Leg blood flow responses Forearm reactive
hyperaemia
Intra-arterial insulin
infusion
Outcome in PCOS Abnormal endothelial
function
Abnormal endothelial
function
Abnormal endothelial function;
improvement with metformin
Abnormal endothelial
function
No difference in
endothelial function
compared with controls
Abnormal insulin –induced
vasodilation in PCOS
Factors associated with
Outcome in PCOS
Insulin resistance,
testosterone, total
cholesterol
C reactive protein,
insulin resistance
Fasting insulin; AUC glucose,
testosterone
Testosterone, Body mass
index
Nil Insulin resistance
Independent association
with PCOS?
? No ? No No
232
A
.J.C
ussons
etal./A
therosclerosis
185
(2006)
227–239
Table 3
Summary of studies of cardiovascular structure IN PCOS
Author Guzick et al. (1996)[83] Talbott et al. (2000)[84] Orio et al. (2004)[71] Vural et al. (2005)[85] Christian et al. (2003)[87] Talbott et al. (2004)[49]
Definition of PCOSa Chronic anovulation, and
clinical or biochemical
hyperandrogenism or
LH:FSHb >2
Chronic anovulation, and clinical
or biochemical hyperandrogenism
or LH:FSH >2
1990 NIHc criteria 2004 Rotterdam criteria 1990 NIH criteria Chronic anovulation, and
clinical or biochemical
hyperandrogenism or
LH:FSH >2
study design 16 PCOS 125 PCOS 30 PCOS 43 PCOS 36 PCOS 61 PCOS
16 Controls 142 Controls 30 Controls 43 Controls 71 Controls 85 Controls
Case-control Case-control Case-control Case-control Case-control Case-control
Technique employed Carotid IMTd Carotid IMT and plaque count Carotid IMT Carotid IMT Electron beam computed
tomography of coronary
arteries
Electron beam computed
tomography of coronary
arteries and aorta
Outcome in PCOS Increased IMT Premature carotid atherosclerosis
in PCOS plus increased IMT in
PCOS group >45yo
Increased IMT Increased IMT Increased coronary artery
calcification
Increased coronary artery and
aortic calcification
Factors associated
with outcome in
PCOS
BMIe, insulin, total
cholesterol, LDL
BMI, insulin, age, waist:hip ratio,
blood pressure, triglycerides.
Free androgen index BMI Low sex hormone
binding globulin
BMI, total cholesterol, LDLf ,
triglycerides
1. Coronary artery
calcification: Age, BMI, waist
circumference, triglycerides,
HDLg, insulin, blood pressure
2. Aortic calcification: as for
1. plus testosterone and fasting
glucose
Independent
association with
PCOS?
No No No Yes No No
a Polycystic ovary syndrome.
b Luteinising hormone:follicle stimulating hormone ratio.
c National Institutes for Health.
d Intima-medial thickness.
e Body mass index.
f Low density lipoprotein.
g High density lipoprotein.
A.J. Cussons et al. / Atherosclerosis 185 (2006) 227–239 233
and ventricular load, as well as with decreased diastolic per-
fusion of the coronary circulation. Arterial stiffness may be
assessed by ultrasonographic estimation of carotid artery dis-
tensibility, by measuring pulse wave velocity (PWV), or by
analysis of the diastolic component of the radial waveform
[64]. In certain patient groups, such as those with renal fail-
ure, increased arterial stiffness has been shown to predict
cardiovascular events[65].
In a small case-control study, Kelly et al. reported
increased pulse wave velocity of the brachial artery, but not
of the aorta, in a PCOS group[66] (Kelly et al., Table 2a
column 3). Similarly, Lakhani et al. demonstrated increased
stiffness of both internal and external carotid arteries in
woman with both PCOS and PCO (ultrasonographic poly-
cystic ovaries alone) compared with controls[67] (Lakhani et
al.,Table 2a column 4). Multivariate analysis suggested inde-
pendent effects of PCOS and PCO on arterial stiffness. That
this study did not show an independent relationship between
insulin resistance or other cardiovascular risk factors and arte-
rial stiffness could, however, be due its small sample size. In
a study of 80 obese women with PCOS Meyer et al. found
a significant relationship between PWV and blood pressure
and between PWV and both insulin and glucose during a
glucose tolerance test[68].
