Best Practice & Research Clinical Endocrinology & Metabolism

Vol. 20, No. 2, pp. 245–260, 2006

doi:10.1016/j.beem.2006.02.003
available online at http://www.sciencedirect.com

Prevention of diabetes and cardiovascular

disease in women with PCOS: Treatment with
insulin sensitizers

Susmeeta T. Sharma MBBS

Research Intern, Division of Endocrinology and Metabolism

John E. Nestler* MD
William G. Blackard Professor of Medicine; Chair, Division of Endocrinology and Metabolism, and Vice Chair,
Department of Internal Medicine
Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980111, Richmond, VA 23298-0111, USA

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in United
States, affecting 6–10% of females in the reproductive age group. Recent studies have shown that
insulin resistance plays an important role in the pathogenesis of PCOS. Traditionally, management
of PCOS consisted mainly of ovulation induction, treatment of acne and hirsutism, and prevention
of endometrial cancer. However, with mounting evidence showing that PCOS is associated with
dysmetabolic syndrome and an increased risk for developing diabetes and heart disease, this can
no longer be our sole focus. Current data support a strong recommendation that women with
PCOS should undergo comprehensive evaluation for diabetes and recognized cardiovascular risk
factors and receive appropriate treatment as needed. Lifestyle modifications remain the first-line
therapy for all obese women with PCOS. However, many obese women with PCOS find weight
loss difficult to achieve and maintain, and this is not an option for lean women with PCOS. For
these reasons, insulin-sensitizing drugs are proving to be a promising and unique therapeutic
option for chronic treatment of PCOS.

Key words: polycystic ovary syndrome; insulin resistance; type 2 diabetes; cardiovascular
disease; insulin-sensitizing drugs; metformin; thiazolidinediones

Polycystic ovary syndrome (PCOS) is the most common cause of female infertility due
to anovulation in the United States, affecting about 6–10% of women of reproductive
age.1,2 It is characterized by chronic anovulation and hyperandrogenism—either in the

* Corresponding author. Tel.: C1 804 828 9695; Fax: C1 804 828 8389.
E-mail addresses: susmeetasharma@yahoo.com, nestler@hsc.vcu.edu (J.E. Nestler).

1521-690X/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved.
246 S. T. Sharma and J. E. Nestler

form of biochemical androgen excess or clinically as hirsutism, acne and/or male-

pattern alopecia. Although the syndrome was described more than half a century ago,
the underlying cause of the disorder continues to be uncertain. However, recent
studies have afforded a better understanding of its pathophysiology and are helping to
form more effective strategies for management of the disorder.
Until recently, the main concerns in women with PCOS were menstrual irregularity,
hirsutism, and infertility. Treatment of PCOS in women who did not desire pregnancy
typically consisted of oral contraceptive pills to induce cyclical menstruation,
administered with or without an anti-androgen such as spironolactone to ameliorate
the signs and symptoms of hyperandrogenism. Women with PCOS who were
interested in fertility were usually treated with clomiphene citrate to induce ovulation.
However, recent studies have clearly shown that insulin resistance is an integral part
of PCOS, and that women with PCOS are at a higher risk for diabetes and heart disease
than the general population. Moreover, clinical trials have shown that low-dose oral
contraceptives increase the incidence of cardiovascular events and may aggravate
insulin resistance and induce glucose intolerance in women. In the light of these
findings, hirsutism and infertility can no longer be the sole considerations when
choosing long-term pharmacological therapy, and the goals of treatment in PCOS need
to be reconsidered.
Our aim here is to emphasize that women with PCOS should no longer be regarded
as merely having reproductive or cosmetic problems, but as having a metabolic disorder
that potentially puts them at high risk for developing diabetes and heart disease. We will
also review the current data, and formulate recommendations for prevention of these
long-term problems.

