Med Clin N Am 91 (2007) 1151–1168

Obesity and the Polycystic Ovary

Syndrome
Michael Magnotti, MD, Walter Futterweit, MD*
Mount Sinai School of Medicine, New York, NY 10029, USA

Polycystic ovary syndrome (PCOS) is the most common metabolic ab-

normality in reproductive-aged women, occurring globally in 6% to 10%
of this population [1–3]. Identification of such women is most important
in that they constitute the largest group of women at risk for the develop-
ment of cardiovascular disease (CVD) and type 2 diabetes mellitus
(T2DM). It is estimated that more than 50% of these women are undiag-
nosed. The fact that it likely affects 4 to 5 million women in the United
States, with distinct metabolic and cardiovascular risk factors and associ-
ated features of metabolic syndrome (MS) (also known as ‘‘insulin resis-
tance syndrome’’), makes diagnosis and treatment at an early stage
imperative for proactive and aggressive management. The past decade has
demonstrated that some of the features of MS, namely, insulin resistance
and compensatory hyperinsulinism, are frequently present in women with
PCOS. The phenotype associated with this syndrome is not restricted to
bothersome cosmetic symptoms in reproductive-aged women, but includes
a cluster of findings present in these women that may have profound health
implications later in their life.
Recognition of the syndrome affords the physician not only an opportu-
nity to reduce the emotional impact of skin manifestations, such as acne,
hirsutism, androgenic alopecia, and infertility, but also to attenuate the
likely later metabolic and CVD complications. The cardinal features of
the syndrome are the presence of hyperandrogenism and hyperinsulinemia,
which often vary over time [4]. Moreover, obesity is often associated with
PCOS [4]. Surprisingly few studies have addressed the frequency of PCOS
in unselected overweight or obese women. In one such study of 113 over-
weight and obese premenopausal women from Spain, however, the

* Corresponding author.
E-mail address: wfutt@ix.netcom.com (W. Futterweit).

0025-7125/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2007.06.010 medical.theclinics.com
1152 MAGNOTTI & FUTTERWEIT

prevalence of PCOS was 28%, compared with the 5.5% prevalence of PCOS
in Spanish lean women [5].
The presence of obesity further contributes to the metabolic derange-
ments of the syndrome. It is well established that obesity is commonly asso-
ciated with insulin resistance. The obese woman with PCOS exhibits not
only the intrinsic insulin resistance of the syndrome but also that related
to the presence of excess adiposity. This is emphasized by the beneficial ef-
fects of a hypocaloric diet [6], exercise [7], and insulin-sensitizing agents [8,9]
on metabolic and reproductive features of the syndrome.
The occurrence of obesity in conjunction with the skin and hair manifes-
tations of the syndrome can have a further negative effect on self-esteem and
self-image [10]. The fear of social rejection makes some women reclusive and
may retard their development of social skills and confidence. Such women
are usually helped considerably once an accurate diagnosis and treatment
of the underlying endocrine and ovarian disorders is obtained. Modification
of lifestyle and correction of the underlying pathophysiologic condition can
help ameliorate psychologic dysfunction.

Diagnostic criteria for polycystic ovary syndrome

Defining the syndrome (phenotype) has been a matter of debate. Until
several years ago, most investigators used an adopted consensus of PCOS
experts at the 1990 National Institute of Child Health and Human Develop-
ment conference [11], which consisted of (1) the presence of oligoamenor-
rhea; (2) clinical and biochemical features of hyperandrogenism; and (3)
the exclusion of other disease states that may mimic PCOS, such as nonclas-
sical congenital adrenal hyperplasia, virilizing syndromes of the ovary or ad-
renal, and Cushing’s syndrome. In 2003, a newer definition of the
syndrome’s phenotype was adopted at the Rotterdam PCOS Consensus
Group Conference [12] to allow for the inclusion of women with regular
menses (present in about 25% of women with PCOS) who manifest the
morphologic changes of polycystic ovaries on ultrasonography [12]. The lat-
ter was not accepted as a diagnostic criterion in the aforementioned 1990
conference. Finally, a recent Phenotype Task Force of the Androgen Excess
Society published their Guidelines stressing the importance of hyperandro-
genism as the cardinal feature of PCOS [13], while accepting the major
guidelines of the 1990 Conference consensus report.
There is a subset of women with PCOS who have regular cycles. This may
vary from 25% to 40% of patients with the syndrome and is mainly com-
prised of women with generally regular menses associated with episodes
of irregularity (oligo-ovulation) [14,15]. In addition, a history of regular
or almost regular cycles does not prove that ovulation has occurred. Docu-
mented ovulation in a menstrual cycle requires biochemical confirmation of
elevated serum progesterone in the luteal phase.
 OBESITY AND THE POLYCYSTIC OVARY SYNDROME 1153

