AACEMetab-CardioPS

INTRODUCTION

Women with polycystic ovary syndrome (PCOS)

constitute the largest group of women at risk for the devel-
opment of cardiovascular disease (CVD) and diabetes.
PCOS is the most common metabolic abnormality in
young women today, occurring in 10% of female patients
of reproductive age (1,2).

The purpose of this position statement is to inform

health care professionals and the public about the need to
identify women with PCOS and, once this diagnosis has
been established, to search for metabolic and cardiovascu-
lar risk factors that may be associated with PCOS.
Physicians should not regard these women as merely hav-
ing cosmetic complaints, or primarily coping with infertil-
ity, but as having potential metabolic disorders that may
be associated with type 2 diabetes mellitus (T2DM) and
cardiovascular events. Although the patient’s immediate
problems and concerns necessitate sensitive attention and
prompt therapy, they should also be seen as an opportuni-
ty to practice proactive preventive medicine. Early case
finding and intervention are expected to result in a
reduction of serious associated medical consequences.
This report will review the available data from studies that
attempt to analyze these risks and their clinical
consequences (3).

DIAGNOSTIC CRITERIA FOR PCOS

A broad range of opinions prevails about the defini-

tion of PCOS. Most authorities in the field accept the

following three criteria as a basis for diagnosis of the
syndrome:

A history of irregular menstrual cycles and anovula-
tion, with onset at puberty. Many investigators
believe that 25% of women with PCOS, in fact, do
have regular menstrual cycles, although these periods
of menstrual bleeding may represent anovulatory
cycles. (Clinical evidence of androgen excess, such
as moderate or severe acne that persists into the late
20s or 30s, hirsutism, and alopecia, is often the initial
presentation to the physician. When such symptoms
are noted, the woman must be questioned regarding
the presence of irregular menstrual cycles.)

The presence of chemically measurable hyperandro-
genism, with documentation of high plasma levels of
ovarian androgens, including total and free testos-
terone (4).

The exclusion of other hormonal disorders with sim-
ilar clinical features, including adult-onset congenital
adrenal hyperplasia, hyperprolactinemia, adrenal or
ovarian androgen-producing adenomas, hypertheco-
sis, and Cushing’s syndrome.

PATHOGENESIS OF PCOS

Genetic studies support the increased frequency of

PCOS in first-degree relatives of affected women. Many
candidate genes have been proposed. Most likely, several
genes are involved in the development of this heteroge-
neous syndrome. Accordingly, many different hypotheses
have been proposed for the pathogenesis of PCOS (5),
including the following:

Hypothalamic-pituitary abnormalities that result in
gonadotropin-releasing hormone and luteinizing hor-
mone dysfunction

A primary enzymatic defect in ovarian or combined
ovarian and adrenal steroidogenesis

A metabolic disorder characterized by insulin resis-
tance in conjunction with compensatory hyperinsu-
linemia that exerts adverse effects on the
hypothalamus, pituitary, ovaries, and, possibly,
adrenal glands

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS

POSITION STATEMENT ON METABOLIC AND CARDIOVASCULAR

CONSEQUENCES OF POLYCYSTIC OVARY SYNDROME

Polycystic Ovary Syndrome Writing Committee

126 ENDOCRINE PRACTICE Vol 11 No. 2 March/April 2005

AACE Position Statement

Abbreviations:
AACE

= American Association of Clinical

Endocrinologists; ACE = American College of
Endocrinology; BMI = body mass index; CRP = C-
reactive protein; CVD = cardiovascular disease; ET-1 =
endothelin-1; HDL = high-density lipoprotein; IGT =
impaired glucose tolerance; IRS = insulin resistance
syndrome; LDL = low-density lipoprotein; PCOS =
polycystic ovary syndrome; T2DM = type 2 diabetes
mellitus; WHR = waist-to-hip ratio

CLINICAL EVALUATION OF PCOS

The history should include a detailed inquiry about

growth and sexual development, menarche, and menstrual
pattern, as well as information to exclude other potential
causes of oligomenorrhea, hirsutism, acne, and infertility.
Physical findings of acanthosis nigricans and a hyperpig-
mented area on the nape of the neck or other areas such as
the axillae or groin are suggestive of insulin resistance.
Measurements of blood pressure, body mass index (BMI),
and waist circumference must be made. Defining the
extent of hirsutism and the degree of acne or alopecia is
also essential.

LABORATORY ASSESSMENT OF
POSSIBLE PCOS

No consensus exists among endocrinologists about

the battery of laboratory tests that must be ordered in the
assessment of women for PCOS. The following are the
most commonly ordered laboratory tests, which are meant
both to confirm the clinical diagnosis of PCOS and to
evaluate for glucose intolerance and cardiovascular risk.
Studies should be performed early in the morning, with the
patient in a fasting state, and, in women with regular
menses, sometime between days 5 and 9 of the menstrual
cycle.

Several determinations of total and free testosterone
levels or a free androgen index performed by a com-
petent laboratory will help assess the status of andro-
gens.

Serum levels of luteinizing hormone and follicle-
stimulating hormone can be determined. An increased
ratio of luteinizing hormone to follicle-stimulating
hormone >2 is found in 60 to 70% of women with
PCOS and is more likely to occur in nonobese than in
obese women.

Measurement of serum sex hormone-binding globulin
may reveal decreased levels in patients with PCOS.

Measurements of serum prolactin, dehydroepiandros-
terone sulfate, and 17

-hydroxyprogesterone will

provide useful information.

A lipid profile can be obtained, including serum high-
density lipoprotein (HDL) and low-density lipopro-
tein (LDL) cholesterol and triglycerides.

Plasma insulin may be measured; clinicians should
remember that methodologic inconsistencies occur
and that insulin levels are not necessary for the diag-
nosis of the insulin resistance syndrome (IRS).

