CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 50, Number 1, 205–225

r 2007, Lippincott Williams & Wilkins

The Metabolic
Syndrome in
Polycystic Ovary
Syndrome
PAULINA A. ESSAH, MD, MS,*
EDMOND P. WICKHAM, MD,* and
JOHN E. NESTLER, MD* w
*Division of Endocrinology and Metabolism, Department
of Internal Medicine; and w Department of Obstetrics
and Gynecology, Medical College of Virginia Campus,
Virginia Commonwealth University, Richmond, Virginia

Abstract: Approximately one-third to one-half of all
women and adolescent girls with polycystic ovary
syndrome (PCOS) has the metabolic syndrome,
associated with increased risk for cardiovascular
disease and type 2 diabetes. Evidence suggests that
insulin resistance is the likely link between PCOS and
the metabolic syndrome. Early screening for im-
paired glucose tolerance, even in adolescents, is
recommended. Lifestyle modification with increased
physical activity and weight reduction remains first-
line therapy. Insulin-sensitizing drugs may also
ameliorate features of the metabolic syndrome in
PCOS but long-term prospective studies are needed
to determine the role of these drugs in the prevention
of the metabolic syndrome.
Key words: polycystic ovary syndrome, metabolic
syndrome, insulin resistance, hyperandrogenism
Correspondence: Paulina A. Essah, MD, Medical
College of Virginia Campus, Virginia Commonwealth
University, P.O. Box 980111, Richmond, VA 23298-
0111. E-mail: paessah@hsc.vcu.edu
Supported in part by NIH K24HD40237 (J.E.N.).
The polycystic ovary syndrome (PCOS)
affects 6% to 10% of women of repro-
ductive age in the United States,1,2
making it the most common cause of
infertility due to anovulation in women.
PCOS was first described by Drs Irving
Stein and Michael Leventhal in Chicago
when, in 1935, they published a descrip-
tion of 7 case reports of women between
ages 20 to 33 who presented with obesity,
amenorrhea, hirsutism, and bilateral
polycystic ovaries.3 Since that time,
significant insight has been gained into
the pathogenesis, treatment, and compli-
cations of PCOS.
An international consensus group
of the European Society for Human
Reproduction and Embryology and the
American Society for Reproductive
Medicine (ESHRE/ASRM)4 recently
established that PCOS is diagnosed by

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205
206 Essah et al
the presence of at least 2 of the following:
oligo-ovulation or anovulation, clinical or
laboratory evidence of hyperandrogenism,
and polycystic ovaries as defined by
ultrasonography. In addition, the defini-
tion requires the exclusion of other medical
conditions that cause irregular menses and
androgen excess. Although not included in
the diagnostic criteria, it is now well
known that insulin resistance with subse-
quent hyperinsulinemia plays a significant
role in the pathogenesis of PCOS.5 Insulin
acts both directly on the ovary and
indirectly through the pituitary gland to
stimulate ovarian androgen production.6,7
Insulin resistance is also a major
contributor to the development of the
metabolic syndrome, a cluster of meta-
bolic derangements that act synergisti-
cally to increase the risk of cardiovascular
disease. Evidence from prospective popu-
lation studies has determined that the
metabolic syndrome is associated with a
2-fold increase in the relative risk of
atherosclerotic vascular disease and a 5-
fold increase in the relative risk for type 2
diabetes mellitus compared with indivi-
duals without the metabolic syndrome.8
Similarly, women with PCOS frequently
present with components of the metabolic
syndrome and are at increased risk for the
development of cardiovascular disease9–11
and type 2 diabetes mellitus.12–15
This article reviews current knowledge
on the prevalence, predictors, and
characteristics of the metabolic syn-
drome in PCOS as well as evidence for
cardiovascular and diabetes risk in
PCOS. In addition, the clinical evalua-
tion and treatment of the metabolic
syndrome in PCOS are discussed.
Evidence-based Approach
Medline, Pub-Med, and the Cochrane
Library Database were searched for
human studies on the metabolic syn-
drome and PCOS dating from 1985 to
present. Pertinent studies are summar-
ized in Table 3 and classified by level of
evidence based on 5 levels ranging from
high certainty (level I) to decreasing
certainty (level V). Level I is a large
(more than 100 participants), rando-
mized trial with low false-positive or
false-negative errors. Level II is a small,
randomized trial with high false-positives
or low false-negative errors. Level III
is a nonrandomized, concurrent, cohort
comparison between participants who
did and did not receive intervention.
Level IV is a nonrandomized, historical
cohort comparison between participants
who currently received intervention and
past participants who had not received
intervention and Level V is a case series
of more than one individual without
controls.16
Diagnostic Criteria for
Metabolic Syndrome
A clustering of abnormalities associated
with insulin resistance was first described
in 1988 by Dr Gerald Reaven, who
coined the term ‘‘syndrome X.’’17 This
syndrome has since evolved to be also
known as, among other names, the
insulin resistance syndrome, dysmeta-
bolic syndrome, dysmetabolic syndrome
X, and, at present, the metabolic syn-
drome. In 2001, the syndrome was noted
as a legitimate cardiac risk factor and
designated an ICD-9 code of 277.7.18
Numerous diagnostic criteria for the
metabolic syndrome have been sug-
gested, but no single recognized guideline
exists. The most commonly used criteria
in clinical practice and research are those
of the National Cholesterol Education
Program-Adult Treatment Panel III
(NCEP-ATP III).18 The American Heart
Association and the National Heart,
Lung, and Blood Institute8 recently
affirmed the utility and validity of these
criteria with some modification (see
Table 1). Other groups use slightly
 Metabolic Syndrome in PCOS 207

