M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 8 6 ( 20 1 8 ) 3 3– 4 3

Available online at www.sciencedirect.com

Metabolism
www.metabolismjournal.com

Female Reproductive Endocrinology

Polycystic ovarian syndrome (PCOS): Long-term

metabolic consequences

Panagiotis Anagnostis a,⁎, Basil C. Tarlatzis a , Robert P. Kauffman b

a
First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
b
Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center School of Medicine, Amarillo, TX, USA

A R T I C LE I N FO AB S T R A C T

Article history: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women
Received 16 July 2017 during their reproductive ages, associated with a plethora of cardiometabolic
Accepted 26 September 2017 consequences, with obesity, insulin resistance and hyperandrogenemia playing a major
role in the degree of such manifestations. These consequences include increased risk of
Keywords: glucose intolerance and diabetes mellitus (both type 2 and gestational), atherogenic
PCOS dyslipidemia, systemic inflammation, non-alcoholic fatty liver disease, hypertension and
Insulin resistance coagulation disorders. Whether this cluster of metabolic abnormalities is also translated in
Diabetes increased cardiovascular disease (CVD) morbidity and mortality in later life, remains to be
Dyslipidemia established. Data so far based on markers of subclinical atherosclerosis as well as
Fatty liver disease retrospective and prospective cohort studies indicate a possible increased CVD risk, mainly
for coronary heart disease. Future studies are needed to further elucidate this issue.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction have been applied in various studies and at different times.

Polycystic ovarian syndrome (PCOS) is the most common
endocrine disorder in women during their reproductive
period, with a prevalence of 6–20%, depending on the criteria
used [1,2]. It is the most common cause of menstrual
disorders and hirsutism [1,2]. Different diagnostic criteria
The first diagnostic attempt was made by the National
Institutes of Health (NIH) in 1990 and included both
hyperandrogenism (either clinical or biochemical) and oligo-
or anovulation, manifested either as frequent (at intervals
< 21 days) or infrequent bleeding (at intervals > 35 days) [3].
The Rotterdam criteria were published in 2003 and are the

Abbreviations: AHA, American Heart Association; AEPCOS, Androgen Excess PCOS Society; apoB, apolipoprotein B; apoA-I,
apolipoprotein A-I; CAD, coronary artery disease; CHD, coronary heart disease; CI, confidence interval; CIMT, carotid artery intima-
media thickness; CRP, C-reactive protein; ESE, European Society of Endocrinology; FMD, flow-mediated dilation; FNPO, follicle number
per ovary; GDM, gestational diabetes mellitus; GWAS, genome-wide association studies; HR, hazards ratio; ICAM, intercellular adhesion
molecule; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IL-6, interleukin-6; IL-18, interleukin-18; IR, insulin resistance;
JIC, Joint Interim Societies; MAPK-ERK, mitogen-activated protein kinase-extracellular signal-regulated kinases; MCP-1, monocyte
chemoattractant protein; MetS, metabolic syndrome; OC, oral contraceptives (OC); OGTT, oral glucose tolerance test; OR, odds ratio;
NAFLD, non-alcoholic fatty liver disease; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; NHLBI,
National Heart Lung and Blood Institute; PAI-1, plasminogen activator inhibitor 1; PCOM, polycystic ovarian morphology; RR, Relative
Risk; T2DM, type 2 diabetes mellitus; TNF-α, tumor necrosis factor-α; WHtR, waist-to-height ratio.
⁎ Corresponding author at: Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle
University of Thessaloniki, Sarantaporou 10, 54640 Thessaloniki, Greece.
E-mail address: anagnwst@med.auth.gr (P. Anagnostis).