The American Association of Clinical Endo-
crinologists (AACE) and the American College of
Endocrinology (ACE) recommend screening for dia-
betes by age 30 years in all patients with PCOS,
including obese and nonobese women. The risk for
diabetes is further heightened by a family history of
diabetes, a personal history of gestational diabetes,

and obesity, sedentary behavior, and ethnicity.
Determination of a blood glucose level after challenge
with a 75-g load of glucose may be performed. The
usefulness of measuring insulin levels at baseline and
2 hours after administration of glucose is under study.
Under some circumstances, earlier testing before the
age of 30 years may be indicated. Because T2DM
evolves over time, women with PCOS who initially
test negative for diabetes should be periodically
reassessed throughout their lifetime.

Pelvic ultrasonography, although nonspecific, affords
a pretreatment view of the ovaries. The effect of treat-
ment of PCOS can be monitored, in part, by noting
ovarian size, follicle number, endometrial lining, and
possible development of benign ovarian dermoids or
other neoplasms (incidence of approximately 5 to
10%) (6). The finding of morphologic evidence of
polycystic ovaries on pelvic ultrasonography in 23%
of apparently normal women limits its specificity in
the diagnosis of PCOS. Several other endocrine
pathologic conditions may mimic the ovarian mor-
phologic appearance in PCOS. Thus, a history of
oligomenorrhea and evidence of ovarian hyperandro-
genism are key elements in defining PCOS.

PCOS AND IRS

The IRS is defined as a cluster of abnormalities and

clinical syndromes that are much more likely to occur in
patients with insulin resistance than in others (7). It iden-
tifies patients at increased risk for T2DM and cardiovas-
cular disease. The prevalence of insulin resistance and
compensatory hyperinsulinemia is increased in women
with PCOS. Most reports indicate that at least 75% of
women with PCOS fulfill the criteria for IRS (8). Not all
patients with insulin resistance have any or all of the
abnormalities and clinical syndromes of the IRS, and these
abnormalities and clinical syndromes can develop in the
absence of insulin resistance. Nevertheless, the likelihood
that a woman with PCOS will have insulin resistance or
hyperinsulinemia is so substantial that all women with
PCOS should undergo assessment for the adverse out-
comes that constitute the IRS.

Each component of the IRS in the subsequent list is a

risk factor for CVD, with greater risk for T2DM or CVD
(or both) occurring in the presence of more abnormalities.
The importance of this clustering of abnormalities recog-
nized as the IRS prompted AACE to promote the institu-
tion of the International Classification of Diseases code
277.7 for IRS (dysmetabolic syndrome X).

On the basis of the 2003 ACE position statement on

IRS, the identifying features of this syndrome (7,9) are as
follows:

Reduction of serum HDL cholesterol level to <50
mg/dL

Increase in serum triglyceride level to >150 mg/dL

AACE Position Statement on Polycystic Ovary Syndrome, Endocr Pract. 2005;11(No. 2) 127

Hypertension, as defined by a blood pressure >130/85
mm Hg

Insulin resistance and increased tendency to have
T2DM

Fasting glucose level of 110 to 125 mg/dL

Glucose level of 140 to 199 mg/dL 120 minutes after
challenge with 75 g of glucose

Both obesity and physical inactivity are major factors

that work synergistically with the inherent postreceptor
defect and lead to insulin resistance in patients with PCOS
(10). Obesity increases the likelihood of occurrence of
insulin resistance. Although not all obese persons have
insulin resistance, obesity is associated with insulin resis-
tance in the majority of women, and most nonobese
women with PCOS and oligomenorrhea also have insulin
resistance (11). Not all women with insulin resistance
have PCOS (12); this finding may be related to genetic dif-
ferences in susceptibility of the ovary and pancreas.
Obesity is often the trigger that precipitates the symptoms
of PCOS in association with biochemical and clinical
hyperandrogenism.

Insulin resistance may be difficult to assess accurate-

ly in the absence of hyperinsulinemic-euglycemic clamp
studies, particularly in the setting of basal insulin levels in
the normal or high-normal range and in the nonobese sub-
group of women with PCOS. Methods that measure only
fasting glucose and insulin levels (including homeostasis
model assessment and the quantitative insulin sensitivity
check index) may be inaccurate in assessing insulin sensi-
tivity in this group of women (13). Therefore, data are
likely to underestimate the frequency of insulin resistance
in patients with PCOS, who have a unique form of insulin
resistance, and in those with mild insulin resistance and
borderline normal fasting glucose and insulin levels.
Perhaps other hormonal and genetic factors, as well as eth-
nicity, may influence the degree of insulin resistance and
contribute to the conflicting reports of the incidence of
insulin resistance in women with PCOS. Because accurate
assessment of insulin sensitivity is impossible in the clini-
cal practice setting, it is prudent to regard all obese women
as likely having insulin resistance and being at risk for the
IRS and to assume that most nonobese women with PCOS
have the IRS as well (14).
TYPE 2 DIABETES MELLITUS

Impaired glucose tolerance (IGT) and frank diabetes

occur in the presence of insulin resistance when the pan-
creatic beta cell is unable to compensate for the insulin
resistance (15).

The incidences of IGT and T2DM are significantly

increased in women with PCOS. In a study from the
University of Pittsburgh, T2DM was noted in 12.6% of
women with PCOS (who had a mean age of 42 years) in
comparison with 1.4% of matched control subjects (16).
Studies have indicated that, on initial evaluation with a 2-
hour glucose tolerance test, 30 to 40% of patients with

PCOS already have IGT or T2DM (17-19). These findings
may prevail even in young teens with PCOS (18). A high-
er prevalence of IGT and T2DM occurs in obese women
with PCOS, particularly those with a family history of
T2DM.