TABLE 1. NCEP-ATP III Diagnostic Criteria for the Metabolic Syndrome

NCEP-ATP III, 2001
Three or more of the following:
Central obesity: waist circumference
>100 cm (40 in) in males, >88 cm
(35 in) in females
Elevated triglycerides: Z150 mg/dL
(1.7 mmol/L)
Reduced HDL-C: <45 mg/dL
(1.0 mmol/L) in males <50 mg/dL
(1.3 mmol/L) in females
Hypertension: blood pressure Z135/
85 mm Hg or on antihypertensive
medication
Elevated fasting plasma glucose:
Z110 mg/dL (6.1 mmol/L)
Modified NCEP-ATP III, 2005
Three or more of the following:
Central obesity: waist circumference >100 cm (40 in) in
males, >88 cm (35 in) in females, but adjust waist
circumference to lower thresholds when individuals or
ethnic groups are prone to insulin resistance.
Elevated triglycerides Z150 mg/dL (1.7 mmol/L) or on
drug treatment for this lipid abnormality
Reduced HDL-C: <45 mg/dL (1.0 mmol/L) in males
<50 mg/dL (1.3 mmol/L) in females, or on drug treatment
for lipid abnormality
Hypertension: systolic blood pressure Z135 mm Hg or
diastolic BP Z85 mm Hg, or on drug treatment for
hypertension
Elevated fasting plasma glucose: Z100 mg/dL (5.6 mmol/L)

different criteria (Table 2), including
the World Health Organization,19 the
European Group for the Study of
Insulin Resistance,20 and the Inter-
national Diabetes Federation.21
Regardless of the diagnostic criteria
used, the fundamental components de-
fining the metabolic syndrome include
central obesity, hypertension, athero-
genic dyslipidemia, and impaired glucose
tolerance or insulin resistance. Other
conditions have been associated with
the metabolic syndrome, including im-
paired vascular regulation (presence of
microalbuminuria or measurement of
endothelial dysfunction), a proinflamma-
tory state (elevated C-reactive protein, or
inflammatory cytokines such as tumor
necrosis factor-a and interleukin-6), and
a prothrombotic state (elevated fibrino-
lytic factors such as plasminogen-activa-
ting factor-1 or elevated clotting factors
such as fibrinogen).21
Pathogenesis of the Metabolic
Syndrome in PCOS
Although the metabolic syndrome and
PCOS have overlapping features and
both increase the risk of cardiovascular
disease, the pathophysiology that may
link the two remains unclear. Some
suggest that PCOS may be an indepen-
dent risk factor for cardiovascular
disease above and beyond that of the
metabolic syndrome.22 Possible theories
regarding the association include: (1)
insulin resistance underlies the pathogen-
esis of both the metabolic syndrome and
PCOS; (2) obesity and related adipose
tissue factors, independently of insulin
resistance, are the major pathogenic
contributors to both conditions; and (3)
vascular and coagulation abnormalities
are the primary pathogenic contributors
to both conditions.
Of these hypotheses, the most popu-
larly supported is that insulin resistance
is the major underlying pathophysiologic
abnormality linking the metabolic syn-
drome and PCOS. Indeed, the comor-
bidities associated with insulin resistance
are well-known to be common to both
conditions. Nevertheless, it is likely
that a combination of various factors
interacts with or results from insulin
resistance to manifest the metabolic
abnormalities of the metabolic syndrome
and PCOS. In addition, genetic suscept-
ibilities and genetic polymorphisms
or mutations likely contribute to the
expression of these manifestations.
208 Essah et al
TABLE 2. Other Diagnostic Criteria for the Metabolic Syndrome
WHO, 1999
Diabetes or impaired fasting
glucose or impaired glucose
tolerance or insulin resistance
(glucose uptake by hyperinsu-
linemic-euglycemic clamp in
lowest 25%)
Plus 2 or more of the following:
Obesity: BMI >30 or waist-
to-hip ratio >0.9 in males or
>0.85 in females
Dyslipidemia: triglycerides Z150
mg/dL (1.7 mmol/L) or HDL-C
<35 mg/dL (0.9 mmol/L) in
males or <45 mg/dL (1.0
mmol/L) in females
Hypertension: blood pressure
>140/90 mm Hg
Microalbuminuria: albumin
excretion>20 mg/min
BP indicates blood pressure; EGIR, European Group for the Study of Insulin Resistance; WHO, World Health Organization.
Metabolic Syndrome in
Women With PCOS
PREVALENCE
Based on the association with insulin
resistance and risks for cardiovascular
disease and type 2 diabetes mellitus, one
could hypothesize that there would be a
greater prevalence of PCOS among
women presenting with the metabolic
syndrome. Korhonen et al23 conducted a
cross-sectional population-based study
of 543 premenopausal women in Finland
to evaluate the sex hormone profile of
women with metabolic syndrome as
defined by the ATP III criteria. Their
results demonstrated that women with
the metabolic syndrome had significantly
higher mean free testosterone levels,
higher free androgen index, and lower
EGIR, 1999 IDF, 2005
Insulin resistance-hyperinsuline- Central obesity (waist circumfer-
mia: top 25% of fasting insulin ence Z94 cm for Europid men
values from nondiabetic popu- and Z80 cm for Europid
lation women, with ethnic specific
values for other groups)
Plus 2 or more of the following: Plus 2 or more of the following:
Central obesity: waist circum- Elevated triglycerides: Z150
ference Z37 in (94 cm) in mg/dL (1.7 mmol/L), or speci-
males or Z32 in (80 cm) in fic treatment for this lipid
females abnormality
Dyslipidemia: triglycerides >177 Reduced HDL-C: <40 mg/dL
mg/dL (2.0 mmol/L) or HDL-C (1.03 mmol/L) in males and
<45 mg/dL (1.0 mmol/L) <50 mg/dL (1.29 mmol/L) in
females, or specific treatment
for this lipid abnormality
Hypertension: blood pressure Elevated BP: systolic blood
Z140/90 mm Hg and/or med- pressure Z130 mm Hg or dia-
ication stolic BP Z85 mm Hg, or
treatment of previously diag-
nosed hypertension
Fasting plasma glucose Z110 Elevated fasting plasma glucose:
mg/dL (6.1 mmol/L) Z100 mg/dL (5.6 mmol/L), or
previously diagnosed type 2
diabetes mellitus
insulin sensitivity compared with women
without the metabolic syndrome, even if
the former group did not exhibit all the
defining characteristics of PCOS.
Conversely, several studies have de-
monstrated a high prevalence of the
metabolic syndrome in women with
PCOS. The prevalence of the metabolic
syndrome in premenopausal women with
PCOS ranges from 33% to 47%. In a
study of 106 women with PCOS, Apri-
donidze et al24 reported a 43% preva-
lence rate, a rate 2-fold higher than the
age-adjusted rate of 24% in women of all
ages in the general US population based
on data from the Third National Health
and Human Examination Survey III
(NHANES III).25 Stratified by decade
of life, the prevalence of metabolic
syndrome in women with PCOS between
ages 20 and 29 was 45% and between