https://doi.org/10.1016/j.metabol.2017.09.016
0026-0495/© 2017 Elsevier Inc. All rights reserved.
34 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 86 ( 20 1 8 ) 3 3– 43
most commonly adopted. According to these, two of the three
following should be fulfilled for diagnosing PCOS:
hyperandrogenism (either clinical or biochemical), oligo- or
anovulation and polycystic ovarian morphology (PCOM)
(defined either by the presence of ≥ 12 follicles 2–9 mm in
maximum diameter or ovarian volume > 10 ml (without a cyst
or dominant follicle) in either ovary [1–3]. According to these
criteria four different phenotypes (combinations) may be
detected. It must be noted that the PCOM criterion set by the
Rotterdam group may be met by 32% of normal ovulatory
women [4]. Therefore, a higher threshold of follicle number
per ovary (FNPO) of ≥ 25 has been recommended, by using
newer technology ultrasound equipment, allowing for maxi-
mal resolution of ovarian follicles. Otherwise, ovarian volume
is suggested instead of FNPO for the diagnosis of PCOM [5].
On the contrary, the Androgen Excess PCOS Society
(AEPCOS) requires the existence of clinical and/or biochemical
hyperandrogenism as a sine qua non for PCOS diagnosis, with
either polycystic morphology or clinical anovulation as the
second criterion [6]. The estimated prevalence of PCOS varies
according to the criteria used. This was reported to be 8.7%
using the NIH criteria, rising to 17.8% under the Rotterdam
criteria and 12% using the AEPCOS definition [7]. No matter
the criteria used, it must be emphasized that the diagnosis of
PCOS is set after exclusion of other causes of androgen excess,
such as non-classical congenital adrenal hyperplasia,
hyperprolactinemia, androgen-secreting ovarian or adrenal
tumors, hypothyrodisim, Cushing's syndrome and acromeg-
aly [1–2]. The diagnosis of PCOS in adolescents in not so
straightforward, since anovulation and PCOM are not suffi-
cient criteria for this purpose. Thus, clinical and biochemical
evidence of hyperandrogenism, excluding the aforemen-
tioned causes, and persistent oligomenorrhea are required,
especially if the latter persists beyond two years after
menarche [2]. No diagnostic criteria exist in peri- and
postmenopausal women. In these cases, a PCOS diagnosis
can be presumed in the presence of a well-documented
history of oligomenorrhea and hyperandrogenism during
their reproductive period [2]. PCOM is uncommon in post-
menopausal women given the apoptosis-driven diminution
in antral follicles [2].
Although the etiology of PCOS has not been fully elucidated,
a series of harmful events during fetal and peripubertal life,
which ultimately affect the woman's metabolic and hormonal
phenotype, coupled with genetic defects and environmental
factors, such as obesity and endocrine disrupting chemicals,
appear to play a major role [1,8]. In particular, intrauterine
growth restriction or exposure to androgens has been associ-
ated with the development of PCOS in adult life [9,10], although
others have not found any association between birth weight
and PCOS development [10]. However, no specific interventions
are recommended in PCOS women to prevent the occurrence of
PCOS in their offspring [2]. Regarding the genetic component of
PCOS etiology, various genome-wide association studies
(GWAS) have been conducted with inconclusive results. These
GWAS involved genes implicated in biosynthesis and activity of
androgens, metabolism (such as the insulin and insulin-
receptor genes) and inflammatory cytokines, such as tumor
necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) genes [11].
Except for the clinical symptomatology associated with
hyperandrogenemia or anovulation, PCOS is also associated
with long-term consequences, such as subfertility, pregnancy
complications, metabolic derangements, such as dysregulation
of glucose homeostasis, dyslipidemia, coagulation disorders,
fatty liver disease, endothelial dysfunction and potential
subclinical atherosclerotic disease.
The purpose of this narrative review was to provide current
knowledge regarding the metabolic consequences in patients
with PCOS and concomitant cardiovascular disease (CVD) risk.
2. Metabolic Consequences in PCOS
2.1. Insulin Resistance and Diabetes Mellitus
Insulin resistance (IR) is a key player in the metabolic
manifestations in PCOS patients and seems to be in part
independent of obesity. Its prevalence is estimated at 30% of
lean and 70% of obese women with PCOS, acknowledging that
“insulin resistance” has been variably defined [12]. Women
with PCOS have a higher risk of IR and glucose intolerance
compared with age- and weight-matched women without
PCOS [12,13]. Ethnicity seems also to modify the metabolic
phenotype related to IR. Hispanic PCOS women have a more
severe phenotype, with a higher prevalence of IR, hypergly-
cemia and hyperandrogenism than non-Hispanic white PCOS
women. Non-Hispanic black PCOS women have the mildest
phenotype [14]. A higher body mass index (BMI) exacerbates
IR to a greater extent in women with than those without
PCOS, irrespective of the definition used [13].
High testosterone and low sex hormone-binding globulin
(SHBG) concentrations are independently associated with IR
[13,15]. With respect to the association of IR and PCOS
phenotype, it has been shown that the hyperandrogenic and
anovulatory phenotype is the most insulin resistant, irrespec-
tive of BMI or central adiposity [15]. FNPO is also related to both
IR and biochemical hyperandrogenaemia [15]. Indeed, a large
study (n = 1212) in women with PCOS, showed that phenotype
1 (all three Rotterdam criteria), is associated with more severe IR
and hyperandrogenemia compared with the other three