Oligomenorrhea is a surrogate marker for probable

PCOS and may predict a 2- to 2.5-fold increase in risk for
T2DM, particularly in the presence of a family history of
T2DM (20). In the Nurses’ Health Study, more than
116,000 women 25 to 42 years old underwent follow-up
for 8 years. A 2- to 2.5-fold increased incidence of T2DM
was present in women with a history of oligomenorrhea
(some of whom had severe cystic acne and hirsutism), in
comparison with the women who had regular menses,
although no physician-based diagnosis of PCOS was
made. Obesity increased the frequency of diabetes in this
population. Because approximately 80% of women with
irregular menses have PCOS, these data are highly sug-
gestive that PCOS is a strong risk factor for T2DM, inde-
pendent of but exacerbated by the presence of obesity
(16).

Because the presence of T2DM abolishes the “gender

gap” in coronary artery disease (21) and because patients
with concurrent diabetes and the IRS have the highest
prevalence of coronary artery disease (22), women with
PCOS, the IRS, and diabetes are likely to have not only an
extremely high risk of coronary artery disease but also the
microvascular consequences of uncontrolled diabetes.

Prevention trials have shown that identification of

IGT is important because intensive lifestyle modification,
with or without pharmacologic intervention, will prevent
the progression to overt T2DM and its consequent risks
(23,24). Therefore, AACE and ACE have already includ-
ed PCOS as an important risk factor for diabetes and have
recommended screening for diabetes by age 30 years in all
patients with PCOS (25).

DYSLIPIDEMIA

Women with PCOS are frequently found to have

atherogenic lipid abnormalities that may reflect underly-
ing insulin resistance, as well as the effects of genetics,
ethnicity, obesity, and lifestyle factors. Low HDL (26) and
high triglyceride levels are found in both obese and
nonobese women who have hyperinsulinemia and PCOS
(27,28). The reciprocal relationship of triglycerides and
HDL is strongly associated with insulin resistance in most
populations and is one factor contributing to the accelerat-
ed atherogenesis detected in these patients. A ratio of
triglycerides to HDL of greater than 3.0 appears to predict
insulin resistance effectively (29). Obesity exacerbates the
elevated triglyceride levels in women with PCOS.

Atherogenic modifications of LDL cholesterol toward

smaller, more dense particles have been demonstrated (30)
in 31 women with PCOS, whose mean age was 26 years,
in comparison with LDL cholesterol particles in control
subjects.

128 AACE Position Statement on Polycystic Ovary Syndrome, Endocr Pract. 2005;11(No. 2)

The combination of low HDL and increased LDL

cholesterol levels is often present in women with PCOS.
In a study in central Pennsylvania of 153 obese or over-
weight (BMI >27 kg/m

) and 42 nonobese non-Hispanic

white women with PCOS having a mean age of 28 years,
lipids were compared with those in control subjects of the
same ethnicity and matched for BMI and waist-to-hip ratio
(WHR) (31). The women with PCOS had higher LDL lev-
els than did the control subjects, independent of obesity.

A large-scale epidemiologic study of 244 women with

PCOS (32) demonstrated elevated levels of LDL and
reduced HDL cholesterol levels in the women with PCOS
younger than age 45 years in comparison with matched
control subjects. Beyond 45 years of age, no significant
lipid differences were found between women with PCOS
and control subjects. This early prolonged exposure to
hyperlipidemia is a significant cardiovascular risk factor
in women with PCOS in comparison with their peers who
had normal menstruation.

ENDOTHELIAL DYSFUNCTION

Women with PCOS have impaired endothelial func-

tion due to altered insulin regulation of endothelial nitric
oxide synthesis, which leads to impaired nitric oxide-
dependent vasodilatation. The arterial consequences of
metabolic dysregulation lead to reduced vascular compli-
ance of large vessels as well as reduced vasodilatation. An
abnormal vasodilatory response correlates with long-term
risk for CVD (33).

Diminished alteration in vascular compliance in

response to insulin in brachial arteries, suggesting
impaired insulin action (that is, insulin resistance), was
demonstrated in studies of brachial arteries of young
women with PCOS (mean age, 26 years) in comparison
with control subjects. This finding links insulin resistance
in vascular tissue with endothelial dysfunction, decreased
arterial compliance, and possible later development of
CVD in patients with PCOS (33,34). Increased endothe-
lin-1 (ET-1) levels, a marker for vasculopathy in patients
with insulin resistance (35), have been noted in patients
with PCOS. Plasma ET-1 levels were increased 5-fold in
obese and nonobese subjects with PCOS over those in
control subjects. These increased ET-1 levels may be an
early sign of abnormal vascular reactivity induced by this
vasoconstrictor polypeptide. Administration of 1,700 mg
of metformin daily for 6 months reduced ET-1 and testos-
terone levels; this result suggests that insulin resistance
and hyperandrogenemia potentially contribute to endothe-
lial injury (35).

HYPERTENSION

As patients with PCOS age, they have a higher inci-

dence of hypertension than do matched control subjects
(36-38). Increased systolic blood pressure has been noted
in patients with PCOS. When blood pressure was moni-

tored for 24 hours, women with PCOS had higher daytime
systolic blood pressure, even after adjustment for BMI,
insulin sensitivity, and body fat distribution, in compari-
son with that in matched control subjects (39). The associ-
ation with hyperinsulinemia in both the obese and the
nonobese subjects in that study was of interest.