ages 30 and 39 was 53%, compared with
6% and 15%, respectively, in women in
the general US population of the same
age ranges. Notably, the prevalence rate
of the metabolic syndrome in women
with PCOS between ages 30 and 39
(53%) was even higher than the reported
44% rate reported in women aged 60 to
69 years from the NHANES III study.
Other studies have demonstrated simi-
lar prevalence rates of the metabolic
syndrome in PCOS (Table 3). Glueck
et al26 reported a 46% incidence of
metabolic syndrome in a group of 138
women with confirmed PCOS. In a
retrospective study of 129 women with
PCOS and 177 normal controls, Dokras
et al29 discovered that the age-adjusted
prevalence rate of the metabolic syn-
drome in women with PCOS was 47.3%
compared with a 4.3% rate in controls.
Furthermore, they noted that compared
by age group, the prevalence of the
metabolic syndrome was significantly
higher in women with PCOS compared
with controls. Ehrmann et al34 reported
that, after excluding 26 subjects with
diabetes, 33.4% of 394 premenopausal
women with PCOS who participated in a
multicenter trial met the ATP III criteria
for the metabolic syndrome. Further-
more, they demonstrated that the pre-
valence of the metabolic syndrome did
not differ significantly between racial
groups.
CHARACTERISTICS AND
PREDICTORS
Using the NCEP-ATP III metabolic
syndrome criteria, Apridonidze et al24
demonstrated that the majority of wo-
men with PCOS present clinically with at
least one component of the metabolic
syndrome. In their cohort, only 9%
of the women lacked any metabolic
abnormalities. Of the metabolic abnorm-
alities diagnostic of the metabolic syn-
drome, low high-density lipoprotein
cholesterol (HDL-C) occurred most
Metabolic Syndrome in PCOS 209
frequently (68%), followed closely by
elevated body mass index (BMI) and
waist circumference (67%), high blood
pressure (45%), hypertriglyceridemia
(35%), and elevated fasting glucose
(4%). Compared to women with PCOS
who did not meet the diagnostic criteria
of the metabolic syndrome, women with
PCOS and the metabolic syndrome more
frequently demonstrated the phenotypic
feature of acanthosis nigricans, a marker
of insulin resistance. Apridonidze et al24
also reported that PCOS women with the
metabolic syndrome had more hyperan-
drogenemia than PCOS women without
the metabolic syndrome. Similarly,
Ehrmann et al34 determined that testos-
terone concentrations were significantly
related to an increasing trend in the
proportion of women with the metabolic
syndrome, although the trend did not
achieve statistical significance after ad-
justing for BMI (P = 0.056). Both stu-
dies noted that sex hormone binding
globulin levels were lower in PCOS
women with the metabolic syndrome,
likely reflecting differences in insulin
resistance as low sex hormone-binding
globulin levels are associated with a
greater degree of insulin resistance.
Several factors have been shown to
predict the risk of metabolic syndrome
among women with PCOS. Fasting
insulin—although not used to diagnose
metabolic syndrome or PCOS—has been
reported to be twice as high in women
who meet the criteria for both PCOS and
metabolic syndrome compared with
women diagnosed with PCOS alone.34
Ehrmann et al34 demonstrated that
the prevalence of metabolic syndrome
in women with PCOS increased in
proportion to fasting insulin concentra-
tions such that women in the highest
quartile of fasting insulin had a 5-fold
greater chance of having metabolic
syndrome compared with those in the
lowest quartile, even after adjusting for
BMI.
 210
Essah et al
TABLE 3. Prevalence and Characteristics of the Metabolic Syndrome Reported from Recent Studies
Study Design/Subjects Study Subjects Prevalence of MS Major Findings Level of
Evidence