The mechanism for increased arterial stiffness reported
in some studies of PCOS remains unclear but, as in the
m olve
e gen
m
5
rter-
i idely
s nly
i erial
s sfibri-
n sally
c yn-
t een
l ely
i ys-
f tion
o nsin
I n of
N da-
t y of
N ely
a jects
w
5
f
vo-
l and
c edi-
ated dilatation (FMD) of the brachial artery with high-
resolution ultrasonography is an established method to assess
endothelial function of conduit arteries. FMD is chiefly medi-
ated by the abluminal release of the potent vasodilator NO
[70].
Mather et al. used FMD of the brachial artery to assess
endothelium-dependent vascular function in PCOS[14]
(Mather et al.,Table 2a, column 5). In spite of significant dif-
ferences in plasma lipids, androgen status, body weight and
insulin resistance between the cases and controls there was
no evidence of impaired endothelial function in the women
with PCOS. In particular there was no significant association
between insulin resistance or androgen status and FMD of
the brachial artery.
By contrast, Orio et al. found impaired FMD of the
brachial artery in normal weight PCOS subjects compared
with controls[71] (Orio et al.,Table 2a, column 6). However,
specific evidence of endothelium-dependent shear-stress
induced vasodilatory dysfunction (rather than an abnormality
at the level of the smooth muscle) could not be inferred from
this study, as GTN-mediated dilatation was not assessed.
The PCOS subjects had higher plasma androgens, and
higher fasting and glucose-stimulated plasma insulin levels.
In this study, direct and independent associations were
found between impaired FMD and insulin resistance. These
findings are supported by the data from Kravariti et al. using
s .
T n to
d jects
w ation
w rone
a MD.
T emia
o ence
e
in
b ilator
r ontrol
s t
a ent
v sis-
t not
w ution
o duit
a
lts of
M stic
c n a
s HDL
l fore
h in the
o
the
i unc-
t
c re is
etabolic syndrome and insulin resistance, may inv
ndothelial dysfunction and altered artery wall colla
etabolism.
.3. Endothelial function
Endothelial function of both conduit and resistance a
es is the surrogate cardiovascular endpoint most w
tudied in PCOS. Endothelial dysfunction signifies not o
mpaired arterial vasodilatation, but also increased art
tiffness, hypertension, increased haemostasis and dy
olysis and increased vascular oxidative stress. It is cau
onnected to uncoupling of endothelial nitric oxide s
hase (ecNOS) due to stoichiometric imbalance betw
-arginine, NADPH and tetrahydrobiopterin, collectiv
mpairing synthesis of nitric oxide (NO). Endothelial d
unction may also involveincreased endothelial cell secre
f the potent vasoconstrictors endothelin-I and/or angiote
I. Increased vascular oxidative stress due to stimulatio
ADPH oxidase and uncoupling of mitochondrial oxi
ive phosphorylation also contribute to the pathobiolog
O [69]. The foregoing molecular mechanisms collectiv
ccount for the endothelial dysfunction reported in sub
ith PCOS, as discussed below.
.3.1. Conduit arteries: macrovascular endothelial
unction
Endothelial dysfunction is an early event in the e
ution of atherosclerosis, preceding plaque formation
linical disease. Measurement of post-ischaemic flow m
imilar techniques[72] (Kravariti et al.,Table 2b, column 1)
his study did, however, use nitrate-mediated dilatatio
emonstrate that the abnormal FMD seen in these sub
as endothelium-dependent. In addition to an associ
ith insulin resistance, this study found total testoste
nd total cholesterol to be independent predictors of F
hese studies therefore suggest that the hyperinsulina
f PCOS, and possibly hyperandrogenaemia, can influ
ndothelial function of conduit arteries.