PROINFLAMMATORY AND
ATHEROGENIC MARKERS

In comparison with control subjects, patients with

PCOS have decreased fibrinolytic activity, higher levels of
plasminogen activator inhibitor-1 (17,40), and increased
C-reactive protein (CRP) levels, all of which are markers
for inflammation and correlate well with an increased risk
for CVD in epidemiologic studies (41-43). Elevated CRP
levels have been found in both obese and nonobese
women with PCOS (42). Treatment directed toward reduc-
tion of cardiovascular risk (smoking cessation, diet,
aspirin, statins, and possibly metformin and thiazolidine-
diones) should probably be more aggressive in those
women with PCOS who have increased CRP levels (7,44).

STUDIES OF CVD IN WOMEN WITH PCOS

Data Suggesting Subclinical CVD Risk

Two major surrogate markers for cardiovascular risk

factors in PCOS are coronary calcifications, identified by
electron beam tomography, and carotid intima-media
thickness, determined by ultrasonography.

A Mayo Clinic study of coronary calcification with

use of electron beam tomography in 36 nondiabetic
women with PCOS, who were 30 to 45 years old, revealed
a mean 3-fold higher level of coronary artery calcification
than in population control subjects (45). In comparison
with obese control subjects, women with PCOS had a 2-
fold increase in coronary artery calcification. A correlation
was found between coronary artery calcification score and
BMI, visceral adiposity, and elevated levels of serum
triglycerides in women with PCOS.

The electron beam tomographic technique for coro-

nary calcium scoring was also used by Talbott et al (46) to
study 102 middle-aged women with PCOS (ages 40 to 61
years; mean age, 46.9) in comparison with 118 control
subjects (mean age, 48.5 years). The mean coronary artery
calcification score for women with PCOS and control sub-
jects was 25.2 and 4.1, respectively. These investigators
found that the presence of PCOS, age, BMI, smoking sta-
tus, increased fasting insulin levels, and low HDL levels
were associated with increased coronary artery calcifica-
tion scores and consequent risk of coronary events. In a
subsequent prospective case-control study, Talbott et al
(47) found that women with PCOS had a higher pre-
valence of both coronary artery calcification and aortic
calcification in comparison with control subjects and had
an increased risk for the metabolic cardiovascular
syndrome.

AACE Position Statement on Polycystic Ovary Syndrome, Endocr Pract. 2005;11(No. 2) 129

Carotid intima-media thickness measured by carotid

ultrasonography is a surrogate marker for coronary risk.
This technique was used to study 125 white women with
PCOS and 142 age- and BMI-matched control subjects
(48). No significant difference in carotid intima-media
thickness was found between control subjects and women
with PCOS who were younger than age 44 years. In con-
trast, women with PCOS who were 45 years of age or
older had a mean carotid intima-media thickness of 0.78
mm in comparison with 0.70 mm in matched control sub-
jects (P = 0.005). The absence of a significant difference
between younger women with PCOS and control subjects
suggests that metabolic alterations in younger women with
PCOS translate into measurable increases in intima-media
thickness by middle age. This occurs despite the well-
known narrowing difference in lipid levels between con-
trol subjects and women with PCOS at the approach of
menopause.

Defined Actual CVD Event Studies

A risk factor model analysis has calculated that

patients with PCOS have a 4-fold to 7-fold higher risk of
myocardial infarction in comparison with age-matched
control subjects (49). This risk factor model analysis was
based on 33 women with PCOS and 132 age-matched con-
trol subjects who underwent assessment in a prospective
population study of 1,462 women in Göteborg, Sweden.
Factors evaluated included age, hypertension, diabetes
mellitus, central obesity, and serum triglyceride concen-
tration.

A profound increase in cardiovascular risk factors is

present in women with PCOS. The aforementioned cohort
of 33 women with PCOS, who had a mean age of 50 years
and a history of a prior ovarian wedge resection, were
compared with 132 age-matched control subjects (37).
Postmenopausal women constituted 30% of the patients
with PCOS and 56% of the control subjects. In compari-
son with the control subjects, the women with PCOS had
the following:

A 7-fold increased prevalence of T2DM (15% versus
2.3% in control subjects)

A 3-fold increased incidence of treated hypertension

A significantly higher WHR

A significant increase in plasma insulin levels and
decrease in sex hormone-binding globulin levels

In a study from the Czech Republic (50), 28 women

with PCOS, who had undergone prior ovarian wedge
resection, were compared with 752 female control subjects
who were 45 to 54 years old. The mean age of both groups
was 51 years, and the groups were matched for BMI,
WHR, hypertension, lipid profiles, and smoking. The fol-
lowing findings in the women with PCOS were reported:

An increased frequency of T2DM—32% versus 8%
of control subjects

An increased frequency of coronary artery disease—
21% versus 5% of control subjects

PCOS was detected by pelvic ultrasonography in 42%

of 143 women younger than age 60 years, who were
undergoing cardiac catheterization for chest pain or valvu-
lar disease (51)—double the frequency in the general
population (52). Patients with PCOS exhibited more
coronary artery segments with >50% stenosis and signifi-
cantly greater clinical heart disease than did women with
normal ovaries ultrasonographically. Ultrasound evidence
of PCOS was associated with clinical hirsutism, elevated
testosterone levels, and a higher incidence of dyslipidemia.

In a study in Holland, increased prevalences of hyper-

tension, diabetes mellitus, and cardiac symptoms were
found in 346 lean (BMI, 24.4 kg/m

) women with PCOS,

who had a mean age of 38.7 years, in comparison with a
population database (53). The prevalence of diabetes mel-
litus in this lean group of women with PCOS was 2.3%,
and the prevalence of hypertension was 9%. Cardiac
symptoms occurred in 3.1% of women with PCOS who
were 45 to 54 years old in comparison with 0.9% in the
control population.

A 10-year follow-up study of a cohort of 127 white

women with PCOS who were older than age 40 years
revealed that 5 of these women had had 8 coronary events,
in comparison with none in a matched control population
of 142 women (54). Cardiac function may be impaired, as
determined by echocardiographic indices, even in young
women (less than 30 years old) with PCOS, independent
of weight (55).