INSULIN RESISTANCE AND PCOS

Stein and Leventhal, between 1925 and 1935, were the first to recognize an association
between bilateral polycystic ovaries and signs of amenorrhea, hirsutism, and obesity.
These manifestations were at that time combined together under the diagnosis
of Stein–Leventhal syndrome.3,4 Since then, after intense investigations and multiple
clinical and biochemical studies, a broad range of endocrine and biological
manifestations has been added to form what is now known as the polycystic ovary
syndrome or PCOS. Perhaps the most important advance has been recent evidence
of the central role of insulin resistance and compensatory hyperinsulinemia in the
pathogenesis of the syndrome. Numerous studies have documented the presence of
insulin resistance in both obese and lean women with PCOS.5–8 Lean women with
PCOS seem to have a form of insulin resistance that is intrinsic to the syndrome and
also poorly understood.9–11 Obese women with PCOS not only have this intrinsic form
of insulin resistance but have the added burden of insulin resistance due to excess
adiposity.12
Insulin resistance has been associated with an increased risk of several disorders,
including diabetes mellitus type 2, hypertension, dyslipidemia, elevated plasminogen
activator inhibitor type I (PAI-1), elevated endothelin-1, endothelial dysfunction, and
heart disease. This clustering of abnormalities with insulin resistance has been termed
syndrome X, insulin resistance syndrome (IRS), or dysmetabolic syndrome.13,14 The
National Cholesterol Education Project’s Adult Treatment Panel III has recently
recognized this syndrome as a major cardiac risk factor and has assigned a separate
 Prevention of diabetes and cardiovascular disease in PCOS 247

ICD-9 code (277.7) to the syndrome.15 In light of its association with insulin resistance,
PCOS is now considered a part of the dysmetabolic syndrome in women. Therefore,
PCOS should be regarded as a general health disorder in women instead of just a
cosmetic or fertility problem. Given that an estimated 6 million women of childbearing
age in the United States may have PCOS, it may arguably be one of the most serious and
prevalent general health concerns of young women.

PCOS AND RISK FOR TYPE 2 DIABETES MELLITUS

Insulin resistance has been recognized as a risk factor for diabetes and may be the
earliest detectable abnormality in individuals who proceed to develop diabetes.
Women with PCOS are now known to be an insulin-resistant group that is at markedly
high risk for developing diabetes.
Prospective clinical studies conducted in the United States have demonstrated a
31–35% prevalence of impaired glucose tolerance and a 7.5–10.0% prevalence of type 2
diabetes mellitus in women with PCOS.16,17 Considering that this is a group of young
women of reproductive age with an expected prevalence of type 2 diabetes of 0.7%, this
is an extremely high prevalence rate. Studies conducted both in the United States and
Australia have also shown that the rate of conversion from impaired glucose tolerance
to frank diabetes mellitus is increased by 5–10-fold in women with PCOS.16,18 A recent
controlled study in the US demonstrated an annual conversion rate from normal
glucose tolerance to impaired glucose tolerance of 16% in women with PCOS.19
Oligomenorrhea is a highly predictive surrogate marker for PCOS, and it is thought
that a woman with eight or fewer menstrual cycles per year has at least an 80% chance
of having PCOS. It has recently been found that oligomenorrhea predicts a 2–2.5-fold
increase in risk for type 2 diabetes mellitus. In the Nurses’ Health Study, more than
101 073 women in the age group of 25–42 years were followed over an 8-year period.
The rate of conversion to type 2 diabetes was found to be approximately 2-fold greater
in women with a history of oligomenorrhea in comparison with women who had
regular menses.20 This was regardless of whether the oligomenorrheic women were
obese or lean, indicating that oligomenorrhea was an independent predictor of type 2
diabetes. Although no physician-based diagnosis of PCOS was made in the study,
considering that almost 80% of women with irregular menses have PCOS, these data
are highly suggestive that PCOS is a strong risk factor for diabetes.
The idea that PCOS is associated with a substantial risk for type 2 diabetes is further
supported by studies that have looked at this from the opposite perspective, i.e. is there
a higher prevalence of PCOS among pre-menopausal women with type 2 diabetes?
A retrospective study at an academic diabetes clinic in Virginia revealed that 27% of
pre-menopausal women with type 2 diabetes had PCOS.21 Another study conducted in
a diabetes clinic in England found an 82% prevalence of anatomically polycystic ovaries
on transvaginal ultrasound in pre-menopausal women with type 2 diabetes.22
Collectively, the above findings indicate that women with PCOS constitute one of
the groups at highest risk for the development of diabetes and that PCOS is almost a
pre-diabetic stage.
Prevention trials have shown that early identification of impaired glucose tolerance,
and intervention in the form of lifestyle modification and/or pharmacological agents,
can prevent the progression to frank diabetes mellitus.23 In light of these findings,
the American Association of Clinical Endocrinologists and American College of
248 S. T. Sharma and J. E. Nestler