Legro Case-control 44 PCOS vs. 80 controls Not reported Compared with controls, women with PCOS had sig. III
et al26 Mean BMI for PCOS: higher BP values, waist-to-hip ratios, TG, LDL-C,
33 ± 7 kg/m2 and sig. lower HDL-C values. IFG was present in
Mean age for PCOS: 3% and type 2 DM in 3% of women with PCOS
31 ± 6 y
Glueck Prospective 138 PCOS 46% using ATP 86% of women with PCOS had elevated waist III
et al27 Mean age: 31 ± 9 y III criteria circumference, 33%had elevated triglycerides,
Mean BMI: not reported 65% had low HDL-C, 45% with elevated blood
pressure, and 5% with IFG
Taponen Case-control 518 PCOS vs. 1036 con- Not reported Compared with controls, women with PCOS had III
et al28 trols from Northern significantly higher BMI, waist-to-hip ratios, and
Finland lower HDL-C levels. No differences were seen in
Mean BMI for PCOS: total cholesterol, LDL-C, BP, or fasting glucose
27.9 kg/m2 values between the 2 groups
Mean age for PCOS: 31 y
Apridonidze Retrospective 106 PCOS All ages: 43% The majority of women with PCOS (91%) had at III
et al24 Mean BMI for PCOS 20 to 29 y: 45% least one metabolic abnormality present. Sixty-
with MS: 39.3 kg/m2 eight percent of women with PCOS had low HDL-
Mean age for PCOS with Z30 y: 53% C, 67% had elevated BMI, 45% had elevated BP,
MS: 31 y using ATP III 35% had elevated triglyceride levels, 4% had
criteria impaired fasting glucose
Dokras Retrospective 129 PCOS vs. 177 con- PCOS: 47.3% Seventy-two percent of women with PCOS had high III
et al29 case-control trols BMI, 64% had low HDL-C, 47% had elevated
Mean BMI for PCOS: Controls: 4.3% triglycerides, 24% with high BP, and 12% had
not reported but most (P<.001) impaired fasting glucose. Women with PCOS have
obese using ATP III an 11-fold increased risk of the MS compared with
Mean age for PCOS: 28 y criteria age-matched controls
Margolin Case-control Seven PCOS vs. 97 Not reported As compared to postmenopausal women without III
et al30 controls PCOS, postmenopausal women with PCOS had
Mean BMI for PCOS: significantly higher BMI, waist circumference,
26.5 ± 4.6 kg/m2 type 2 DM, and dyslipidemia. There were no
Mean age for PCOS: significant differences in the prevalence of hyper-
56.3 ± 5.5 y tension.
Vural et al31 Case-control 43 PCOS vs. 43 controls PCOS: 2.3% Women with PCOS had significantly higher BMI, III
Ages 18 to 22 using ATP III waist-to-hip ratios, and lower HDL-C levels than
Mean BMI for PCOS: criteria, 11.6% controls. Carotid IMT was also significantly
23.4 ± 4.7 kg/m2 using WHO higher in women with PCOS. No differences were
Mean age for PCOS: criteria seen in total cholesterol, LDL-C, and FG values
21.4 ± 1.8 y between groups
Rabelo Retrospective Thirty-nine Puerto Rican PCOS: 44% Seventy-one percent of women with PCOS had low V
Acevedo women with PCOS using obesity HDL-C, 43% had elevated triglycerides, 37% had
and Vick32 Mean BMI: 36 kg/m2 and other ATP type 2 DM, 36% had elevated BP, and 10% had
Mean age: 29.4 y III criteria impaired glucose tolerance
Vrbikova Retrospective 69 PCOS vs. 73 controls PCOS: 1.6% There was no significant difference in the prevalence III
et al33 Mean BMI for PCOS: Controls: 0% of MS between the groups. Women with PCOS
23.0 kg/m2 using ATP III had significantly higher BMI, waist circumference,
Mean age for PCOS: criteria BP, and total cholesterol values, and significantly
24.0 y lower HDL-C levels. There were no differences in
fasting glucose or triglycerides

Metabolic Syndrome in PCOS

Ehrmann Retrospective 394 PCOS PCOS: 33.4% 80% of women with PCOS had elevated waist II
et al34 multicenter Mean BMI for PCOS using ATP III circumference, 66% had low HDL-C, 32% had
trial with MS: 40.4 kg/m2 criteria elevated triglycerides, 21% had elevated BP, and
Mean age for PCOS with 5% had IFG. Thirty-eight percent of PCOS