Clinical androgen excess in women may signal a risk

for coronary artery disease. Hirsutism, acne, and an
increased WHR were associated with more severe coro-
nary artery disease on angiography in 102 women older
than age 60 years (56), in comparison with age-matched
nonhirsute women.

Oligomenorrhea is a good surrogate marker for the

potential development of CVD; more than 80% of women
with oligomenorrhea have been thought to have PCOS.
The prospective Nurses’ Health Study of more than
101,000 women linked a history of menstrual irregularity
not only to a 2- to 2.5-fold increase in risk of diabetes mel-
litus (20) but also to an increased risk of mortality due to
fatal coronary artery disease. When 82,439 nurses in this
study underwent surveillance during a mean follow-up
period of 14 years (57), a history of oligomenorrhea (at
ages 20 to 35 years) was associated with a 100% increased
incidence of fatal and 50% increased incidence of nonfatal
coronary artery disease, after adjustment for age, cigarette
smoking, and BMI.

The two following studies did not find an increase in

cardiovascular risk or death rate in women with PCOS, but
the predictive power of these studies may be limited by
methodologic issues.

In the United Kingdom, 786 women diagnosed with

PCOS (in most cases by undergoing a wedge resection of

130 AACE Position Statement on Polycystic Ovary Syndrome, Endocr Pract. 2005;11(No. 2)

the ovaries) between 1930 and 1979 were identified from
hospital records and followed for a mean of 30 years (58).
On analysis of the data, diabetes mellitus was found to be
commonly mentioned as contributing to mortality in this
group with PCOS. The standardized mortality ratio
(observed/expected deaths) for women with PCOS was
0.83 in comparison with the national average of 0.90. The
conclusion was that women with PCOS do not have a
higher-than-average mortality from circulatory disease,
despite the numerous risk factors for CVD.

In a retrospective UK study of 319 women with

PCOS, most of whom had a tissue diagnosis by ovarian
wedge resection (mean age, 57 years; range, 38 to 98), the
incidence of coronary artery disease was not higher than
that among women in the general population (36).
Nonetheless, a 2.5-fold higher incidence of T2DM and
nonfatal cerebrovascular events was noted in comparison
with that in the age- and BMI-matched population-based
control subjects. In this UK study, only 26% of patients
demonstrated obesity (BMI, >30 kg/m

), the mean BMI of

the study subjects being 26 kg/m

. The incidence of

obesity in the United States is higher, ranging from 50 to
60%.

Summary and Synthesis of Data on

Cardiovascular Risk

In summary, several lines of evidence strongly sup-

port the concept that women with PCOS are at high risk
for cardiovascular and metabolic disease.

The prevalences of both T2DM, a myocardial infarc-
tion-equivalent state, and IGT, a condition associated
with increased cardiovascular risk, are substantially
increased in patients with PCOS. Accordingly, the
AACE and ACE recommend screening for diabetes in
all patients with PCOS by age 30 years.

Multiple recognized cardiovascular risk factors are
present in excess in women with PCOS (often several
simultaneously). The result is a higher-than-usual
prevalence of the Adult Treatment Panel III- and
AACE-defined metabolic IRS in patients with PCOS.

Imaging studies in women with PCOS have uniform-
ly identified a higher prevalence of anatomic and
functional abnormalities indicative of existing under-
lying cardiovascular disease or dysfunction in com-
parison with findings in age-matched control subjects.

These observations are remarkable for their abun-

dance, uniformity, and consistency, and they predict an
increased risk for adverse cardiovascular events in patients
with PCOS. To date, however, no prospective longitudinal
study has assessed cardiovascular outcomes specifically in
women with PCOS. Nonetheless, it is notable that a
prospective large-scale study of women with oligomenor-
rhea who underwent follow-up for 1

decades reported a

2-fold increased risk for fatal myocardial infarction in this
population (20). Most likely, a large proportion of these

women had PCOS. Hence, this study provides indirect
confirmation of increased adverse cardiovascular out-
comes in patients with PCOS.

Despite the absence of prospective longitudinal stud-

ies, retrospective epidemiologic studies have been per-
formed to assess cardiovascular outcomes in PCOS.
Unfortunately, these studies have been of variable quality,
and they have differed from one another with respect to
diagnostic criteria, anthropometric and phenotypic charac-
teristics, duration of follow-up, therapeutic intervention
with bilateral wedge resection of the ovaries, and other
factors. Nonetheless, most of these studies have confirmed
an increased risk for adverse cardiovascular outcomes in
patients with PCOS.

Collectively, the foregoing substantive evidence indi-

cates that women with PCOS are at high risk for CVD.
Even in the absence of definitive outcome studies, the evi-
dence supports a strong recommendation that women with
PCOS should undergo comprehensive evaluation for rec-
ognized cardiovascular risk factors and receive appropri-
ate treatment based on findings.

TREATMENT OF PCOS

Well-defined published data indicate a high risk for

development of T2DM and CVD in women with PCOS. In
view of the lack of protective effect of female sex on CVD
risk in patients with diabetes (21,59), the associated risks
of CVD are magnified in women with diabetes who have
PCOS. Clearly, this situation means that PCOS is a gener-
al health disorder of young women, with potential for
reversal of some of the associated risk with early diagno-
sis and treatment (44). Lifestyle modification with weight
loss and exercise, avoidance of tobacco, correction of lipid
abnormalities, and use of metformin may be of value.
Metformin therapy not only reduces hyperinsulinism and
improves steroidogenic dysfunction (60) but also is help-
ful in achieving better regularity of menses and fertility
potential (61). Thiazolidinediones have also been shown
to decrease androgen levels, improve ovulation, and
reduce progression to overt T2DM in patients with PCOS
and IGT (62-64).