phenotypes. Phenotypes 4 (oligo- or anovulation and PCOM) in
obese/overweight women and 2 (hyperandrogenemia and oligo-
or anovulation) in both normal and obese/overweight women
show greater IR than phenotype 3 (hyperandrogenemia and
PCOM), which does not differ from BMI-matched healthy women
[16]. Adrenal hyperandrogenemia (DHEAS, Δ4-androstenedione)
does not seem to deteriorate IR [17].
Many mechanisms have been proposed for the development
of IR in PCOS. The main one is a post-binding defect in insulin
signaling due to increased serine phosphorylation and de-
creased tyrosine phosphorylation of insulin receptor and
insulin receptor substrate-1, which affects metabolic pathways
both in classic insulin targets (adipocytes, skeletal muscles) and
ovaries. Decreased insulin receptor-β abundance in omental
adipose tissue, decreased glucose transporter 4 (GLUT4) in
subcutaneous adipocytes (leading to decreased glucose uptake),
mitochondrial dysfunction, constitutive activation of serine
kinases in the mitogen-activated protein kinase/extracellular
signal-regulated kinases (MAPK-ERK) pathway and genetic
disruption of insulin signaling in the central nervous system,
 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 8 6 ( 20 1 8 ) 3 3– 4 3
are additional contributors in the development of IR in PCOS
women. A defect in glucose-stimulated insulin secretion in
PCOS, independent of obesity leading to increased risk of DM
has also been reported in PCOS women. In general,
hyperinsulinemia is a result of both increased basal insulin
secretion and decreased hepatic insulin clearance, which
augments androgen production, since insulin acts as a co-
gonadotropin and modulates ovarian steroidogenesis through
its cognate receptor. Vice versa, androgens alter insulin action
(although to a modest extent) in the classic target tissues and
increase visceral adiposity in PCOS women [18].
The prevalence of impaired glucose tolerance (IGT) and
diabetes mellitus type 2 (T2DM) in PCOS patients is 23–35% and
4–10%, respectively, depending also on certain risk factors, such
as obesity and family history; in lean PCOS the respective
prevalence is 10–15% and 1–2% [18,19]. One of the very few
prospective studies on the prevalence of T2DM in European
PCOS population showed a cumulative incidence of T2DM of
16.9% [incidence rate: 1.05 per 100 person-years (95% CI:
0.75–1.41)]. The initial prevalence of T2DM was 2.2% and it
rose to 39.3% after a mean follow-up of 19 years. Independent
predictors of the development of diabetes were BMI, fasting
glucose and glucose area under the curve at baseline, whereas
the likelihood decreased as SHBG increased [20]. A meta-
analysis has shown that the odds ratio (OR) of IGT, T2DM and
metabolic syndrome (MetS) in PCOS is 2.48 [95% Confidence
Interval (CI) 1.63, 3.77], 4.43 (95% CI 4.06, 4.82) and 2.88 (95% CI
2.40, 3.45), respectively [21]. Subgroup analysis of studies with
BMI-matched populations reveals the same risks. The OR for
IGT in lean PCOS women is OR 3.22 (95% CI 1.26, 8.24) [21]. The
lifelong risk in a woman with PCOS for developing T2DM
increases with BMI, fasting glucose and glucose area under the
curve at the initial diagnosis, whereas it decreases as SHBG
levels increase with age [13,22]. PCOS is also associated with a
higher risk of developing gestational diabetes mellitus (GDM)
[in a recent meta-analysis the Relative Risk (RR) was 2.78; 95%
CI: 2.27–3.40; P < 0.001] [23]. Of note, dysregulation of glucose
homeostasis may be evident even in adolescents with PCOS,
although data are not robust, taking also into account the
discrepancies in the definition used in these women. In one
study, the reported prevalence of impaired fasting glucose (IFG),
IGT and T2DM in this subpopulation of PCOS women was 3%,
15.2% and 1.5%, respectively. The frequency of IGT was equal
between obese and non-obese PCOS adolescents [24].
According to the recent position statement by the European
Society of Endocrinology (ESE), an oral glucose tolerance test
(OGTT) is recommended in all obese PCOS women and in lean
PCOS older than 40 years, with a positive history of GDM or
family history of T2DM [1]. Assessment of serum insulin
concentrations and insulin resistance indices are not routinely
recommended [1]. On the contrary, the Endocrine Society [2]
and ESHRE/ASRM [25] recommend the use of OGTT in all
adolescents and adult women with PCOS, due to their high risk
in developing IGT and T2DM [2]. Both societies recommend
against the use of hemoglobinA1c (HbA1c), as a screening test
for such purposes, except for the cases of inability or unwill-
ingness of the patient to complete an OGTT [2]. There is no
evidence on the optimal time of rescreening, but it has been
arbitrarily suggested every three to five years, except for an
earlier worsening in clinical symptomatology [2].
35
2.2. Dyslipidemia
A higher prevalence of lipid abnormalities has been reported
in PCOS women with a prevalence of 70% [26]. In general,
dyslipidemia in PCOS is characterized by increased levels of
low density lipoprotein cholesterol (LDL-c) and very-low
density lipoprotein cholesterol (VLDL-c), with high serum
triglyceride (Tg) and free fatty acid concentrations, as well as
decreased high density lipoprotein cholesterol (HDL-c) levels,
particularly HDL2-c, due to decreased apolipoprotein A-I
(apoA-I) [26–28]. Notably, LDL-c concentrations can be normal
or borderline high, but this does not correspond to the quality
of LDL particles, since LDL exists as subfractions of various
size and atherogenic potential. In PCOS, smaller and dense
LDL particles predominate constituting a more atherogenic
lipid profile converging that of T2DM [29]. PCOS women have