MS: 29.2 y women with MS had IGT compared with 19%
of PCOS women without MS
To convert inches to centimeters, multiply by 2.54; to convert triglyceride values to millimoles per liter, multiply by 0.0113; to convert HDL-cholesterol values to millimoles per liter,
multiply by 0.0259; to convert glucose values to millimoles per liter, multiply by 0.0555.
ATP indicates Adult Treatment Panel; BP, blood pressure; DM, diabetes mellitus; IFG, impaired fasting glucose; MS, metabolic syndrome; TG, triglycerides; WHO, World Health
Organization.

211
212 Essah et al
In addition, this same group of investi-
gators reported that obesity, a key
determinant of insulin concentrations,
has an independent effect on the risk
for metabolic syndrome in women with
PCOS. Among their cohort of 394
women with PCOS, women in the high-
est quartile for BMI had a 14-fold
increased chance of having the metabolic
syndrome. Further, they found that
women with PCOS who have a family
history of diabetes meet a greater
number of individual diagnostic criteria
for the metabolic syndrome than
women with a negative family history.
Risk for Type 2 Diabetes
Mellitus in Women With
PCOS
Insulin resistance and compensatory
hyperinsulinemia are well-recognized
pathogenic factors in both metabolic
syndrome and PCOS. Among women
with PCOS, 30% to 40% have impaired
glucose tolerance and 7.5% to 10% have
type 2 diabetes by their fourth dec-
ade.12,13 Legro et al14 recently reported
an annual conversion rate of 16% from
normal to impaired glucose tolerance
among women with PCOS. Data from
the US and Australia suggest the con-
version rate from impaired glucose tol-
erance to frank diabetes is 5- to 10-fold
higher among women with PCOS.12,35
Converse to evidence that women with
PCOS have a high risk of type 2 diabetes,
studies have also revealed that a higher
prevalence of PCOS is present among
premenopausal women with type 2
diabetes. A retrospective study at an
academic diabetes clinic in Virginia36
reported that 27% of premenopausal
women with type 2 diabetes had PCOS.
In addition, a study conducted at a
diabetes clinic in England found an
82% prevalence of anatomically poly-
cystic ovaries on transvaginal ultrasound
in premenopausal women with type 2
diabetes.37
The presence of insulin resistance links
PCOS, metabolic syndrome, and dia-
betes. Lean women seem to have a form
of insulin resistance intrinsic to the
syndrome, whereas obese women have
the intrinsic PCOS-linked insulin resis-
tance as well as the added burden of
insulin resistance due to increased adip-
osity.38,39 Taken as a whole, women with
PCOS are among the cohorts at greatest
risk for the development of diabetes,
with the diagnosis of PCOS almost a
prediabetic condition. Not surprisingly,
the American Association of Clinical
Endocrinologists recommends routine
screening for diabetes with an oral
glucose tolerance test by the age of 30
for all women with PCOS.40
Risk for Cardiovascular
Disease in Women With
PCOS
In comparison with normally cycling
women of similar age, women with PCOS
have been reported to have an increased
prevalence of several cardiovascular risk
factors, including hypertension, dyslipide-
mia, and surrogate markers for early
atherosclerosis. In addition, PCOS has
been associated with evidence of endo-
thelial dysfunction and subclinical cardio-
vascular disease.
The majority of premenopausal
women with PCOS have blood pressures
in the normal range.41 However, com-
pared with controls, women with PCOS
have higher ambulatory daytime systolic
and mean arterial pressures and a higher
prevalence of labile blood pressure in-
dependent of insulin sensitivity, possibly
representing a prehypertensive state.42
Furthermore, overweight adolescents
with PCOS already demonstrate at
an early age abnormalities in nocturnal
blood pressure regulation.43 With