In view of the potential for and actual presence of

numerous cardiovascular and metabolic risk factors in
most women with PCOS, the role of the clinical endocri-
nologist is essential in the following:

Early recognition of the syndrome.

Lifestyle modification, with emphasis on the need for
controlled eating patterns and regular aerobic exer-
cise. Encouragement should be offered by an empath-
ic physician, who will monitor the patient carefully
during the course of treatment.

Measurement of glucose (and possibly insulin levels).
An oral glucose challenge may be considered, partic-
ularly in obese women with PCOS and those with a
family history of T2DM.

AACE Position Statement on Polycystic Ovary Syndrome, Endocr Pract. 2005;11(No. 2) 131

Detection and treatment of lipid abnormalities, with
dietary measures first and then use of appropriate
medications, such as a statin, fibrate, niacin, or eze-
timibe (or some combination of these agents), as nec-
essary.

Careful attention to and treatment of blood pressure
abnormalities.

Measurement of atherogenic markers (CRP, fibrino-
gen, and possibly homocysteine).

Consideration of metformin therapy as the initial
intervention in most women with PCOS, particularly
in those who are overweight or obese. Metformin
improves many metabolic abnormalities in PCOS and
may improve menstrual cyclicity and the potential for
pregnancy. Of note, metformin has not been approved
by the US Food and Drug Administration for use in
PCOS, although abundant medical literature supports
its efficacy.

The use of a nonandrogenic oral contraceptive agent
and an antiandrogen such as spironolactone for the
skin manifestations of PCOS. The presence of hair
thinning requires the maximal dose of spironolactone
in conjunction with an oral contraceptive agent.
Ancillary use of electrolysis and laser therapy may
also be helpful.

The use of thiazolidinediones in patients with IGT or
frank diabetes. The use of these agents to improve
hyperandrogenism and ovulation is considered only
investigational at this time. Thiazolidinediones are
category C drugs; their use is contraindicated during
pregnancy.

REFERENCES

Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer

ES, Yildiz BO. The prevalence and features of the poly-
cystic ovary syndrome in an unselected population. J Clin
Endocrinol Metab. 2004;89:2745-2749.

Hart R, Hickey M, Franks S. Definitions, prevalence and
symptoms of polycystic ovaries and polycystic ovary syn-
drome. Best Pract Res Clin Obstet Gynaecol. 2004;18:671-
683.

Legro RS. Polycystic ovary syndrome and cardiovascular
disease: a premature association? Endocr Rev. 2003;
24:302-312.

Ayala C, Steinberger E, Smith KD, Rodriguez-Rigau L,

Petak SM. Serum testosterone levels and reference ranges
in reproductive-age women. Endocr Pract. 1999;5:322-
329.

Futterweit W. Pathophysiology of polycystic ovarian syn-
drome. In: Redmond GP, ed. Androgenic Disorders. New
York: Raven Press, 1995: 77-166.

Futterweit W, Scher J, Nunez AE, Strauss L, Rayfield

EJ. A case of bilateral dermoid cysts, insulin resistance,
and polycystic ovarian disease: association of ovarian
tumors with polycystic ovaries with review of the litera-
ture. Mt Sinai J Med. 1983;50:251-255.

Insulin Resistance Syndrome Task Force. American
College of Endocrinology position statement on the insulin
resistance syndrome. Endocr Pract. 2003;9:236-252.

Glueck CJ, Papanna R, Wang P, Goldenberg N, Sieve-

Smith L. Incidence and treatment of the metabolic syn-
drome in newly referred women with confirmed polycystic
ovarian syndrome. Metabolism. 2003;52:908-915.

Expert Panel on Detection, Evaluation, and Treatment

of High Blood Cholesterol in Adults. Executive
Summary of the Third Report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III). JAMA. 2001;285:
2486-2497.

10.

McLaughlin T, Abbasi F, Kim HS, Lamendola C,

Schaaf P, Reaven G. Relationship between insulin resis-
tance, weight loss, and coronary heart disease risk in
healthy, obese women. Metabolism. 2001;50:795-800.

11.

Dunaif A, Segal KR, Futterweit W, Dobrjansky A.
Profound peripheral insulin resistance, independent of obe-
sity, in polycystic ovary syndrome. Diabetes. 1989;38:
1165-1174.

12.

Ovalle F, Azziz R. Insulin resistance, polycystic ovary
syndrome, and type 2 diabetes mellitus. Fertil Steril. 2002;
77:1095-1105.

13.

Diamanti-Kandarakis E, Kouli C, Alexandraki K,

Spina G. Failure of mathematical indices to accurately
assess insulin resistance in lean, overweight, or obese
women with polycystic ovary syndrome. J Clin Endocrinol
Metab. 2004;89:1273-1276.

14.

Nestler JE. Insulin resistance syndrome and polycystic
ovary syndrome. Endocr Pract. 2003;9(Suppl 2):86-89.

15.

Dunaif A, Finegood DT. Beta-cell dysfunction indepen-
dent of obesity and glucose intolerance in the polycystic
ovary syndrome. J Clin Endocrinol Metab. 1996;81:942-
947.

16.

Talbott EO, Zborowski JV, Boudreaux MY. Do women
with polycystic ovary syndrome have an increased risk of
cardiovascular disease? Review of the evidence. Minerva
Ginecol. 2004;56:27-39.

17.

Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan

MK, Imperial J. Prevalence of impaired glucose tolerance
and diabetes in women with polycystic ovary syndrome.
Diabetes Care. 1999;22:141-146.

18.

Legro RS, Kunselman AR, Dodson WC, Dunaif A.
Prevalence and predictors of risk for type 2 diabetes melli-
tus and impaired glucose tolerance in polycystic ovary syn-
drome: a prospective, controlled study in 254 affected
women. J Clin Endocrinol Metab. 1999;84:165-169.