Endocrinology have recommended screening for diabetes with an oral glucose

tolerance test by the age of 30 years in all patients with PCOS.24

PCOS AND RISK FOR CARDIOVASCULAR DISEASE

When compared with normally cycling women of similar age, women with PCOS have
been found to have an increased prevalence of several cardiovascular risk factors,
including hypertension25–27 and dyslipidemia.28–31 The disorder has also been found to
be associated with an increase in subclinical atherosclerotic disease and endothelial
dysfunction.32–38 These findings suggest that women with PCOS are at a higher risk for
early-onset cardiovascular disease. Given the high prevalence of PCOS in the female
population, the disorder may potentially account for a significant proportion of
atherosclerotic heart disease observed in younger women.
Dyslipidemia may be the most common metabolic abnormality in PCOS, and the
prevalence of an abnormal low-density lipoprotein (LDL) cholesterol level (borderline
or high) by National Cholesterol Education Program guidelines approaches 70% in
PCOS.39 Low high-density lipoprotein (HDL) cholesterol and high triglyceride levels
are frequently found in both obese and lean women with PCOS40,41, with low HDL
cholesterol levels found in 70% of women with PCOS.42 It is well known that LDL
subclasses are important predictors of cardiovascular disease.43 Small, dense LDL
particles have been associated with an increased relative risk of CAD that ranges from 3
to 7 fold.44 Multiple studies have shown a high prevalence of these atherogenic LDL
particles in women with PCOS in comparison with those in control subjects.45 The
findings of early and prolonged exposure to dyslipidemia confer significant
cardiovascular risk to these women.
Several46,47, but not all48, studies have shown that, with increasing age, women with
PCOS have a higher incidence of hypertension than do age-matched control subjects.
Increased systolic blood pressure has been noted in patients with PCOS, and this
persisted even after adjustment for body mass index (BMI), insulin sensitivity, and body
fat distribution.49
Women with PCOS also display increased levels of newly recognized surrogate
markers for early atherosclerosis, such as increased PAI-132,33, endothelin-134, and
C-reactive protein concentrations.35 Moreover, several studies have indicated an
association of PCOS with impaired endothelial function, presumably due to altered
insulin regulation of endothelial nitric oxide synthesis, which leads to impaired nitric
oxide-dependent vasodilatation.36–38 This in turn correlates with a long-term risk for
cardiovascular disease in this group of women.
Two major anatomic markers for subclinical cardiovascular disease in PCOS are
coronary calcifications, identified by electron beam tomography, and carotid intima-
media thickness, determined by ultrasonography. A Mayo Clinic study by Christian and
colleagues revealed a 3-fold higher level of coronary artery calcification in non-diabetic
women with PCOS than in population control subjects.50 When compared with obese
control subjects, women with PCOS had a 2-fold increase in coronary artery
calcification. These findings have been confirmed by several other studies which
showed a higher prevalence of both coronary artery calcification and aortic calcification
in women with PCOS in comparison with control subjects.51,52 Another powerful
demonstration of the early atherogenic process in PCOS is the study by Talbott et al
 Prevention of diabetes and cardiovascular disease in PCOS 249