Pathogenesis of polycystic ovary syndrome

An understanding of the pathogenesis of PCOS substantiates the concept
that it seems to be a multigenic disorder. Clinical studies support an in-
creased frequency of PCOS in first-degree relatives of affected women as
suggested by a higher prevalence of glucose intolerance, insulin resistance,
and hyperandrogenemia [16–18]. Many candidate genes for PCOS have
been proposed. A number of these genes may alter the hypothalamic-pitui-
tary-ovarian axis and others may play a major role in the pathogenesis of
insulin resistance, and the associated phenotype of this heterogeneous disor-
der [19]. Recent studies have demonstrated a candidate gene near the insulin
receptor gene locus [20,21]. In addition, several alternative hypotheses have
been proposed for the pathogenesis of PCOS [22], including
1. Hypothalamic-pituitary abnormalities that result in gonadotropin-
releasing hormone and luteinizing hormone dysfunction.
2. A primary enzymatic defect in ovarian or combined ovarian and adrenal
steroidogenesis.
3. A metabolic disorder characterized by insulin resistance in conjunction
with compensatory hyperinsulinemia that exerts adverse effects on the
hypothalamus, pituitary, ovaries, and adrenal glands.

Clinical features of polycystic ovary syndrome

The manifestations of PCOS are quite varied, and depend on ethnicity,
environmental factors, and the presence and severity of obesity and insulin
resistance. The most common clinical features are listed in Box 1. There are
no pathognomonic characteristics of the syndrome, but the combination of
oligoamenorrhea and clinical or biochemical findings of androgen excess are

Box 1. Clinical manifestations of PCOS

Menstrual dysfunction or infertility
Hirsutism
Acne
Alopecia
Visceral (android, central) fat distribution and obesity
Miscellaneous
Sleep apnea
Acanthosis nigricans and skin tags

Data from Futterweit W, Diamanti-Kandarakis E, Azziz R. Clinical features of the

polycystic ovary syndrome. In: Azziz R, Nestler JE, Dewailly D, editors. Androgen
excess disorders in women: polycystic ovary syndrome and other disorders. 2nd
edition. Totowa (NJ): Humana Press; 2006. p. 155–67.
1154 MAGNOTTI & FUTTERWEIT

most commonly noted. The presence of polycystic ovaries as defined on ul-

trasonography is frequently noted, but this alone does not establish the di-
agnosis [23,24]. Weight gain and an inability to lose weight are common
major complaints in women with PCOS. The intensity varies, but a persistent
weight gain of 10 to 15 pounds per year may be noted. As women gain
weight the clinical features of hirsutism, acne, menstrual cyclicity, and ob-
structive sleep apnea frequently worsen. Associated with the weight gain
is increased appetite with a tendency to compulsive ingestion of carbohy-
drate-rich foods. Episodes of postprandial hyperinsulinemia may occur in
mid-afternoon and be associated with symptoms of hypoglycemia.
Because this article reviews the impact, pathophysiology, and associated
risks of obesity and MS in PCOS, the reader may wish to review articles on
other aspects of clinical findings, diagnosis, risks for later complications, ul-
trasonographic morphology of ovaries, and management of women with
PCOS [1,4,14,24–28].