19.

Palmert MR, Gordon CM, Kartashov AI, Legro RS,

Emans SJ, Dunaif A. Screening for abnormal glucose tol-
erance in adolescents with polycystic ovary syndrome. J
Clin Endocrinol Metab. 2002;87:1017-1023.

20.

Solomon CG, Hu FB, Dunaif A, et al. Long or highly
irregular menstrual cycles as a marker for risk of type 2
diabetes mellitus. JAMA. 2001;286:2421-2426.

21.

Mak KH, Haffner SM. Diabetes abolishes the gender gap
in coronary heart disease. Eur Heart J. 2003;24:1385-1386.

22.

Alexander CM, Landsman PB, Teutsch SM, Haffner

SM (Third National Health and Nutrition Examination

Survey [NHANES III], National Cholesterol Education

Program [NCEP]). NCEP-defined metabolic syndrome,
diabetes, and prevalence of coronary heart disease among
NHANES III participants age 50 years and older. Diabetes.
2003;52:1210-1214.

23.

Knowler WC, Barrett-Connor E, Fowler SE, et al

(Diabetes Prevention Program Research Group).
Reduction in incidence of type 2 diabetes with lifestyle
intervention or metformin. N Engl J Med. 2002;346:393-
403.

132 AACE Position Statement on Polycystic Ovary Syndrome, Endocr Pract. 2005;11(No. 2)

24.

Azen SP, Peters RK, Berkowitz K, Kjos S, Xiang A,

Buchanan TA. TRIPOD (Troglitazone in the Prevention
of Diabetes): a randomized, placebo-controlled trial of
troglitazone in women with prior gestational diabetes mel-
litus. Contrl Clin Trials. 1998;19:217-231.

25.

ACE Consensus Statement Writing Committee.
American College of Endocrinology consensus statement
on guidelines for glycemic control. Endocr Pract. 2002;
8(Suppl 1):5-11.

26.

Wild RA, Painter PC, Coulson PB, Carruth KB,

Ranney GB. Lipoprotein lipid concentration and cardio-
vascular risk in women with polycystic ovary syndrome. J
Clin Endocrinol Metab. 1985;61:946-951.

27.

Talbott E, Clerici A, Berga SL, et al. Adverse lipid and
coronary heart disease risk profiles in young women with
polycystic ovary syndrome: results of a case-control study.
J Clin Epidemiol. 1998;51:415-422.

28.

Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in
polycystic ovary syndrome correlates with increased car-
diovascular risk independent of obesity. Fertil Steril. 2000;
73:150-156.

29.

McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola

C, Reaven G. Use of metabolic markers to identify over-
weight individuals who are insulin resistant. Ann Intern
Med. 2003;139:802-809.

30.

Dejager S, Pichard C, Giral P, et al. Smaller LDL parti-
cle size in women with polycystic ovary syndrome com-
pared to controls. Clin Endocrinol (Oxf). 2001;54:455-462.

31.

Legro RS, Kunselman AR, Dunaif A. Prevalence and
predictors of dyslipidemia in women with polycystic ovary
syndrome. Am J Med. 2001;111:607-613.

32.

Talbott E, Guzick D, Clerici A, et al. Coronary heart dis-
ease risk factors in women with polycystic ovary syn-
drome. Arterioscler Thromb Vasc Biol. 1995;15:821-826.

33.

Paradisi G, Steinberg HO, Hempfling A, et al.
Polycystic ovary syndrome is associated with endothelial
dysfunction. Circulation. 2001;103:1410-1415.

34.

Kelly CJ, Speirs A, Gould GW, Petrie JR, Lyall H,

Connell JM. Altered vascular function in young women
with polycystic ovary syndrome. J Clin Endocrinol Metab.
2002;87:742-746.

35.

Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I.
Increased endothelin-1 levels in women with polycystic
ovary syndrome and the beneficial effect of metformin
therapy. J Clin Endocrinol Metab. 2001;86:4666-4673.

36.

Wild S, Pierpoint T, McKeigue P, Jacobs H.
Cardiovascular disease in women with polycystic ovary
syndrome at long-term follow-up: a retrospective cohort
study. Clin Endocrinol (Oxf). 2000;52:595-600.

37.

Dahlgren E, Johansson S, Lindstedt G, et al. Women
with polycystic ovary syndrome wedge resected in 1956 to
1965: a long-term follow-up focusing on natural history
and circulating hormones. Fertil Steril. 1992;57:505-513.

38.

Conway GS, Agrawal R, Betteridge DJ, Jacobs HS.
Risk factors for coronary artery disease in lean and obese
women with the polycystic ovary syndrome. Clin
Endocrinol (Oxf). 1992;37:119-125.

39.

Holte J, Gennarelli G, Berne C, Bergh T, Lithell H.
Elevated ambulatory day-time blood pressure in women
with polycystic ovary syndrome: a sign of a pre-hyperten-
sive state? Hum Reprod. 1996;11:23-28.

40.

Ehrmann DA, Schneider DJ, Sobel BE, et al.
Troglitazone improved defects in insulin action, insulin
secretion, ovarian steroidogenesis, and fibrinolysis in
women with polycystic ovary syndrome. J Clin Endocrinol
Metab. 1997;82:2108-2116.

41.

Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM,

Sattar N. Low grade chronic inflammation in women with

polycystic ovarian syndrome. J Clin Endocrinol Metab.
2001;86:2453-2455.

42.

Boulman N, Levy Y, Leiba R, et al. Increased C-reactive
protein levels in the polycystic ovary syndrome: a marker
of cardiovascular disease. J Clin Endocrinol Metab.
2004;89:2160-2165.

43.