Tarkun et al. also found significant differences
oth endothelium-dependent and independent vasod
esponses of the brachial artery between PCOS and c
ubjects using a similar vascular technique[15] (Tarkun e
l., Table 2b, column 2). Impaired endothelium-depend
asodilatation was found to be correlated with insulin re
ance and high sensitivity C-reactive protein levels, but
ith plasma testosterone levels, challenging the contrib
f hyperandrogenaemia to endothelial dysfunction in con
rteries.
These more recent studies contradict the earlier resu
ather et al., despite all studies employing similar diagno
riteria for PCOS. Mather et al. based their findings o
maller sample size and on PCOS cases with plasma
evels that did not differ from controls and may have there
ad a lesser degree of insulin resistance than subjects
ther studies.
A study from Diamanti-Kandarakis et al. supports
mportance of insulin resistance in the endothelial dysf
ion seen in PCOS[73] (Diamanti-Kandarakis et al.,Table 2b,
olumn 3). This study demonstrates not only that the
234 A.J. Cussons et al. / Atherosclerosis 185 (2006) 227–239
impairment of endothelial dysfunction in PCOS but also that
it is reversed by metformin therapy.
On balance the weight of evidence from studies of conduit
arteries supports the presence of endothelial dysfunction in
women with PCOS and a link with insulin resistance. Insulin
resistance may contribute to endothelial dysfunction of con-
duit arteries by diverse mechanisms that affect the biology
of NO [74]. Classically, insulin resistance due to impaired
phosphatidyl 3-kinase and Akt signalling decreases the acti-
vation of ecNOS and release of NO[75]. Elevated cellular
free fatty acids, increased redox potential due to accumu-
lated NAPH, and deficiency in tetrahydrobiopterin could
contribute to ecNOS uncoupling with decreased formation
of NO and over production of the pro-oxidant, peroxynitrite
[76]. We propose that these molecular mechanisms operate
in concert to induce endothelial dysfunction related to the
insulin resistance of PCOS. Whether hyperandrogenaemia
contributes to uncoupling of ecNOS and increased vascular
oxidative stress remains unknown.
5.3.2. Resistance arteries: microvascular endothelial
function
Invasive studies employing other methodologies, such as
intra-arterial infusion of vasoactive agents with thermodilu-
tional or plethysmographic assessment of limb blood flow,
have also shown endothelial dysfunction of the microcircu-
l o the
b e to
v sig-
n e of
e
men
w ses
t gly-
c
w eter.
T the-
l t tha
t ed to
t othe-
l ree
o lev-
e nd an
i eat-
m en
c ial
f ance,
t vels.
T ow-
e e and
i
OS
w ea-
s teries
t ulin
[ s,
however, do not strictly represent changes in the whole
body model. In contrast, Bickerton et al. found no differ-
ences in reactive hyperaemia of the forearm microcirculation,
measured by standard occlusion plethysmography, between
PCOS women and age/weight matched controls[81] (Bick-
erton et al.,Table 2b, column 5). This arterial response is less
reflective of endothelial function, being dependent not only
on NO, but also on the release of prostaglandins, the opening
of potassium channels, changes in pH, and on smooth mus-
cle tone. However, the study groups might also not have had
a comparable level of insulin resistance, which would have
confounded interpretation of the data. This is made clearer
by the study of Carmassi et al. measuring forearm vasodi-
latation mediated by intra-arterial insulin infusion in PCOS
women with and without insulin resistance[82] (Carmassi et
al.,Table 2b, column 6). This study demonstrated that insulin
resistance rather than PCOS confers endothelial dysfunction
in this vascular bed.
In aggregate, the above studies of arterial dilatory func-
tion clearly point to the presence of endothelial dysfunction
in different arterial beds in PCOS and to a close associa-
tion of endothelial dysfunction with insulin resistance and a
less consistent one with hyperandrogenaemia. Similar mech-
anisms probably account for the impact of insulin resistance
on the biology of NO in both conduit and resistance arteries
in women with PCOS.