Weight gain and obesity in polycystic ovary syndrome

Weight gain in PCOS often intensifies peripubertally. It may well be an
inciting factor for the development of menstrual dysfunction; dysfunctional
bleeding; and signs of hyperandrogenism, such as hirsutism, acne, and alo-
pecia. The body mass index (BMI) (weight in kilometers per meters squared)
may serve as a modest predictor of oligomenorrhea and associated features
of PCOS [29]. In a study by van Hooff and colleagues [29], both obese and
lean adolescent girls with PCOS were at high risk for developing persistent
oligomenorrhea. In another study of 230 girls aged 16 to 25 years there was
a significantly increased prevalence of elevated BMI in women with PCOS
than in matched controls [24]. Obesity (BMI O30 kg/m2) or being over-
weight (BMI O25 kg/m2) is frequently present in women with PCOS with
a reported wide range of 38% to 88% [27,30]. Sixty percent of women
with PCOS in the United States are obese [14], but the frequency seems to
be lower in other populations [31]. Differences in the prevalence of obesity
vary among different ethnic groups, suggesting that both environmental
and genetic factors are of importance in determining individual
susceptibility.
As in normal women, the development of obesity in PCOS is associated
with increased insulin resistance. In addition, most of the PCOS population
has a greater degree of insulin resistance than age- and BMI-matched con-
trols [32]. This disparity is amplified in those women with PCOS who are
also obese, leading to a higher degree of insulin resistance than either con-
dition alone, whereas lean PCOS subjects tend to have a lesser degree of
insulin resistance [32–34].
Many women with PCOS may relate a rather sudden onset of weight gain
over 6 to 18 months, which further induces symptoms of menstrual
 OBESITY AND THE POLYCYSTIC OVARY SYNDROME 1155

dysfunction with infertility, acne, and hirsutism. The weight gain is usually
associated with an increase in carbohydrate craving and postprandial symp-
toms of hypoglycemia. The latter include lack of concentration, hunger,
sweats, headaches, tremulousness, poor concentration, irritability, and
sleepiness caused by an exaggerated response of insulin following a carbohy-
drate-rich meal. A central (abdominal, visceral) distribution of fat (Fig. 1) is
often present in both obese and lean women with PCOS. Obesity may be
a major factor that exacerbates the symptoms and signs of PCOS rendering
them more susceptible to developing T2DM, cardiovascular events, and re-
productive abnormalities. The evidence that PCOS is associated with in-
creased risk for CVD is steadily mounting.
Obesity also seems to play a pathogenetic role in the development of
PCOS [35]. Obesity is frequently associated with insulin resistance, which
acts synergistically with luteinizing hormone to intensify ovarian hyperan-
drogenism, decrease hepatic production of sex hormone-binding globulin
(SHBG), and reduce insulin-like growth factor binding protein-1 [36]. More-
over, obesity reinforces the genetic predisposition to hormonal anovulatory
disorders in PCOS. Metabolic complications including impaired glucose tol-
erance (IGT) leading to T2DM (in approximately 40% of subjects with
obesity), hypertension, dyslipidemia, and possible development of estro-
gen-dependent tumors (eg, endometrial carcinoma) are more common in
obese patients with PCOS than in lean women with PCOS. Weight loss in

Fig. 1. Central fat distribution in a 31-year-old woman with polycystic ovary syndrome.
1156 MAGNOTTI & FUTTERWEIT

patients with hyperandrogenism, with or without the clinical presence of

PCOS, should be the first therapeutic option because it decreases androgen
levels, increases SHBG, and may restore ovulation. The increase in insulin
sensitivity from as little as a 7% reduction in body weight can restore fertil-
ity, and decrease hirsutism in some women with androgen excess [6,37,38].
Investigators have also demonstrated that abnormalities in 17,20-lyase ac-
tivity diminish in parallel to the reduction of hyperinsulinemia in women
with PCOS [39].