also higher concentrations of oxidized LDL-c, irrespective of
BMI, which further increases CVD risk. Predictors of oxidized
LDL-c are apoB/apoA-I ratio in normal weight and TC/HDL-c
ratio in obese PCOS patients. [30]. This atherogenic profile is
exacerbated by obesity and IR [26–29]. In particular, IR
increases the hepatic secretion of VLDL (the major source of
Tg), decreases the elimination of VLDL and chilomicrons from
the circulation and increases the clearance of apolipoprotein
A, the major component of HDL-c [31].
A meta-analysis showed that, compared with age-
matched controls, PCOS women had 26.39 (95% CI 17.24,
35.54) mg/dl higher Tg levels, 6.41 (95% CI 3.69, 9.14) mg/dl
lower HDL-c and 18.82 (95% CI 15.53, 22.11) mg/dl higher non-
HDL-c levels. LDL-c levels were also higher even in studies
with BMI matching [8.32 mg/dl, 95% CI (5.82,10.81)]. The latter
remained also higher in normal weight PCOS [9.20 mg/dl,
95%CI (4.68, 13.72)] [32]. Ethnic and environmental factors
seem to contribute to differences in the prevalence of lipid
disorders amongst PCOS women. In fact, the prevalence of
low HDL-c (< 50 mg/dl) and high Tg levels in PCOS women
from the USA is estimated at 66.7% and 34.9%, respectively,
whereas the respective percentages in Italian PCOS women
are 49.1% and 7.4% Tg [33].
Lipoprotein (a) [Lp(a)] concentrations and apoB (the major
apolipoprotein of atherogenic lipoproteins and indicator of
small and dense LDL particles), which are considered indepen-
dent risk factors for CVD, may also be elevated in PCOS women
[28,34] (in 24% and 14% respectively) [34]. Notably, more than
one third of PCOS women with normal plasma lipid profile may
have elevated Lp(a), apoB or small, dense LDL levels [34].
Atherogenic dyslipidemia is more profound in obese
PCOS. Although obesity seems to further worsen lipid profile,
this is regardless of BMI [32]. Some studies have linked
hyperandrogenemia to dyslipidemia [35], but, in others,
testosterone was not associated with PCOS atherogenic
lipid profile [29].
2.3. Abdominal Obesity-Metabolic Syndrome (MetS)
As shown above, obesity is a key contributor to the clinical
and metabolic manifestations of PCOS patients. However,
what is of utmost importance is the body's distribution of
adipose tissue. It is not the increased BMI that matters as
much as the central fat distribution. Indeed, abdominal
36 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 86 ( 20 1 8 ) 3 3– 43
obesity has been considered as an independent risk factor for
CVD [36]. Comparisons between BMI (an index of general
obesity) and waist-to-height ratio (WHtR) (an index of
abdominal obesity), has shown that WHtR is more strongly
associated with T2DM and metabolic syndrome (MetS). WHtR
is also superior to BMI in predicting incidents of CVD, CVD
mortality and all-cause mortality [37].
The prevalence of overweight (BMI: 25–29.9 kg/m2) and
obesity (BMI > 30 kg/m2) in PCOS can reach up to 80%, with a
higher BMI and waist-hip ratiocompared with their age-
matched controls in the general population [38]. A meta-
analysis showed that PCOS women are at two and three-fold
higher risk of being overweight or obese, respectively,
compared with their non-PCOS counterparts [RR for over-
weight: 1.95 (95% CI 1.52, 2.50); for obesity: 2.77 (95% CI 1.88,
4.10); for central obesity: 1.73 (95% CI: 1.31, 2.30)]. This
prevalence is also affected by ethnicity, since it is higher in
Caucasian compared with Asian women [RR: 10.79 (5.36,
21.70) versus 2.31 (1.33, 4.00), respectively] [39]. Adipose fat
distribution in PCOS shifts to android pattern, both in lean
and obese women, compared with non-PCOS women [38–41].
Moreover, lean PCOS women are characterized by a lower
amount of body fat in the upper region and a higher leg
subcutaneous adipose tissue reduction, resembling the fat
pattern in children before their sex specific body fat distribu-
tion. On the other hand, obese PCOS women exhibit a
significantly increased upper trunk obesity, appearing as
“super-apples”, resembling the T2DM pattern [40,41]. Obesity
and concomitant hyperinsulinemia further increases bio-
available androgen levels, mainly due to decreased concen-
trations of SHBG [38]. On the other hand, the prevalence of
PCOS is higher (about five-fold) in premenopausal overweight
and obese women compared with normal-weight from the
general population [42]. Hyperandrogenemia may also con-
tribute to abdominal adiposity in PCOS women [38].
“MetS” is a term used to incorporate a cluster of metabolic
abnormalities, including abdominal obesity, hyperglycemia,
hypertension and dyslipidemia, with IR playing a pivotal role
in its pathogenesis. MetS is associated with a five-fold higher
risk for T2DM and two-fold higher risk for CVD [43]. It
generally affects about 20–25% of the Mediterranean popula-
tion [43]. The prevalence of MetS depends on the definition
used. Different criteria have been proposed by various
organizations. The latest were proposed by the Joint Interim
Societies (JIC) and require at least three of the following:
central obesity (waist circumference > 94 cm for men and
> 80 cm for women in the Mediterranean population); Tg
levels > 1.7 mmol/l (150 mg/dl); HDL-c levels > 1.0 mmol/l
(40 mg/dl) for men and > 1.3 mmol/l (50 mg/dl) for women;
fasting blood glucose levels > 6.1 mmol/l (110 mg/dl) [44]. With
the JIC criteria, the prevalence of MetS rises up to 45.7%, but is
less predictive of CVD compared with that based on the
International Diabetes Federation (IDF), National Cholesterol
Education Program Adult Treatment Panel III (NCEP ATP III)
and the American Heart Association/National Heart Lung and
Blood Institute (AHA/NHLBI) definition (respective prevalence