6
6
car-
d h an
e
trols
u T in
t
fi ty or
p that
C cts
c ting
c edic-
t o
r the
P tions
s rosis
m
gnif-
i ght
P
T l
e one
b T,
w
I aled
ation and resistance vessels in PCOS. By contrast t
rachial artery, vasodilatation of the forearm in respons
asoactive stimuli (e.g. acetylcholine) may also involve a
ificant component attributed to the endothelial releas
ndothelium-derived hyperpolarizing factor[77,78].
Paradisi et al. reported that compared with controls wo
ith PCOS had impaired leg blood flow (LBF) respon
o methacholine and to hyperinsulinaemia during a eu
aemic clamp[13] (Paradisi et al.,Table 2b, column 4). LBF
as measured by an intravenous thermodilution cath
hat LBF response to sodium nitroprusside, an endo
ium independent vasodilator, was not assessed mean
he demonstrated defect could not necessarily be localis
he endothelial cell as opposed to smooth muscle. End
ial dysfunction was positively correlated with the deg
f insulin resistance and with plasma free testosterone
ls. Using the same techniques, Paradisi et al. also fou
mprovement of endothelial function after 3 months of tr
ent with troglitazone, a thiazolidinedione, in PCOS wom
ompared with controls[79]. The improvement in endothel
unction was associated with a decrease in insulin resist
estosterone, and plasminogen activator inhibitor 1 le
he effects of glitazones on endothelial function may, h
ver, be independent of improvement in insulin resistanc
nvolve a PPAR� effect on the expression of ecNOS[80].
Resistance to the vasodilator effects of insulin in PC
as confirmed by Kelly et al. in an ex vivo study that m
ured the contractile response of gluteal resistance ar
o noradrenaline before and after incubation with ins
66] (Kelly et al., Table 2a, column 3). Ex vivo studie
t
. Morphological studies
.1. Carotid wall thickness
CIMT has been shown in several studies to predict
iovascular events, with increasing CIMT associated wit
levated age-adjusted cardiovascular risk[64].
Guzick et al. assessed women with PCOS and con
sing carotid ultrasonography and found increased CIM
he PCOS group[83] (Guzick et al.,Table 3, column 1). This
nding was independent of dyslipidaemia but not obesi
lasma insulin levels. Talbott et al., however, reported
IMT values were only different in older PCOS subje
ompared with controls, and after adjusting for coexis
ardiovascular risk factors PCOS was not a significant pr
or of CIMT [84] (Talbott et al.,Table 3, column 2). They als
eported a significantly greater carotid plaque index in
COS subjects compared with controls. These observa
uggest that in women with PCOS subclinical atheroscle
ay not manifest until the perimenopause.
More recently, two studies have demonstrated a si
cant difference in CIMT between young, normal wei
COS women comparedwith controls[71] (Orio et al.,
able 3, column 3; Vural et al.,Table 3, column 4). Vura
t al. found that PCOS, BMI and a reduced sex horm
inding globulin were all independent predictors of CIM
hich again suggests an effect of insulin resistance[85].
n the study by Orio et al., multivariate analyses reve
A.J. Cussons et al. / Atherosclerosis 185 (2006) 227–239 235
a direct correlation between CIMT and the free androgen
index, suggesting a contribution of hyperandrogenaemia to
progression of atherosclerosis in PCOS. By contrast, in a
larger study increased CIMT was inversely correlated in mul-
tivariate analysis with plasma DHEAS and androstenedione
levels, suggesting an intriguing vasculoprotective effect of
hyperandrogenaemia in PCOS[86]. However, in this study a
strong independent positive association was also found with
lower plasma high density lipoprotein cholesterol, indica-
tion an opposing aggravating effect of dyslipidaemia and by
implication insulin resistance. A vasculoprotective effect of
DHEAS was also suggested by Meyer et al. in a study of
80 obese women with PCOS, where higher DHEAS cor-
responded to significantly lower CIMT[68]. Whether ele-
vated DHEAS actually benefits atherogenesis in PCOS, how-
ever, requires further research in different subtypes of this
condition.