Visceral (central, android) fat distribution and obesity

A central (abdominal, visceral, android) distribution of fat is often pres-
ent in both obese and lean women with PCOS (see Fig. 1). Abdominal obe-
sity may be clinically defined as a waist circumference of more than 88 cm
(O35 in) in women, and more than 102 cm (O40 in) in men. In Asian
women a waist circumference of more than 30 in may indicate increased vis-
ceral fat distribution. A major initial pathogenetic factor in the develop-
ment of MS (see later) seems to be visceral adiposity leading to insulin
resistance. The link to insulin resistance may partially be explained by the
frequently associated increased levels of free fatty acids that can inhibit
the insulin signaling mechanism, leading to decreased glucose transport to
skeletal muscle [40]. It is important to note that visceral adiposity does
not necessarily correlate with the BMI. Visceral fat in nonobese women
with PCOS contributes significantly to high serum triglyceride and fasting
insulin levels [41]. As visceral adiposity increases, the insulin sensitivity de-
clines [42,43].
The metabolic and cardiovascular risks in PCOS seem to correlate with
abdominal obesity. Altered parameters of inflammation with insulin resis-
tance and visceral obesity are often present in PCOS [44].

Acanthosis nigricans and skin tags

Acanthosis nigricans with or without skin tags are cutaneous markers of
hyperinsulinism [45,46]. In the absence of a paraneoplastic syndrome, acan-
thosis nigricans is an epiphenomenon of dermal hyperplasia, which may be
seen on the nape of the neck, axillae, groin, inner lips of vulvae, periumbil-
ical, and inframammary areas, and on the dorsum of fingers and knuckles.
They appear as brownish gray, velvety, or verrucous hyperparakeratotic
pigmented areas, more commonly seen in obese women of Hispanic or Af-
rican-American descent (Figs. 2 and 3), although they may also be noted oc-
casionally in obese and lean (BMI !25 kg/m2) white populations. Skin tags
are infrequent in most women before the age of 40 years and, if present be-
fore that age, suggest the presence of hyperinsulinism.
 OBESITY AND THE POLYCYSTIC OVARY SYNDROME 1157

Fig. 2. Acanthosis nigricans and hirsutism in a 29-year-old patient with polycystic ovary
syndrome.

Polycystic ovary syndrome and metabolic syndrome

MS is defined as a cluster of abnormalities that are more likely to occur in
patients with insulin resistance, particularly those who are obese. It identifies
patients at increased risk for T2DM and CVD. The prevalence of insulin re-
sistance and compensatory hyperinsulinemia is increased in women with
PCOS. Data vary, but one report indicates that 75% of women with
PCOS fulfill the criteria for MS [47]. Recently, a report noted that adoles-
cents with PCOS have an increased risk of MS with hyperandrogenemia
that is independent of obesity or insulin resistance [48]. Not all patients
with insulin resistance have any or all of the features present in MS. Fur-
thermore, clusters of the latter can develop in the absence of insulin resis-
tance. Nevertheless, the likelihood that a woman with PCOS has insulin
resistance leading to hyperinsulinemia is so substantial that all women
with PCOS should undergo diagnostic testing for the components of MS.
The prevalence of MS in women with PCOS under the age of 20 has been
reported as high as 23% [49]. It is not surprising that with advancing age
(30–39-year-old group) this same study reported that the rate increased to
53% [49]. This suggests that diligent follow-up of women with PCOS at
all ages should be maintained for the cluster of features comprising MS [50].
Both obesity and physical inactivity are major factors that work synergis-
tically with the inherent postreceptor defect and lead to insulin resistance in
women with PCOS [32]. Obesity increases the likelihood of occurrence of in-
sulin resistance. Although not all obese subjects are insulin resistant, obesity
is frequently associated. Most obese and nonobese oligomenorrheic women
with PCOS have insulin resistance [32,51].
1158 MAGNOTTI & FUTTERWEIT

Fig. 3. Acanthosis nigricans and skin tags in a 37-year-old Hispanic woman with polycystic
ovary syndrome.