which revealed increased thickening of carotid intima-media in middle-aged women

with PCOS compared to age-matched normal women.53
Given the high prevalence of cardiovascular risk factors in PCOS, it is not surprising
that multiple studies have shown an increased prevalence of metabolic syndrome (MBS)
in women with PCOS.42,53 A recent study reported the prevalence of MBS in women
with PCOS as 43%54, which is 2-fold higher than the age-adjusted prevalence rate of
24% in women nationally, based on data obtained from women who participated in the
NHANES III survey.55 It is well known that the MBS is associated with a heightened risk
for developing diabetes, cardiovascular disease, and mortality. Therefore, this increased
prevalence of MBS in women with PCOS puts them at a significantly increased risk for
adverse cardiovascular outcomes and mortality.
Several studies have reported an increased prevalence of heart disease in PCOS or in
women with the anatomic finding of polycystic ovaries.56–58 PCOS was detected by
pelvic ultrasonography in 42% of 143 women younger than 60 years who underwent
cardiac catheterization for chest pain or valvular disease; this is double the frequency in
the general population.56 Another study conducted in Holland revealed an increased
prevalence of hypertension, diabetes, and cardiac symptoms (3.1% in PCOS versus 0.9%
in controls) in lean women with PCOS in comparison with a population database.57
In contrast, a study conducted in the United Kingdom that reviewed death
certificates of 786 women who were diagnosed with PCOS at an average age of 26.4
years and followed for an average duration of 30 years failed to show a statistically
significant increase in cardiovascular mortality compared to expected numbers from
actuarial tables.59 However, it should be noted that the number of women studied here
was limited and that the women were relatively young at follow-up. These limitations
decreased the predictive power of the study. In fact, in the study the ratio of observed
to expected deaths from ischemic heart disease was increased by 1.4-fold, but this was
not statistically significant. Moreover, there was a 2.4-fold increase in the ratio of deaths
from ‘diabetes’, and the majority of these would be expected to have been from
myocardial infarction.
The Nurses Health Study, which followed 82 439 women for 14 years, is probably a
more instructive study due to the large number of women assessed and a greater
statistical predictive power.60 Women with highly irregular menses were found to have
significantly increased relative risks of 1.5 for coronary heart disease and 1.9 for fatal
myocardial infarction compared with eumenorrheic women. As stated earlier,
oligomenorrhea is a highly predictive surrogate marker for PCOS, and thus this
study provides indirect confirmation of increased adverse cardiovascular outcomes in
women with PCOS. It is important to emphasize that to date no definitive, large-scale,
prospective, outcome study has assessed cardiovascular mortality specifically in women
with PCOS. Nonetheless, the current evidence supports a strong recommendation
that women with PCOS should undergo comprehensive evaluation for recognized
cardiovascular risk factors and receive appropriate treatment as indicated.61,62

CLINICAL SIGNIFICANCE OF INSULIN RESISTANCE IN PCOS

The association of PCOS with insulin resistance, and the consequent increase in the risk
for developing type 2 diabetes and cardiovascular disease, has several important clinical
implications. It indicates that PCOS is not only an infertility problem or a cosmetic
annoyance, but it is foremost a general health problem. Therefore, any therapy for
250 S. T. Sharma and J. E. Nestler