43.5%, 24.5% and 26.3%) [44]. The prevalence of MetS is higher
in PCOS compared with the general population (ranging from
33% to 47% in most studies, increasing to 53% in ages 30–
39 years) [45–47]. In a representative study from the US
population using the NCEP ATP III criteria the prevalence in
PCOS was 46.4% versus 22.8% in the general population [46].
However, others have reported similar rates with the general
(e.g. Mediterranean) population), that is, 21.4%, applying the
NCEP ATP III criteria [48]. Interestingly, a large study from the
Mediterranean (Greek) population showed higher prevalence
of MetS in PCOS women than in controls only when the NCEP
ATP III criteria were applied (15.8% versus 10.1%, respectively)
but not with the other MetS definitions (JIC, IDF, AHA/NHLBI)
[49]. The prevalence of MetS also differed according to the
definition of PCOS. In particular, the prevalence was higher in
PCOS women defined both by the Rotterdam and NIH criteria
compared with controls (regardless of the applied MetS
definition), but it was equal when only Rotterdam criteria
were used [49]. Of note, the former study from the Mediter-
ranean (Spanish) population used the NIH criteria [48].
Therefore, no safe conclusions can be made with respect to
the prevalence of MetS in PCOS due to the heterogeneity of
definitions used and the populations studied.
Contributors to the pathogenesis of obesity in PCOS are some
mutations in the peroxisome proliferator activated receptor-γ
(PPAR-γ) gene [50], which enhance adipogenesis, eating behavior
(mainly due to the association of hyperandorgenism with
increased appetite) [51], reduced secretion of cholecystokinin,
which reduces satiety [52], and increased levels of neuropeptide
Y, which increases appetite (perhaps due to dysregulated
secretion of ghrelin both in obese and lean PCOS women) [53].
Androgens seem to play a significant role in the pathogenesis of
MetS in PCOS. The prevalence of MetS is higher in
hyperandrogenic than non-hyperandrogenic anovulatory
women with PCOS (24.8% vs 0%). Interestingly, free androgen
index and waist circumference are independently associated
with the presence of MetS and/or IR [54]. Accordingly, in another
study, the non-hyperandrogenic PCOS phenotype was associated
with a milder phenotype compared with the other phenotypes
according to the Rotterdam criteria [the respective prevalences of
MetS in the full PCOS (three criteria), oligo-and/or anovulatory
hypeandrogenic, ovulatory hyperandrogenic PCOM and ovulato-
ry PCOM non-hyperandrogenic phenotypes were 28.5%, 25.5%,
8.3% and 7.2%] [55].
Visceral obesity is associated with increased levels of
proinflammatory factors such as TNF-α, IL-6 and
interleukin-18 (IL-18), which are secreted by activated tissue
marcophages that infiltrate adipose tissue and seem to be
implicated in the pathogenesis of IR [56]. Increased concen-
trations of TNF-α [57] have been detected in PCOS women,
irrespective of obesity, as well as IL-6 [58] andIL-18 [59],
although not by all studies [60]. Moreover, IL-6 gene polymor-
phisms have been associated with total testosterone and lipid
parameters (such as HDL-c and Tg) in PCOS women [61].
Increased systemic inflammation, as indicated by increased
concentrations of C-reactive protein (CRP), has been demon-
strated in PCOS, compared with BMI-matched controls [62].
CRP, more specifically high-sensitivity CRP, has been recog-
nized as an independent predictor of CVD [63]. Whether this
systemic inflammation plays a causal role in the pathogen-
esis of PCOS or is just a consequence of the metabolic and
hormonal milieu remains to be clarified. In general, there is
an adipose tissue functional derangement in PCOS patients.
Adipose hypertrophy has been reported by several studies,
 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 8 6 ( 20 1 8 ) 3 3– 4 3
associated with hyperandrogenemia, which further contrib-
utes to the pathogenesis of IR. Adipocyte hypertrophy is also
associated with reduced catecholamine induced lipolysis in
subcutaneous lipolysis adipocytes [64].
2.4. Adipokines
A link between adiposity, IR, systemic inflammation and
concomitant increased risk of atherosclerosis is provided by a
group of cytokines, secreted by adipose tissue, also called
“adipokines”. The main representatives of this category are
adiponectin and leptin. The former exerts insulin sensitizing
and anti-inflammatory properties; low adiponectin circulat-
ing levels are usually found in obesity and MetS [65]. A meta-
analysis has shown lower adiponectin concentrations in both
lean and obese PCOS women compared with their healthy
counterparts, regardless of the degree of obesity [66]. Specific
adiponectin gene polymorphisms are associated with higher
(T45G) or lower (G276T) risk of PCOS, highlighting a specific
role of this adipokine in the pathogenesis or metabolic
consequences of PCOS [67].
In contrast to adiponectin, leptin has a central and peripheral
regulatory role, by increasing satiety and controlling appetite and
energy expenditure, according to the levels of energy stored as
body fat. High leptin concentrations are associated with systemic
inflammation, IR and high risk of atherosclerosis [65]. A meta-
analysis showed higher leptin levels in PCOS women compared
with their healthy counterparts. This difference was evident in
obese PCOS only, compared with obese non-PCOS, regardless of
BMI. In the non-obese PCOS, leptin levels were moderately higher
compared with non-obese controls [68]. Leptin may also contrib-
ute to hyperandrogenism by promoting steroidogenesis and
inhibiting neuropeptide Y, which leads to high gonadotropin
releasing hormone (GnRH) and lutenizing hormone (LH) levels