6.2. Arterial calcification
Coronary artery calcification reflects the underlying
degree of atherosclerosis and is predictive of clinical events.
In the coronary circulation, electron beam computer tomog-
raphy has been employed to demonstrate increased arte-
rial calcification in PCOS women compared with controls
[87] (Christian et al.,Table 3, column 5). After adjusting
f of
c ting
p inci-
d a 9
y
e as
d ding
c mia,
a aortic
c tos-
t le of
h mple-
m soci-
a aries
[
ely
d l evi-
d tance
i usal
f ed,
e the
v
7
ate
e ween
P ongs
s due
to small sample sizes, bias in case-control designs and use of
non-standard definitions of PCOS.
The evidence, based solely on association studies to
date, indicates that insulin resistance and obesity may be
the mediators of early ventricular abnormalities, endothe-
lial dysfunction, arterial stiffness, and both carotid and
coronary atherosclerosis. The mechanisms likely relate
to the consequences of insulin resistance. These include
dyslipoproteinaemia, hypertension, increased oxidative
stress, low-grade inflammation, altered haemostasis and
dysfibrinolysis, as well as alterations in myocardial ener-
getics and collagen turnover. Uncoupling of ecNOS activity
with decreased production of NO and overgeneration of
peroxinitrite is probably a central event in initiating the
endothelial dysfunction and atherothrombosis.
The role of hyperandrogenaemia in contributing to the car-
diovascular abnormalities reviewed remains unclear and con-
troversial. Although androgens may have been proposed as
factors in cardiovascular risk in PCOS, the minority of stud-
ies reviewed showed an independent association of androgens
with impaired cardiovascular structure or function. This fur-
ther reinforces the view that cardiovascular risk in PCOS
resides in insulin resistance rather than hyperandrogenaemia.
Moreover, the pro-atherogenic effect of androgens is not
supported by observational and clinical studies in women
in general. In PCOS, androgens, particularly DHEAS, have
b
dis-
e wing
s icted
i ugh
w COS
m final
c for
t ative
s then
i terial
a e
c the
h e
o OS,
t data
d nts in
w
ians
s in
w
a ovas-
c ening
f sulin
r glu-
c t the
d eight
g cise,
a har-
m and
or BMI, dyslipidaemia remained a positive predictor
oronary calcification. Talbott et al. reported an interes
rospective, case-control study showing an increased
ence of coronary and aortic arterial calcification over
ear follow-up period in women with PCOS[49] (Talbott
t al.,Table 3, column 6). The degree of calcification w
ependent on features of the metabolic syndrome, inclu
entral obesity, elevated blood pressure and dyslipidae
nd hence insulin resistance. In that study, the degree of
alcification was also positively related to plasma tes
erone levels, questioning a putative atheroprotective ro
yperandrogenaemia in PCOS. These reports are co
ented with angiographic data in women showing an as
tion between coronary artery disease and polycystic ov
88].
The foregoing reports of arterial calcification collectiv
emonstrate that women with PCOS have morphologica
ence of coronary atherosclerosis and that insulin resis
n particular, rather than PCOS per se, is the major ca
actor. By contrast to the morphological changes review
ndothelial dysfunction is more likely to be a feature of
asculopathy of young women with PCOS.
. Conclusions and future perspectives
While the epidemiology is inconclusive, recent surrog
ndpoint studies strongly support an association bet
COS and cardiovascular disease. Discrepancies am
ome studies reviewed to generate this notion may be
t
een negatively correlated with CIMT.
An hypothesis for the pathogenesis of cardiovascular
ase in PCOS based on the data reviewed and allo
equential and interactive effects of genetic factors is dep
n Fig. 1. This figure summarises potential pathways thro
hich the cardiovascular risk factors associated with P
ay translate in to clinical cardiovascular disease. A
ommon path prior to the expression of clinical disease
he risk factors associated with PCOS centres on oxid
tress, inflammation and endothelial dysfunction, which
nduce physical and morphological changes, such as ar
nd ventricular stiffness and atherosclerosis[89]. Prospectiv
linical endpoint studies, however, are required to verify
ypothetic scheme shown inFig. 1. In spite of the presenc
f these cardiovascular risk factors in women with PC
here are currently no adequate prospective outcome
ocumenting the real prevalence of cardiovascular eve
omen with PCOS.