PCOS should optimally target not only the ovulatory dysfunction and hyperandrogen-
ism but also the co-morbidities of the dysmetabolic syndrome associated with it.
When evaluating women with PCOS, physicians should include assessments of
glucose tolerance (via an oral glucose tolerance test), lipids, blood pressure, and
possibly other reversible cardiovascular risk factors such as homocysteine. Several
studies have documented that fasting serum glucose levels may be normal in women
with PCOS despite the presence of impaired glucose tolerance or type 2 diabetes
revealed when a formal glucose tolerance test is performed.63–65 Therefore, it is
important to remember that measurement of fasting serum glucose is not an effective
screening tool to rule out impaired glucose tolerance and diabetes in women with
PCOS, and that an oral glucose tolerance test should be performed, particularly in
obese women with PCOS and those with a family history of type 2 diabetes.
Long-term treatment of PCOS should focus not only on the conventional outcomes
of regularization of menses and amelioration of hyperandrogenism, but should also
attempt to prevent progression of metabolic abnormalities to type 2 diabetes and
cardiovascular disease. The traditional treatment for PCOS has been oral contra-
ceptives (OCs), but several studies suggest that, in women with PCOS, OCs may
aggravate insulin resistance, decrease glucose tolerance, and enhance cardiovascular
risk.66–71 A recent meta-analysis of all the pertinent studies estimating the risk of
cardiac or vascular arterial events associated with the use of low-dose, combined OCs
in the population at large described a 1.85-fold increased risk for myocardial infarction
and a 2.12-fold increased risk for ischemic stroke.72 In healthy women the risk of
cardiovascular outcomes is minimal, and with current use of OCs, though this risk is
doubled, it continues to be minimal and is outweighed by the benefits of contraception.
Moreover, OCs are used only for limited periods of time in the general population.
However, in contrast to the population at large, women with PCOS are at a higher
baseline risk for adverse cardiovascular outcomes, and are traditionally exposed to oral
contraceptives for prolonged periods of time (2–3 decades). These factors specific to
PCOS presumably increase the risk for adverse vascular outcomes in this population,
and thus it might be prudent for physicians to reconsider the use of oral contraceptives
as first-line therapy in women with PCOS not requiring contraception.
In contrast to the traditional treatment is the more recent and novel use of insulin-
sensitizing drugs for chronic therapy of PCOS. These agents have been shown to
improve insulin sensitivity in non-diabetic women with PCOS, and to convert impaired
glucose tolerance to normal glucose tolerance. Several studies have reported that these
drugs have beneficial effects on multiple cardiovascular risk factors in PCOS, including a
decrease in serum triglycerides, decrease in PAI-1 concentrations, and decrease
in blood pressure.73,74 There is also indirect evidence from the diabetes literature,
such as the UKPDS study,75 that insulin-sensitizing drugs may decrease the risk of
cardiovascular events in insulin-resistant individuals.
Various outcome studies have shown that interventions to improve insulin
sensitivity can prevent or delay the development of diabetes in individuals at high
risk.23,76 A study conducted in Finland reported that improved insulin sensitivity,
achieved through a combination of diet and exercise, reduced progression to type 2
diabetes by 58% over 4 years in obese men with impaired glucose tolerance.76 More
recently, an NIH study by the Diabetes Prevention Program Research Group, followed
3234 non-diabetic high-risk individuals for an average period of 2.8 years and observed
that lifestyle interventions reduced the incidence of diabetes by 58% and treatment
with metformin led to a risk reduction of 31%.23 These findings strongly suggest that
improving insulin sensitivity, with lifestyle modifications or insulin-sensitizing drugs,
 Prevention of diabetes and cardiovascular disease in PCOS 251

reduces the risk for developing diabetes. Women with PCOS are an insulin-resistant
group at markedly increased risk for type 2 diabetes. Therefore, it seems reasonable to
presume that the demonstrated efficacy of lifestyle interventions and insulin-sensitizing
drugs in individuals with impaired glucose tolerance or a history of gestational diabetes
should be applicable to them as well.

INSULIN-SENSITIZING DRUGS

Lifestyle modifications, including a weight-reducing diet and exercise, are rec-

ommended as the first-line therapy for all obese women with PCOS. However, many
obese women with PCOS find weight loss difficult to achieve and maintain. Moreover,
about 10–30% of women with PCOS are lean, and weight loss is not an option for them.
For these reasons, insulin-sensitizing drugs are being used more frequently and have
come to play an important role in the chronic therapy of PCOS. We first emphasize that
whenever insulin-sensitizing drugs are used for the long-term treatment of PCOS, it is
important to confirm that treatment has resulted in regular ovulation occurring every
2–3 months in order to obviate the risk for endometrial hyperplasia or cancer. There
are two classes of insulin-sensitizing drugs that are commercially available for use:
biguanides (metformin) and thiazolidinediones (mainly rosiglitazone and pioglitazone).