[69]. Other adipokines implicated in the pathogenesis of insulin
resistance are resistin, visfatin, apelin, vaspin, chenmerin and
omentin-1 [65], although conflicting data exist regarding their
role in PCOS. Regarding resistin, differences between PCOS and
non-PCOS are not robust, except perhaps in some populations
(i.e. Chinese) [64]. Interestingly, a local role of resistin in PCOS
pathogenesis cannot be excluded, since increased gene expres-
sion has been detected in adipocytes of PCOS patients [64].
Regarding visfatin, contradictory findings exist in studies in PCOS
populations, despite its association with IR, pro-inflammatory
markers and endothelial dysfunction [64,70]. However, increased
gene expression has been reported in both omental and
subcutaneous adipose tissue [64]. Moreover, a recent meta-
analysis showed higher concentrations in PCOS compared with
non-PCOS women, irrespective of BMI, IR and total testosterone
levels [71]. Regarding omentin-1, lower levels have been found
in PCOS compared with healthy controls, by another
recent meta-analysis, associated with HOMA-IR, but without
correlation with BMI and total testosterone concentrations
[72]. With respect to the other adipokines conflicting data
exist in PCOS women [64].
An intriguing role in the pathogenesis of PCOS and its
metabolic consequences, such as IR, emerges for adipose tissue
and its derived adipokines. In addition to their implication in IR
and atherosclerotic disease, these molecules may also affect
sex steroid production and fertility in PCOS women.
37
2.5. Other Metabolic Consequences in PCOS
2.5.1. Non-alcoholic Fatty Liver Disease (NAFLD)
NAFLD constitutes a wide spectrum of pathologic conditions
from simple steatosis, characterized by lipid accumulation in
the liver parenchyma to non-alcoholic steatohepatitis
(NASH), characterized by chronic inflammation and fibrosis
[73]. The prevalence of NAFLD has increasingly risen during
the last decades, affecting 6–45% of the general population. It
is even higher in patients with T2DM (70%) and in morbidly
obese patients (up to 90%). NAFLD and NASH have also been
associated with increased risk of CVD. NAFLD can rarely lead
to cirrhosis and hepatocellular carcinoma. Despite the recent
progress in indices and techniques diagnosing different
stages of NAFLD, liver biopsy remains the gold standard
method [73].
Increased prevalence of NAFLD has also been reported in
PCOS women (27–62%) [74–76]. Notably, an increased preva-
lence of PCOS has been also described in females of reproduc-
tive age with NAFLD [75], suggesting an interplay between these
two conditions or common pathogenetic pathways. IR seems to
play the main pathogenetic role as it has been associated with
the development of NAFLD independently of obesity (BMI or
waist circumference) [76]. Serum androgens seem also to
independently predict NAFLD irrespective of other con-
founders, such as BMI. A recent meta-analysis reported an OR
of 2.54 (95% CI 2.19–2.95), which is higher in those with
hyperandrogenism (classic phenotype) compared to PCOS
women without hyperandrogenism [77]. Despite the well-
established interplay between obesity, IR and NAFLD, this and
other studies [78] highlight the significant and unique contri-
bution of hyperandrogenemia to the metabolic phenotype of
PCOS women. Of course, the presence of IR per se leading to
hyperandrogenemia further contributes indirectly to the path-
ogenesis of NAFLD in PCOS patients. Notably, the prevalence of
advanced liver disease (NASH with fibrosis) in women with
PCOS is higher than their non-PCOS counterparts [79].
2.5.2. Hypertension
Although data are not robust, PCOS women seem to be at
increased risk for hypertension, at least in later post-
reproductive life. In general, the prevalence of hypertension
(mainly systolic) in PCOS premenopausal women is estimated
at 9–25.7%, higher than the general population [80–83]. Older
studies showed higher mean arterial pressure and ambulato-
ry systolic pressure in PCOS compared with non-PCOS
subjects, independently of BMI and IR [83] or no difference at
all in these parameters [84]. Alarmingly, the physiological
nocturnal drop in both systolic and diastolic pressure may not
be observed in 51% and 23% of PCOS women, respectively [82].
Moreover, some studies in postmenopausal women support
the notion that the presence of PCOS during reproductive ages
confers a higher risk for developing hypertension after
menopause [81,85]. Except for obesity and IR, an independent
pathogenetic role of androgens in the prevalence of hyperten-
sion has been suggested through activation of the renin-
angiotensin system [86]. Moreover, others found higher preva-
lence of hypertension in both normo- and hyperandrogenic
women with PCOS compared with healthy controls, indepen-
dently from BMI, suggesting other pathogenetic pathways [87].
38 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 86 ( 20 1 8 ) 3 3– 43
2.5.3. Coagulation Disorders
PCOS has been associated with disturbances in the coagulation
and fibrinolysis systems, suggesting a potential prothrombotic
state, although data are conflicting and emerge from small
studies. Increased levels of plasminogen activator inhibitor 1
(PAI-1) and fibrinogen have been found in PCOS compared with
healthy controls, irrespective of BMI. These disorders of
fibrinolysis and coagulation are associated with low SHBG and
hyperinsulinemia [88]. Impaired global fibrinolytic capacity has
also been confirmed by others using a method based on the
amount of generated D-dimers when fibrinolysis is stopped by
adding aprotinin [89]. However, others did not confirm the
difference in PAI-1 [90]. Regarding other coagulation factors,