increasing age, the incidence of hyperten-
sion in PCOS rises. Postmenopausal
women with PCOS have a 2-fold in-
creased prevalence of hypertension com-
pared with aged-matched controls.44
Dyslipidemia has been reported to
occur frequently in women with PCOS,
with the abnormal lipoprotein profile
characterized by reduced HDL-C levels,
elevated triglyceride levels, elevated low-
density lipoprotein cholesterol (LDL-C)
levels, and higher LDL-to-HDL ratios.45
Both obese and lean women with PCOS
have dyslipidemia, with lean women
more often presenting with reduced
levels of HDL-C and an HDL-subfrac-
tion known as HDL-2.46 Of note, a low-
HDL-C level is an especially strong
predictor of cardiovascular disease in
women. Additionally, in women with
PCOS, the more atherogenic, small dense
LDL form comprises a larger percentage
of the circulating LDL-C pool compared
with control subjects.47 Prolonged expo-
sure to atherogenic dyslipidemia confers
substantial cardiovascular risk to these
women.
In addition to hypertension and dys-
lipidemia, women with PCOS display
several surrogate markers for early
atherosclerosis and cardiovascular dis-
ease, including increased C-reactive pro-
tein concentrations,48–50 plasminogen-
activator inhibitor type 1,51–54 endothe-
lin-1,55 leukocytes,56 and reduced fibri-
nolysis.57 Furthermore, several studies
have indicated an association of PCOS
with impaired endothelial function.58–60
Arterial endothelial dysfunction, defined
as an abnormal vasodilatory response to
appropriate stimuli, is one of the earliest
markers of arterial damage and plaque
formation in atherosclerosis.61 This
abnormality in endothelial reactivity is
presumably due to altered insulin regula-
tion of endothelial nitric oxide synthesis,
which leads to impaired nitric oxide-
dependent vasodilation. Furthermore,
the presence of peripheral endothelial
Metabolic Syndrome in PCOS 213
dysfunction demonstrates a close rela-
tionship with similar dysfunction in the
coronary circulation and correlates with
angiographic evidence of coronary artery
disease.62,63
Several studies have documented an
increased risk of subclinical cardiovas-
cular disease in women with PCOS. In
1990, Wild et al64 evaluated 102 women
presenting for coronary artery catheter-
ization for past symptoms and signs of
hyperandrogenism and reported that a
history of significant hirsutism and acne
as well as an elevated waist-to-hip ratio
were more common in women with
confirmed coronary artery disease.
Indeed, increased waist circumference
and waist-to-hip ratio are independently
associated with risk of coronary
heart disease even after controlling for
BMI, hypertension, diabetes, and hyper-
lipidemia.65
The extent of coronary artery calcifi-
cation correlates closely with the athero-
sclerotic plaque burden66 and also
predicts an increased risk of cardiac
events.67 Two major anatomic markers
for subclinical cardiovascular disease are
coronary artery calcifications, identified
by electron beam tomography, and
carotid intima-media thickness, deter-
mined by ultrasonography or angiogra-
phy.39 Christian et al68 evaluated 36
premenopausal women with PCOS and
71 ovulatory women between ages 30
and 45 for coronary artery calcifications.
They reported that coronary artery
calcifications were more prevalent in
PCOS women (39%) than in BMI-
matched controls (21%; odds ratio, 2.4;
P = 0.05) or nonobese women of similar
age (9.9%; odds ratio, 5.9; P<0.001).
In a powerful demonstration of the
early atherogenic process in PCOS,
Talbott et al9 revealed increased thicken-
ing of carotid intima-media in middle-
aged women with PCOS compared with
age-matched normal women. In a pros-
pective study of 61 middle-aged women
214 Essah et al
with PCOS and 85 age-matched controls,
this same group of investigators reported
a higher prevalence of coronary artery
calcification and aortic calcification, as
measured by electron beam tomography,
in women with PCOS than controls.69
Orio et al70 also performed an interest-
ing case-control study examining cardio-
vascular risk profile by echocardiography
in 30 asymptomatic young women with
PCOS (<35 years of age) and 30 age and
weight-matched healthy controls. Their
results revealed that independent of
weight, women with PCOS had a higher
left atrium size as well as decreased left
ventricular performance and diastolic fill-
ing, as demonstrated by a lower left
ventricular ejection fraction and a higher
left ventricular mass index, respectively,
compared with controls.
Metabolic Syndrome in
Adolescents With PCOS
Similar to the pattern seen in young adult
women, PCOS is a common cause of
menstrual irregularities in adolescent
girls.71,72 Menstrual irregularities and evi-
dence of clinical hyperandrogenism will be
present in approximately two-thirds of
adolescents with PCOS, and the majority
of adolescents with PCOS are over-
weight.71,72 Because weight gain, increased
hair growth, acne, and menstrual irregula-
rities may represent normal changes
during puberty, the syndrome may be
underdiagnosed in this younger patient
population.71 Although relatively few stu-
dies have specifically reported the preva-
lence of the metabolic syndrome among
adolescents with PCOS, they suggest that
early metabolic abnormalities may be
present in these teenage girls that, when
present in adulthood, are associated with
an increased risk of the development of
type 2 diabetes and cardiovascular disease.
As previously mentioned, no single set
of criteria has been universally accepted
to diagnose metabolic syndrome among
adults, and the various criteria currently
in use cannot simply be applied to the
pediatric population as normal values
for components such as adiposity, blood
pressure, and lipids are age and sex
specific. However, most pediatric
researchers use definitions based on
modified ATP III or World Health
Organization criteria (Tables 1 and 2,
respectively).
Based on modified NCEP-ATP III
criteria (waist circumference Z90th per-
centile for age and sex; blood pressure
Z90th percentile for age, sex, and height;
HDLr40 mg/dL; serum triglycerides
Z110 mg/dL; glucose Z110 mg/dL),
Cook et al73 examined cross-sectional
data from NHANES III and estimated
that metabolic syndrome was present in
2.1% of adolescent girls. However, the
syndrome was present in 28.7% of over-
weight adolescents (BMI Z95th percen-
tile for age and sex). Using slightly
different definitions, other groups have
estimated the prevalence of metabolic
syndrome among overweight adolescents
to be between 23.3% and 38.7%,19–23
reaching approximately 50% in severely
overweight children.74
Other studies have used modified
NCEP-ATP III criteria to estimate the
prevalence of metabolic syndrome
among adolescent girls with PCOS.
Leibel et al75 reported a metabolic
syndrome prevalence of 19.4% among
girls with PCOS, a rate 3-fold higher
than BMI and ethnicity-adjusted rates
previously estimated using the NHANES
III data. When a waist circumference
>88 cm and more broadly defined
abnormalities of glucose homeostasis
(fasting plasma glucose Z100 mg/dL,
impaired glucose tolerance, or type 2
diabetes) were substituted, the preva-
lence of metabolic syndrome increased
to 27.8%. Of note, adolescents with
PCOS meeting metabolic syndrome cri-
teria had significantly higher BMI and