Metformin

Metformin is a biguanide first developed in 1957 for the treatment of type 2 diabetes. It
has the important effect of lowering glucose levels in diabetic patients without causing
hypoglycemia. Its primary mechanism of action is the reduction of hepatic
gluconeogenesis, which is found to be pathologically increased in insulin-resistant
states, leading to fasting hyperinsulinemia.77 It may also increase peripheral insulin
sensitivity in other body tissues as supported by evidence that metformin lowers insulin
requirements in type 1 diabetic patients.78,79 In addition, at least two studies suggest
that metformin, when given to non-diabetic women with PCOS, specifically improves
peripheral insulin sensitivity, as demonstrated by euglycemic insulin clamps.73,74
The most serious, albeit rare, adverse effect of metformin is lactic acidosis, but this
has been reported almost exclusively in high-risk populations due to renal insufficiency,
liver disease, or congestive heart failure. The more common side-effects of metformin
are gastrointestinal, and these can usually be minimized by starting at a low dose and
gradually titrating up to the optimal dose.
The first published study of the use of metformin to treat PCOS was conducted by
Velazquez et al in 1994.80 This was an uncontrolled study in which 26 obese women
with PCOS were treated with metformin (1500 mg/day) for a total of 8 weeks.
Metformin use significantly decreased serum insulin concentrations, lowered serum-
free testosterone, and led to three spontaneous pregnancies among the 26 women
treated. Subsequently, Nestler and Jakubowicz published a randomized, blinded, and
placebo-controlled study in 1996 using metformin (1500 mg/day) for 4–8 weeks in 24
obese women with PCOS.81 They observed that in women treated with metformin
(in the absence of any weight change) there was a decrease in circulating insulin levels,
decreases in GnRH-stimulated LH release and ovarian androgen production, a 44%
decrease in serum free testosterone levels, and a rise in serum sex-hormone binding
globulin (SHBG).
252 S. T. Sharma and J. E. Nestler

Since then, over 20 placebo-controlled studies using metformin, conducted

primarily in obese women with PCOS, have demonstrated improvements in ovulation
or reduction in androgens in women with PCOS.73,74,82–86 With regard to lean women
with PCOS, a study by Nestler and Jakubowicz published in 1997 showed that
metformin decreased fasting and glucose-stimulated insulin levels, decreased free and
total testosterone, decreased basal and GnRH-stimulated LH release, and increased
SHBG specifically in lean and normal-weight (BMI 18–24 kg/m2) women with PCOS.87
These findings emphasize the key pathogenic role of insulin resistance in lean women
with PCOS as well.
One of the unique benefits that metformin and other insulin-sensitizing drugs offer
over previous forms of therapy is the correction of underlying metabolic abnormalities
associated with the insulin resistance syndrome, such as hyperinsulinemia, dyslipidemia,
and hypertension. As discussed earlier, there is indirect evidence from the diabetes
literature showing a decreased incidence of development of diabetes in high-risk
individuals on treatment with metformin.23 Several studies conducted in insulin-
resistant populations—including PCOS, impaired glucose tolerance, and diabetes—
have also reported a beneficial effect of metformin on the cardiovascular risk profile.
These effects include a decrease in total cholesterol and serum triglycerides, decrease
in serum PAI-1 concentrations, decrease in C-reactive protein levels, and a decrease in
blood pressure.74,80,88 The United Kingdom Prospective Diabetes Study (UKPDS)
reported a reduced incidence of myocardial infarction in obese type 2 diabetic patients
assigned to receive initial treatment with metformin monotherapy.75 The effects of
metformin on cardiovascular risk factors have been variable from study to study, but no
aggravation of cardiovascular risk factors has ever been reported. Thus, in contrast to
the traditional treatment of PCOS, metformin does not appear to be harmful from the
cardiovascular risk perspective, and may actually be beneficial.
A few studies have found no beneficial effect of metformin in PCOS.89–91 Of these
studies, one suggested that metformin did not offer additional benefit over weight loss
alone in obese women with PCOS.89 Another study used low—probably subclinical—
doses of metformin (total of 1000 mg/day).91 One study failed to show any effect of
metformin in women with PCOS who were morbidly obese (BMI as high as 50 kg/m2),
which may suggest that women with extreme obesity and overwhelming insulin
resistance might not respond to metformin therapy.90