such as von Willebrand's factor, factor II, factor VII, protein C,
protein S, factor V Leiden, prothrombin G20210A and anti-
thrombin, no difference between PCOS and non-PCOS has been
demonstrated [89,91,92]. Finally, increased homocysteine con-
centrations have been demonstrated in PCOS, independent of
BMI [93].
The effect of oral contraceptives (OC) in augmenting the
risk of venous thromboembolism should also be taken into
account in women with PCOS (three- to six-fold higher RR,
although the absolute risk seems to be low, depending on the
estrogen dose and the generation of OC (higher with 30 μg/d
of ethinyl-estradiol and the third OC generation) [94]).
Patient's characteristics, such as age, BMI, smoking and
positive family history for thrombophilia should also be
taken into account. BMI does not seem to be significantly
affected by OC or anti-androgens [94]. OC may also increase IR
and alter lipid profile, by increasing Tg and HDL-c and
decreasing LDL-c/HDL-c ratio, although data are inconsistent
and contradictory, depending again on the dose of OC and
patient's characteristics (BMI, age, family history of diabetes)
[94–96]. OC may also increase systemic inflammation, as
indicated by the levels of intercellular adhesion molecule
(ICAM)-1, TNF-α and monocyte chemoattractant protein
(MCP)-1 [96]. OC may be weakly associated with increased
CVD risk, although the quality of evidence is low [94].
Progestogen only pills or hormone releasing intrauterine
devices do not increase the risk of venous thromboembolism.
The risk is increased only when progestogen is combined with
ethinyl-estradiol and is lowest with levonogestrel [97].
3. Cardiovascular Risk in PCOS. Is it Indeed
Increased?
All the aforementioned data suggest an increased cardio-
metabolic risk profile in PCOS women. However, if this risk is
translated into increased risk for cardiovascular events
remains to be established, taking also into account that the
phenotype of PCOS may improve with aging. Well designed,
high quality longitudinal studies are needed, specifically
focusing on the association of the clinical aspects of PCOS,
such as abdominal obesity and IR with CVD risk. Most
prospective studies in the general population have
shown that hyperinsulinemia is independently associat-
ed with the presence of atherosclerosis and CHD [98].
The evidence is not robust for abdominal obesity. This
parameter cannot improve CVD risk prediction, independently
of other traditional factors, such as hypertension, diabetes and
dyslipidemia [99].
Another significant parameter is that the prevalence of
CVD in the young population is very low and strongly
increases during the 50s [1,2]. Several studies indicate an
increased subclinical atherosclerosis in PCOS, by various
indices such as coronary artery calcification scores [60,100],
carotid artery intima-media thickness (CIMT) [101,102] and
endothelial dysfunction measured by flow-mediated dila-
tion (FMD) [101,103], compared with controls, even from
early reproductive ages. Arterial stiffness, another marker
of CVD, is also increased in PCOS women compared with
their non-PCOS counterparts [104]. Meta-analyses have
confirmed these results, despite increased heterogeneity
between studies [105,106]. Interestingly, in one of them,
the decreased FMD in PCOS was not affected by age and
BMI [106].
It must also be noted that most of these studies were
limited by small sample sizes and included young women
of reproductive age. The presence of venous thromboem-
bolism is also associated with a lower risk of developing
atherosclerotic CVD [107]. Except for the traditional CVD
risk factors, androgens may be implicated in the devel-
opment of CVD, although it is not clear if they play a
protective or detrimental role on the cardiovascular
system. Total testosterone and Δ4-androstenedione con-
centrations are positively, whereas DHEAS and SHBG are
negatively, associated with CIMT [102,103]. However,
others found no association between clinical and/or
biochemical hyperandrogenemia and atherosclerotic dis-
ease [104].
Regarding the difference in the incidence of CVD events
between PCOS and non-PCOS, few studies exist. In a
retrospective population based cohort study from Australia
(n = 2566), PCOS women (median age 35.8 years) had more
hospitalizations for ischemic heart disease (0.8 versus 0.2%)
and cerebrovascular disease (0.6 versus 0.2%) compared with
their non-PCOS counterparts [108]. It must be emphasized
that the CVD risk in young ages is very low and a
hospitalization study may overestimate this phenomenon.
One study that reviewed death certificates of 786 women in
the UK (with a diagnosis of PCOS at an average age of
26.4 years and a mean follow-up time of 30 years) failed to
show a statistically significant increase in cardiovascular
mortality [109]. However, it must be noted that the
diagnosis of PCOS was based on historical data during a
period of 49 years (1930–1979) and was not supported by
hormonal assessments. The same authors in a later study,
including 309 postmenopausal women, did not show a
difference in all-cause and CVD mortality neither in
coronary heart disease (CHD), but they did notice a higher
OR for cerebrovascular disease in PCOS women [2.8 (95% CI
1.1–7.1)] [110]. Another retrospective cohort study (n = 309,
mean age 43.7 years, follow-up time 23.7 years) did not
show any difference in CVD events between PCOS and non-
PCOS women [111]. However, another retrospective cohort
study from the UK, including 2301 PCOS women (mean
age 36.3 years) followed for 20 years, showed higher
incidence of myocardial infarction and angina compared
 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 8 6 ( 20 1 8 ) 3 3– 4 3 39