free testosterone levels than those with-
out metabolic syndrome in this study.
In a cohort of 49 adolescents (mean
age 17 ± 2 y) with PCOS, Coviello et al76
reported a metabolic syndrome preva-
lence rate of 37% using the previously
outlined criteria of Cook et al.73 This
already high prevalence rate increased
alarmingly to 63% in those adolescents
with PCOS who also had a BMI >95th
percentile. In contrast, none of the girls
with a normal BMI (<85th percentile)
meet the criteria for metabolic syndrome.
The risk of metabolic syndrome was
increased over 4-fold among adolescents
with PCOS compared with BMI-
matched controls from NHANES III
cohort. Furthermore, among PCOS ado-
lescents, the odds of having metabolic
syndrome increased significantly as
estimates of bioavailable testosterone
increased, even after adjusting for BMI.
Certainly these findings suggest that, like
their adult counterparts, adolescents
with PCOS are at increased risk of
developing the metabolic syndrome, but
the exact impact of the metabolic
changes in adolescents with PCOS
remains to be seen.
The majority of adolescents with
PCOS are overweight, and these young
patients typically have android or central
adiposity,71,72 a key component of meta-
bolic syndrome. Recently, Lee et al77
demonstrated that in children and ado-
lescents, waist circumference predicted
insulin sensitivity as measured by a
hyperinsulinemic-euglycemic clamp after
controlling for BMI. Moreover, nonob-
ese adolescents with PCOS also demon-
strate increased abdominal adiposity. In
a study of 32 nonobese adolescent girls
with PCOS (mean BMI 21.9 ± 0.4 kg/m2;
mean age 14.6 y), Ibanez and de Zegher78
reported that lean girls with PCOS have
approximately twice as much abdominal
fat as measured by dual x-ray absorptio-
metry compared with age and height and
weight-matched controls.
Metabolic Syndrome in PCOS 215
As in adults, overweight adolescent girls
with PCOS display significant insulin
resistance. Despite similar fasting glucose
levels, obese, hyperandrogenemic girls
have higher fasting insulin levels compared
with controls.79 Furthermore, Lewy et al76
demonstrated an approximately 50% re-
duction in in vivo insulin sensitivity in 12
overweight adolescent girls with PCOS
(mean BMI 33.1 ± 1.8 kg/m2) compared
with BMI-matched controls, and this
severe degree of insulin resistance was
compensated by an increase in both first
and second-phase insulin in the PCOS
group. These results suggest an insulin
resistance intrinsic to the syndrome among
adolescents independent of body weight or
central adiposity. Overweight adolescents
with PCOS demonstrate an even greater
burden of insulin resistance than lean
adolescents with PCOS. Silfen et al80
reported a more than 2-fold increase in
fasting insulin levels and a significant
decrease in estimations of insulin sensitiv-
ity in overweight as compared to normal
weight adolescents with PCOS.
As expected by this degree of insulin
resistance, overweight adolescents with
PCOS are at increased risk for the
development of impaired glucose tolerance
and type 2 diabetes.26,81 A study of 27
adolescent girls with PCOS across a range
of BMI (mean BMI 38.4 kg/m2, range 20.4
to 54.4 kg/m2), reported a prevalence of
abnormal glucose tolerance of 33%.82
Eight of the subjects had impaired glucose
tolerance and 1 subject met the criteria for
overt type 2 diabetes. Interestingly, the
leanest subject was among those identified
with impaired glucose tolerance. Of these 9
subjects, only 2 would have been identified
as having abnormal glucose metabolism
based on fasting plasma glucose levels
alone. The progression from normal to
impaired glucose tolerance in adolescents
with PCOS seems to correspond with a
decrease in first-phase insulin secretion
rather than an increase in insulin resistance
based on findings by Arslanian et al.40
216 Essah et al
In summary, adolescent girls with PCOS
have an increased risk of impaired glucose
tolerance and diabetes, but screening tests
based on fasting glucose may not reliably
detect these abnormalities.
Clinical Evaluation of
Metabolic Syndrome
in PCOS
The association of PCOS with insulin
resistance and the consequent increase
in the risk for type 2 diabetes and
cardiovascular disease indicates that
PCOS is not only a reproductive pro-
blem but also a general health problem.
Therefore, evaluation and therapy for
PCOS should not focus only on the
ovulatory dysfunction and hyperandro-
genemia but also on the comorbidities
of the metabolic syndrome associated
with it.
When evaluating women with PCOS,
including younger adolescents, physicians
should assess for the presence of compo-
nents of metabolic syndrome. Therefore,
clinical evaluation should include assess-
ments of blood pressure, waist circumfer-
ence and/or BMI, fasting lipid profile, and
glucose tolerance by a 2-hour oral glucose
tolerance test. Some PCOS experts also
recommend laboratory studies for cardio-
vascular risk markers such as C-reactive
protein and homocysteine. Several studies
have documented that fasting serum
glucose levels may be normal in women
with PCOS despite the presence of im-
paired glucose tolerance or type 2 dia-
betes.82–84 Therefore, the measurement of
fasting serum glucose is not an effective
screening tool to exclude impaired glucose
tolerance and diabetes in women with
PCOS, and that an oral glucose tolerance
test should be performed, particularly in
obese women or adolescents with PCOS
and those with a family history of type 2
diabetes.
TREATMENT
Lifestyle Modification
Reduction of insulin resistance is the
primary goal for treatment of metabolic
syndrome in women with PCOS. Life-
style modification through increased
physical activity and reduction in body
weight, especially waist circumference,
represents the first-line therapy for meta-
bolic syndrome in PCOS. Successful
maintenance of exercise and weight loss
can lower blood pressure, central adip-
osity, and very low density lipoprotein
cholesterol while improving HDL-C and
insulin sensitivity.85
No specific dietary macronutrient com-
position has been shown to confer distinct
benefit beyond the improvements gained
from weight reduction. Hypothesizing that
increased satiation with protein compared
with carbohydrate would facilitate weight
loss and improve insulin sensitivity, Moran
et al86 randomized 28 overweight women
with PCOS to 12 weeks of an energy-
restricted low carbohydrate, high protein
diet versus a low protein, high carbo-
hydrate diet. Both energy-restricted diets
led to similar degrees of weight loss
(6.9 ± 0.8 kg for the low protein diet and
8.5 ± 1.1 kg for the high protein diet) and
subsequent improvement in metabolic
parameters (decreases in total cholesterol
by 8.8%, triglycerides by 12.5%, and
LDL-C by 9.8%) that occurred indepen-
dently of dietary composition. The high
protein diet resulted in minor differential
improvements only for HDL-C, total
cholesterol to HDL-C ratio, and area
under the curve for glucose compared with
the low protein diet.
More recently, Douglas et al87 com-
pared the effects of 3 different eucaloric
diets in 11 women with PCOS ranging in
BMI from 24 to 36 kg/m2: (1) a diet rich
in monounsaturated fatty acids (17%),
(2) a diet low in carbohydrates (43% of
total calories), and (3) a ‘‘standard’’
American Diabetes Association diet