Thiazolidinediones

Thiazolidinediones are a class of insulin-sensitizing drugs that enhance glucose uptake

mainly in the adipose and muscle tissues. Their primary mechanism of action is via the
activation of g-peroxisome proliferation activator receptors (PPARg receptors).
Binding of thiazolidinediones to these nuclear receptors induces gene transcription and
activates genes that encode insulin action. The first thiazolidinedione to become
available in the United States was troglitazone. However, owing to numerous reports of
fatal liver toxicity linked to troglitazone during the post-marketing phase92, it was
withdrawn by the FDA in 1999. Notably, the two thiazolidinediones (TZDs) currently
available, rosiglitazone and pioglitazone, have not demonstrated similar hepatotoxicity.
A review of the troglitazone literature can help us to make suppositions about the
likely effects of this class of drug in PCOS. There are currently eight published trials that
have assessed the effects of troglitazone in PCOS. All of them have demonstrated that
troglitazone decreases circulating insulin, decreases LH, reduces hyperandrogenemia,
 Prevention of diabetes and cardiovascular disease in PCOS 253

and increases the ovulation rate in women with PCOS, with variable effects on the lipid
profile.93–97 A direct comparison of metformin and troglitazone has not been
attempted in any of the trials.
There are limited data on the use of rosiglitazone and pioglitazone in the treatment
of PCOS. Currently, there are eight published trials using rosiglitazone98–101 and six
published trials using pioglitazone102–104 in the treatment of PCOS. All of these trials
have demonstrated improvements in ovulation rates, menstrual cyclicity, insulin
sensitivity, endothelial dysfunction, and androgen concentrations in PCOS women.
Recently, Baillargeon et al conducted a randomized, placebo-controlled trial in a
group of 100 non-obese women with PCOS with no clinical or biochemical evidence
of insulin resistance, and studied the effects of metformin, rosiglitazone, and a
combination of these drugs in these women.100 They observed that treatment with
either insulin-sensitizing drug led to an increase in the ovulation rate compared to
placebo, which was significantly greater with metformin than rosiglitazone; combination
therapy was not found to be more potent than metformin alone. There was a similar
decrease in serum testosterone levels in all treatment groups. Measures of insulin
sensitivity improved significantly after treatment with metformin and combination
therapy, but not with rosiglitazone alone. These findings suggest that insulin-sensitizing
drugs are useful in the treatment of non-obese women with PCOS even when they do
not have any overt evidence of insulin resistance, with metformin having a greater
beneficial effect than rosiglitazone. However, it should be emphasized that this study
was performed in a relatively rare subset of PCOS women (i.e. lean women with
normal indices of insulin sensitivity).
To date, there has been only one head-to-head published trial of metformin versus a
TZD conducted in typical obese women with PCOS. This was a study conducted
recently in Mexico comparing the effects of pioglitazone and metformin in obese
women with PCOS. They found that pioglitazone was as effective as metformin in
improving insulin sensitivity and hyperandrogenism in this population.104 However,
pioglitazone was associated with a simultaneous increase in weight and BMI, while
metformin was found to promote weight loss. Future long-term, prospective,
controlled studies are needed to further characterize the effects of these drugs in
women with PCOS.
Although, increasingly, more clinical trials using thiazolidinediones are being
conducted in women with PCOS, the majority of the reported studies have used
metformin. Hence, the weight of scientific evidence is greatest for this drug. Moreover,
metformin has been available worldwide for several decades, and its adverse effects and
toxicities are well delineated. In addition, of all the commercially available insulin-
sensitizing drugs, only metformin has a reassuring safety profile in pregnant women105
and is associated with facilitation of weight loss. Therefore, metformin is the currently
preferred insulin-sensitizing drug for chronic treatment of PCOS. If future outcome
studies indicate that TZDs have significant salutary cardiovascular actions or preserve
b-cell function better than metformin, then TZDs may be preferred for the chronic
treatment of PCOS.