Ridker PM. Clinical application of C-reactive protein for
cardiovascular disease detection and prevention.
Circulation. 2003;107:363-369.

44.

Nestler JE. Polycystic ovarian syndrome: metabolic and
cardiovascular complications. In: Kreisberg RA, program
director. Clinical Endocrinology Update 2003 Syllabus.
Chevy Chase, MD: The Endocrine Society Press, 2003:
299-303.

45.

Christian RC, Dumesic DA, Behrenbeck T, Oberg AL,
Sheedy PF II, Fitzpatrick LA. Prevalence and predictors
of coronary artery calcification in women with polycystic
ovary syndrome. J Clin Endocrinol Metab. 2003;88:2562-
2568.

46.

Talbott E, Zborowski JV, McHugh-Pemu K, et al.
Metabolic cardiovascular syndrome and its relationship to
coronary calcification in women with polycystic ovarian
syndrome. Presented at: 3rd International Workshop on
Insulin Resistance, February 17-19, 2003, New Orleans,
LA.

47.

Talbott EO, Zborowski JV, Rager JR, Boudreaux MY,
Edmundowicz DA, Guzick DS. Evidence for an associa-
tion between metabolic cardiovascular syndrome and coro-
nary and aortic calcification among women with polycystic
ovary syndrome. J Clin Endocrinol Metab. 2004;89:5454-
5461.

48.

Talbott EO, Guzick DS, Sutton-Tyrrell K, et al.
Evidence for association between polycystic ovary syn-
drome and premature carotid atherosclerosis in middle-
aged women. Arterioscler Thromb Vasc Biol.
2000;20:2414-2421.

49.

Dahlgren E, Janson PO, Johansson S, Lapidus L, Oden
A. Polycystic ovary syndrome and risk for myocardial
infarction: evaluated from a risk factor model based on a
prospective population study of women. Acta Obstet
Gynecol Scand. 1992;71:599-604.

50.

Cibula D, Cifkova R, Fanta M, Poledne R, Zivny J,
Skibova J. Increased risk of non-insulin dependent dia-
betes mellitus, arterial hypertension and coronary heart dis-
ease in perimenopausal women with a history of the
polycystic ovary syndrome. Hum Reprod. 2000;15:785-
789.

51.

Birdsall MA, Farquhar CM, White HD. Association
between polycystic ovaries and extent of coronary artery
disease in women having cardiac catheterization. Ann
Intern Med. 1997;126:32-35.

52.

Polson DW, Adams J, Wadsworth J, Franks S.
Polycystic ovaries—a common finding in normal women.
Lancet. 1988;1:870-872.

53.

Elting MW, Korsen TJ, Bezemer PD, Schoemaker J.
Prevalence of diabetes mellitus, hypertension and cardiac
complaints in a follow-up study of a Dutch PCOS popula-
tion. Hum Reprod. 2001;16:556-560.

54.

Talbott E, Zborowski J, Boudreaux M. Polycystic ovary
syndrome (PCOS): the effect on cardiovascular health and
disease risk. In: Daya S, Harrison RF, Kempers RD, eds.
Advances in Fertility and Reproductive Medicine:
Proceedings of the 18th World Congress on Fertility and
Sterility, Montreal, Canada, May 23-28, 2004.
International Congress Series, 1266. New York, NY:
Elsevier, 2004: 233-240.

AACE Position Statement on Polycystic Ovary Syndrome, Endocr Pract. 2005;11(No. 2) 133

55.

Orio F Jr, Palomba S, Cascella T, et al. Early impair-
ment of endothelial structure and function in young nor-
mal-weight women with polycystic ovary syndrome. J Clin
Endocrinol Metab. 2004;89:4588-4593.

56.

Wild RA, Grubb B, Hartz A, Van Nort JJ, Bachman W,
Bartholomew M. Clinical signs of androgen excess as risk
factors for coronary artery disease. Fertil Steril.
1990;54:255-259.

57.

Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle
irregularity and risk for future cardiovascular disease. J
Clin Endocrinol Metab. 2002;87:2013-2017.

58.

Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs

HS. Mortality of women with polycystic ovary syndrome
at long-term follow-up. J Clin Epidemiol. 1998;51:581-586.

59.

Gu K, Cowie CC, Harris MI. Diabetes and decline in
heart disease mortality in US adults. JAMA. 1999;281:
1291-1297.

60.

Nestler JE, Jakubowicz DJ. Lean women with polycystic
ovary syndrome respond to insulin reduction with decreas-
es in ovarian P450c17 alpha activity and serum androgens.
J Clin Endocrinol Metab. 1997;82:4075-4079.

61.

Nestler JE, Stovall D, Akhter N, Iuorno MJ,
Jakubowicz DJ. Strategies for the use of insulin-sensitiz-
ing drugs to treat infertility in women with polycystic
ovary syndrome. Fertil Steril. 2002;77:209-215.

62.

Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y,
Kurabayashi T, Tanaka K. Effect of troglitazone on
endocrine and ovulatory performance in women with
insulin resistance-related polycystic ovary syndrome.
Fertil Steril. 1999;71:323-327.

63.

Belli SH, Graffigna MN, Oneto A, Otero P, Schurman
L, Levalle OA. Effect of rosiglitazone on insulin resis-
tance, growth factors, and reproductive disturbances in
women with polycystic ovary syndrome. Fertil Steril.
2004;81:624-629.

64.

Baillargeon JP, Jakubowicz DJ, Iuorno MJ,
Jakubowicz S, Nestler JE. Effects of metformin and
rosiglitazone, alone and in combination, in nonobese
women with polycystic ovary syndrome and normal
indices of insulin sensitivity. Fertil Steril. 2004;82:893-
902.

134 AACE Position Statement on Polycystic Ovary Syndrome, Endocr Pract. 2005;11(No. 2)