(56% carbohydrates, 31% fat, and 16%
protein). Their results revealed that the
low carbohydrate diet resulted in a
greater decrease in fasting insulin
and acute insulin response to glucose
compared with the other diets, suggest-
ing that a low carbohydrate diet may
improve metabolic outcomes.
In summary, no one dietary composi-
tion has clearly been proven ideal for
women with PCOS. However, one group
has suggested that, based on the evidence
to date, a diet low in saturated fat
and high in fiber from predominantly
low-glycemic-index-carbohydrate foods
is generally suitable for women with
PCOS.88
Insulin-sensitizing Drugs
Pharmacologic reduction in insulin levels
should be considered for management
for obese women who fail weight loss
and for possible prevention of diabetes in
PCOS, particularly among lean women.
Metformin, a biguanide, and the thiazo-
lidinediones, pioglitazone and rosiglita-
zone, have been used to reduce insulin
resistance, though the latter 2 agents are
less acceptable for routine use due to
concerns about their use in pregnancy
associated with their designation as
pregnancy Class C drugs.
Metformin inhibits the output of
hepatic glucose and may influence
ovarian steroidogenesis directly.89 A
meta-analysis of 13 studies examining
metformin use in 543 women reported
significant improvement in levels of
fasting insulin, blood pressure, and
LDL-C independent of weight changes.90
No significant effect of metformin on
HDL-C or triglyceride levels was identi-
fied in this meta-analysis. A Cochrane
review reported similar improvements
in metabolic parameters although there
was no evidence of metformin-induced
weight loss.91 Metformin has also been
reported to reduce serum plasminogen-
activating inhibitor-1,52 reduce C-reac-
Metabolic Syndrome in PCOS 217
tive protein,92 and increase endothelin-
155 levels in women with PCOS. In a
recent randomized, double-blind, place-
bo-controlled trial of 40 obese women
with PCOS, Lord et al93 reported that a
3-month course of metformin significantly
improved lipid profile but had no effect on
visceral adiposity. Among lean women
with PCOS, metformin has been demon-
strated to reduce fasting and glucose-
stimulated insulin levels. Similar benefits
have been observed with metformin treat-
ment among adolescents with PCOS, with
studies demonstrating significant weight
loss,94–96 improved insulin sensitivity,94
decreased testosterone levels,94,95,97 de-
creased total cholesterol,96 and increased
HDL with metformin.97
The thiazolidinediones increase insulin
sensitivity and insulin-stimulated glucose
update in the liver, skeletal muscle, and
adipose tissue, with only modest effects
on hepatic glucose output. Their primary
mechanism of action is via the activation
of g-peroxisome proliferation activator
receptors (PPAR-g receptors). Binding
of thiazolidinediones to these nuclear
receptors induces gene transcription and
activates genes that encode insulin ac-
tion. Data from 8 published trials using
rosiglitazone and 6 published trials using
pioglitazone demonstrate improvements
in insulin sensitivity, endothelial dys-
function, and androgen concentrations
among women with PCOS.91 Thiazolidi-
nediones have not yet been studied in
adolescent patients.
Few studies to date have directly
compared metformin and thiazolidine-
diones for treatment of PCOS. In a
randomized controlled trial, 100 lean
women with PCOS who had no bio-
chemical evidence of insulin resistance
were randomized to 6 months of either
placebo, metformin, rosiglitazone, or a
combination metformin and rosiglita-
zone.98 Systolic blood pressure decreased
significantly in all active treatment
groups [ – 4.1 mm Hg (95% confidence
218 Essah et al
interval (CI) – 4.8, – 3.4) for metformin;
– 2.9 mm Hg (95% CI – 3.7, – 2.1) for
rosiglitazone; and – 4.9 mm Hg (95% CI
– 5.7, – 2.1) for combination therapy].
Weight increased significantly only with
rosiglitazone monotherapy (+ 1.1 kg, CI
0.8-1.5), and the final weight on rosigli-
tazone monotherapy was greater than
with the other therapies (P<0.001).
Fasting serum insulin and indices of
insulin sensitivity improved significantly
after metformin and combination ther-
apy but not after rosiglitazone therapy
alone. Another trial comparing metfor-
min and pioglitazone in obese Mexican
women with PCOS showed no difference
between the 2 drugs with regard to
improving insulin sensitivity and hyper-
androgenism, but pioglitazone was asso-
ciated with an increase in body weight
and BMI whereas metformin promoted
weight loss.99 Still another trial of
30 women with PCOS on 3-months
of therapy reported that although
metformin more significantly improved
hyperandrogenism, rosiglitazone more
significantly improved insulin sensitiv-
ity.100 Effects on lipid profile by
the 2 drugs were found to be similar.
Combination Lifestyle and Metformin
Evidence has demonstrated that a com-
bination of metformin and lifestyle
modification improves the metabolic
profile in women with PCOS to a greater
degree than either measure alone. In a
notable randomized pilot study, Hoeger
et al101 randomized 38 overweight and
obese women with PCOS to a 48-week
course of one of 4 treatment arms:
metformin, placebo, lifestyle and metfor-
min, and lifestyle and placebo. Modest
weight loss occurred in all groups, but
the greatest weight loss occurred in the
combination lifestyle and metformin
group. Although no difference was noted
among groups in area under the curve of
insulin during an oral glucose tolerance
test (the study was not powered to detect
differences in insulin sensitivity), the
weight loss in the combination lifestyle
and metformin group suggests that this
treatment may be more beneficial for
treating metabolic syndrome in PCOS.
Pasquali et al102 reported that 6 months
of treatment with metformin combined
with a hypocaloric diet resulted in a
significant reduction in body weight and
visceral fat mass compared with hypoca-
loric diet and placebo. Other studies,103
but not all104 have also supported meta-
bolic improvements with combination
metformin and dietary weight loss
compared with either alone.
Oral Contraceptives
The traditional treatment for PCOS has
been oral contraceptives, but several
studies suggest that oral contraceptives
may aggravate insulin resistance, de-
crease glucose tolerance, and enhance
cardiovascular risk.91,105–109 A recent
meta-analysis of pertinent studies esti-
mating the risk of cardiac or vascular
arterial events associated with the
current use of low-dose combined oral
contraceptives in the population at large
reported a 1.85-fold increased risk for
myocardial infarction and a 2.12-fold
increased risk for ischemic stroke.97 In
healthy women, the risk of cardiovascu-
lar outcomes is minimal, and the benefits
of contraception outweigh the risks.
However, in contrast to the population
at large, women with PCOS are at a
higher baseline risk for cardiovascular
disease and are traditionally exposed to
oral contraceptives for prolonged peri-
ods of time (sometimes 2 to 3 decades).
Therefore, health providers should
consider the possible use of insulin-
sensitizing agents as first-line therapy
in women with concomitant metabolic
syndrome and, although debatable,
in women with PCOS not requiring
contraception.

Summary
Considerable overlap exists between
PCOS and the metabolic syndrome,
and evidence suggests that insulin resis-
tance rather than obesity is the likely
pathogenic link. One-third to nearly half
of all women diagnosed with PCOS meet
criteria for the metabolic syndrome and
over 90% of all women with PCOS have
at least one adverse cardiovascular risk
factor, suggesting an increased risk of
cardiovascular disease in the syndrome.
Furthermore, these metabolic abnormal-
ities may be already present in adoles-
cence. The insulin resistance associated
with PCOS increases the risk of glucose
intolerance, diabetes, and dyslipidemia,
and treatment improving insulin sensi-
tivity with weight loss and/or pharma-
cotherapy has proven beneficial.
Early screening for glucose intolerance
is essential in all women with PCOS,
even those who are young adolescents.
Long-term prospective studies are
needed to characterize the role of in-
sulin-sensitizing drugs in the chronic
treatment of PCOS and the potential
treatment or prevention of metabolic
syndrome among these women.
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