From a clinical perspective, we suggest that physic
hould continue to identify cardiovascular risk factors
omen with PCOS and treat these accordingly[90]. This
ccounts for the heightened risk of diabetes and cardi
ular disease with increasing age in these women. Scre
or insulin resistance, using a fasting plasma glucose:in
atio, and impaired glucose tolerance, using an oral
ose tolerance test, afford earlier opportunities to preven
evelopment of diabetes. Prevention and reversal of w
ain and obesity through prudent diet and regular exer
nd treatment of dyslipidaemia are crucial. Specific p
acological treatments that improve insulin resistance
236 A.J. Cussons et al. / Atherosclerosis 185 (2006) 227–239
Fig. 1. Hypothetical scheme for the pathogenesis of cardiovascular disease in PCOS. This figure summarises potential pathways through which the cardiovascular
risk factors associated with PCOS may translate into clinical cardiovascular disease. This scheme is hypothetical, however, and while supported byvalid a
priori studies requires examination and verification in prospective clinical outcome studies.
dysglycaemia, such as metformin[91], thiazolidinediones
[92] and acarbose[93], may be warranted in at risk women
given that these agents also benefit ovulatory function and
androgen abnormalities. However, their impact on the devel-
opment of diabetes and cardiovascular events in women with
PCOS remains to be investigated.
From an investigational angle, there are multiple avenues
for research. First, there is a need for more rigorous prospec-
tive studies of cardiovascular outcomes in PCOS, with bet-
ter definition of baseline variables, including measures of
insulin resistance, hyperandrogenaemia and vascular func-
tion. Long-term cohort studies are particularly needed in
young women with PCOS. These studies should be of
large sample size sufficient to investigate the roles of per-
tinent genes, including those regulating, for instance, dyslip-
idaemia, oxidative stress, the renin-angiotensin-aldosterone
system and the biology of NO. Second, based on these studies
additional diagnostic criteria for PCOS should be defined to
identify subtypes, particularlythose at risk of cardiovascular
disease, including those with particular adverse metabolic
and cardiovascular phenotypes. Third, short-term trials of
pertinent interventions, for example lipid regulators, antiox-
idants, and insulin sensitisers, on surrogate cardiovascular
outcomes are warranted to generate new hypotheses for test-
ing in clinical endpoint studies. These should include the
impact of the most commonly used therapeutic interven-
tions in PCOS, the oral contraceptive pill and anti-androgen
therapy, since their effect on cardiovascular events remains
A.J. Cussons et al. / Atherosclerosis 185 (2006) 227–239 237
unknown. Fourth, large-scale clinical outcome trials should
be designed based on the initial findings of epidemiological
and vascular studies. In sum, in our view the high incidence
of PCOS in women of reproductive age and its implications
for cardiovascular health make future research in this area a
priority from both public health and clinical perspectives.
Acknowledgement
Dr. Andrea Cussons is supported by a postgraduate
research scholarship from the National Health and Medical
Research Council of Australia.
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	Cardiovascular disease in the polycystic ovary syndrome: New insights and perspectives
	Introduction
	Cardiovascular risk factors in PCOS
	Biochemical
	Insulin resistance
	Hyperandrogenaemia
	Dyslipidaemia
	Other risk factors
	Clinical
	Metabolic syndrome
	Cardiovascular epidemiology of PCOS
	Studies of subclinical cardiovascular disease
	Functional studies
	Ventricular function
	Arterial stiffness
	Endothelial function
	Conduit arteries: macrovascular endothelial function
	Resistance arteries: microvascular endothelial function
	Morphological studies
	Carotid wall thickness
	Arterial calcification
	Conclusions and future perspectives
	Acknowledgement
	References