RECOMMENDATIONS AND FUTURE DIRECTIONS

PCOS, a prevalent disorder in young women, has traditionally been regarded as an

infertility or a cosmetic problem. In the past, the aims of therapy consisted mainly of
254 S. T. Sharma and J. E. Nestler

ovulation induction, treatment of acne and hirsutism, and prevention of endometrial

cancer. However, recent recognition of the prominent role of insulin resistance in the
pathophysiology of the syndrome has shown that PCOS is a general health disorder
associated with metabolic abnormalities, which lead to an increased risk for developing
diabetes and cardiovascular disease. Moreover, oral contraceptives—the traditional
therapy for PCOS—are now known to increase the risk for adverse cardiovascular
outcomes and may aggravate insulin resistance. In light of these findings, hirsutism and
infertility can no longer be the sole considerations when choosing long-term
pharmacological therapy, and the goals of treatment in PCOS need to be reconsidered.
After reviewing the current evidence, we recommend that when evaluating women
with PCOS, physicians should consider the following:

1. Early recognition of the syndrome to reduce the incidence and severity of potential
sequella associated with the disorder.
2. Screening for impaired glucose tolerance and diabetes by determining serum
glucose 2 hours after the ingestion of 75 g dextrose, particularly in obese women
with PCOS and those with a family history of type 2 diabetes.
3. Comprehensive evaluation for recognized cardiovascular risk factors and
appropriate treatment as necessary. This includes screening for dyslipidemia,
hypertension, metabolic syndrome, and possibly measurement of atherogenic
markers such as serum CRP and homocysteine levels.
4. Assessment of cardiovascular risk factors and performance of an oral glucose
tolerance test prior to and 3–4 months after initiation of OCs to monitor for
possible detrimental effects of OCs.
5. Lifestyle modification with diet and exercise remain the first-line therapy for obese
women with PCOS.
6. Consideration of insulin-sensitizing drugs as the initial therapy in women with
PCOS, especially those who are overweight or are at a particularly high risk for
developing diabetes. When using them for long-term therapy, ovulation occurring
every 2–3 months should be confirmed. Metformin is the currently preferred
insulin-sensitizing drug for chronic treatment of PCOS, and has been shown to
improve the metabolic profile, menstrual cyclicity, and fertility in women with
PCOS, and is associated with weight loss. Although there is abundant evidence to
support the efficacy of metformin in PCOS, it should be noted that metformin has
not been approved by the US Food and Drug Administration for use in PCOS.
7. Another class of insulin-sensitizing drugs is the thiazolidinediones, mainly
rosiglitazone and pioglitazone. There are limited data on the use of these drugs
in the treatment of PCOS. Future outcome studies are needed to further
characterize the role of these drugs in chronic treatment of PCOS.

Although, recent advances have afforded us a better understanding of the

pathophysiology of PCOS and have helped to form more effective strategies of
management, there remain several aspects of the disorder, which need further
investigation. We know that OCs are associated with an increased incidence of adverse
cardiovascular outcomes, and evidence suggests that they may aggravate insulin
resistance and/or induce glucose intolerance in PCOS. However, prospective long-term
studies are required to better define the effects of OCs on the metabolic and
cardiovascular risk profile in this population. Randomized controlled trials must also
be conducted to assess whether treatment with insulin-sensitizing drugs prevents
the development of diabetes and cardiovascular disease in women with PCOS.
 Prevention of diabetes and cardiovascular disease in PCOS 255

Head-to-head trials of various insulin-sensitizing drugs and studies looking at the

combination of insulin-sensitizing drugs with OCs can further help us to form an optimal
treatment strategy for PCOS.

Practice points

† early diagnosis of the syndrome

† comprehensive evaluation for impaired glucose tolerance, diabetes, and other
recognized cardiovascular risk factors
† lifestyle modifications—the first line of therapy
† consideration of insulin-sensitizing drugs like metformin and thiazolidinediones
as initial therapy, especially in obese PCOS women and those at risk of
developing diabetes; in this case ovulation occurring every 2–3 months should
be confirmed
† assessing the risks and benefits of oral contraceptives and tailoring therapy to
the individual

Research agenda

† long-term prospective studies are needed to further characterize the role of

insulin-sensitizing drugs in chronic treatment of PCOS
† prospective long-term studies need to be done looking at the effects of oral
contraceptives on metabolic and cardiovascular parameters in PCOS
† studies looking at the combination of oral contraceptives and insulin-sensitizing
drugs are required to form an optimal treatment strategy for PCOS

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