Table 1 – Studies reporting data on cardiovascular disease events in women with PCOS.
Study PCOS (n) Age (yrs) Follow-up (yrs) Design CHD events CVD events Other/total CVD
(author, year) (OR or HR) (OR or HR) events (OR or HR)

Hart, 2015 2566 35.8 14 Retrospective cohort

2.89 (1.68–4.97) 2.58 (1.43–4.67)
Pierpoint, 1998 786 20–74 30 Retrospective cohort
1.40 (0.75–2.40) 0.23 (0.03–0.85)
Wild, 2000 319 56.7 31 Retrospective cohort
1.5 (0.7–2.9) 2.8 (1.1–7.1)
Mani, 2013 2301 36.3 20 Retrospective cohort
From 2.6 (1.0–6.3) to
12.9 (3.4–8.6)
Iftikhar, 2012 309 46.7 23.7 Retrospective cohort 0.74 (0.32–1.72) 1.05 (0.28–3.92) 5.67 (0.51–63.7)
Schmidt, 2011 35 61–79 21 Prospective cohort No difference No difference
with controls with controls
Merz, 2016 25 62.6 9.3 Prospective cohort 0.82 (0.37–1.81)
Wang, 2011 1974 26.9 40 Prospective cohort 1.42 (1.03–1.94) 0.85 (0.49–1.47) 1.21 (0.97–1.52)
[After adjustment for
BMI: 1.35 (0.98–1.85)]
Solomon, 2002 82,479 47.8–48.6 14 Prospective cohort Non-fatal CHD: 1.30 (0.97–1.74)
1.25 (1.07–1.47)
Fatal CHD: 1.67
(1.35–2.06)
de Groot, 2011 83,061 Meta-analysis 2.02 (1.47–2.76)
Zhao, 2016 104,392 20–73.8 7–40 Meta-analysis 1.44 (1.13–1.84) 1.30 (1.09–1.56)

PCOS: polycystic ovary syndrome; CHD: coronary heart disease; CVD: cardiovascular disease; OR: odds ratio; HR: hazard ratio.

with the local female population, with the highest OR in
the group of >65 years old [from 2.6 (95% CI: 1.0–6.3) to 12.9 (CI:
3.4–48.6)] [112].
Data from prospective cohort studies provide stronger
evidence. In one of them, no difference in myocardial
infarction, stroke and mortality was reported between 35
PCOS women (61–79 years) and 120 age-matched controls,
after 21 years of follow-up [85]. In another (n = 295) cohort
study of postmenopausal women, the diagnosis of PCOS
(defined by their premenopausal history) was not associated
with angiographically documented coronary artery disease
(CAD) or mortality [113]. Conversely, another prospective
cohort study demonstrated that women with irregular cycles
(n = 1974) had an increased risk for CHD mortality [age
adjusted hazards ratio (HR) 1.42, 95% CI 1.03–1.94] compared
with women with regular menses. This risk was attenuated
after adjustment for BMI (adjusted HR 1.35, 95% CI 0.98–1.85).
No significant difference was found for CVD and cerebrovas-
cular mortality [114]. However, in another prospective cohort
study (n = 82,479, from the Nurses' Health Study) conducted
on the same concept, women with irregular cycles (n = 1974)
did have an increased risk for non-fatal and fatal CHD
mortality (age adjusted RR 1.25 and 1.67, respectively; 95% CI
1.07–1.47 and 1.35–2.06, respectively), but without difference
for stroke, compared to women with regular menses. This risk
remained significant after adjustment for BMI [115].
To better clarify whether CVD risk is indeed increased in
PCOS compared with non-PCOS women, two meta-analyses
have been conducted so far. The first included five controlled
observational studies, published between 2000 and 2008. The
RR for CHD, including fatal and non-fatal myocardial infarction
or stroke was 2.02 (95% CI 1.47–2.76), which remained signifi-
cant after adjustment for BMI [RR: 1.55 (95% CI 1.27–1.89)] [116].
The other more recent meta-analysis included five case-control

Fig. 1 – Pathogenesis of cardiovascular disease risk in PCOS women.

40 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 86 ( 20 1 8 ) 3 3– 43
and five cohort studies. According to this, the OR for CVD in
PCOS was 1.30 (95% CI 1.09–1.56), without any difference with
respect to study design. Regarding the type of CVD, the OR was
increased for CHD (1.44; 95% CI 1.13–1.84) [117]. The data from
the aforementioned studies are presented briefly in Table 1.
In general, in aged PCOS women the available data are not
sufficient for safe conclusions. The pathogenesis of the
potentially increased CVD risk in PCOS are presented in Fig. 1.
The main findings suggest that the number of CVD events in
aged PCOS patients is similar to those without PCOS or only
marginally increased, but it is lower than that expected on the
basis of risk calculation during younger ages. In general, there is
a discrepancy between CVD risk and late events in aged PCOS,
the mechanisms for which are unclear. Progressive normaliza-
tion of CVD risk during late reproductive age may play a main
role. Furthermore, in the majority of cases, the severity of PCOS
reduces during lifetime, perhaps due to spontaneous reduction
of ovarian and adrenal androgens. The emergence of ovulatory
cycles with aging leads to improvement in lipid profile and
reduction in prevalence of MetS [1,2].
4. Conclusions
PCOS is associated with significant metabolic consequences,
mediated by obesity and IR, but also by independent
pathways. These consequences include increased risk of IGT
and T2DM, atherogenic dyslipidemia, systemic inflammation
due to increased secretion of pro-inflammatory factors by
adipose tissue, NAFLD, hypertension and potential coagula-
tion disorders. Whether this apparent increased CVD risk in
reproductive ages is translated to increased CVD morbidity
and mortality in later life, remains to be established. Data so
far, based on markers of subclinical atherosclerosis, some
retrospective and prospective cohort studies, indicate a
possible increased CVD risk, mainly for CHD.
Conflict of Interest
The authors have no conflict of interest to disclose.
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