Insulin resistance is difficult to assess accurately in a clinical setting with-

out the gold-standard of hyperinsulinemic-euglycemic clamp studies. This
particularly applies in the setting of basal insulin levels in the normal or
high-normal range and in the nonobese subgroup of women with PCOS.
Methods that measure only fasting glucose and insulin levels (including ho-
meostasis model assessment and the quantitative insulin sensitivity check in-
dex) may be inaccurate in assessing insulin sensitivity in these women [52]. It
is not unlikely that data may underestimate the frequency of insulin resis-
tance in PCOS subjects with borderline normal fasting glucose and insulin
levels. Perhaps other hormonal and genetic factors, and ethnicity, may influ-
ence the degree of insulin resistance and contribute to conflicting reports of
varying prevalence of insulin resistance in women with PCOS. Because ac-
curate assessment of insulin sensitivity is difficult in a clinical practice set-
ting, it is prudent to regard all obese women with PCOS as likely to have
insulin resistance and at risk for MS, and assume that most nonobese
women with PCOS have some if not most of the features of MS [51].

Polycystic ovary syndrome and the risk for type 2 diabetes mellitus
Epidemiologic studies indicate a high rate of IGT of 31% to 35% and
a 7.5% rate of T2DM, at the initial evaluation of young women with
 OBESITY AND THE POLYCYSTIC OVARY SYNDROME 1159

PCOS. These studies comprised primarily obese and overweight subjects

with PCOS [53,54]. Comparative rates of IGT and T2DM in the 20- to
44-year-old United States female population have been reported as 7.8%
for IGT and 1% for undiagnosed diabetes [54]. A large population study
showed that normal fasting blood glucose with IGT identifies subjects
with an adverse CVD risk factor and possible risk of sudden death [55].
Other risk factors in large population studies include increasing age, BMI,
and visceral body fat distribution affecting conversion to IGT [55]. Data re-
lating to conversion of IGT to T2DM (5–10 fold) and those with normogly-
cemia and normal glucose tolerance to IGT and T2DM vary in different
PCOS populations [53,54,56] and the presence of first-degree relatives
with T2DM increases the risk. The need for retesting at frequent intervals
is necessary because the fasting blood glucose and glycohemoglobin levels
usually are normal even in IGT and are a poor guide to indicating conver-
sion of normal glucose tolerance to IGT, and T2DM in PCOS [55,57]. In
a recent controlled study of changes in glucose tolerance in a 3-year time
span involving 71women with PCOS (mean age, 28 years; mean BMI, 27
kg/m2) and normal controls, the conversion rate of those with IGT to
T2DM was 2.2% per year [58]. The data demonstrated, however, a pro-
nounced conversion rate of 16% per year to IGT in the women with
PCOS and normal glucose tolerance. This report is likely to be followed
by further prospective studies of other PCOS women with normal glucose
intolerance and their conversion rate to IGT and T2DM.
In a study of women attending a diabetic clinic in an academic center,
27% of the premenopausal women had PCOS [59]. An 82% prevalence of
ultrasonographic morphology of premenopausal women at a T2DM clinic
in the United Kingdom has also been recorded [60].

Adipokines, obesity, and metabolic syndrome

In recent years, research has demonstrated that adipose tissue secretes
a variety of endocrinologically active substances, known collectively as ‘‘adi-
pokines.’’ These substances have a wide range of effects that are slowly being
elucidated. They have been closely linked to such processes as regulation of
appetite, insulin resistance, and immune modulation, and may play an
important role in the pathogenesis of various disease states.
The first adipokine to be discovered was leptin, the product of the ob
gene. It was noted that mice deficient in this protein became morbidly obese
and developed severe insulin resistance and type 2 diabetes. In humans, lep-
tin is produced largely by adipocytes, but also in smaller quantities by a va-
riety of other tissues. Leptin is involved in the regulation of appetite and
body weight, acting as a signal to the hypothalamus to decrease appetite
and increase energy expenditure. Levels of leptin are proportional to total
body fat content and are higher in females than males [61,62]. Because of
1160 MAGNOTTI & FUTTERWEIT

this, any gain in body fat causes a rise in leptin levels, signaling the hypo-
thalamus to decrease food intake and increase energy expenditure, thereby
promoting weight loss. If intact, this mechanism should ensure the mainte-
nance of normal body weight, but given the current obesity epidemic, there
must be more to the story. What happens to leptin in obesity?
As expected, leptin levels are generally very high in obese patients. De-
spite these elevated levels, however, obese patients do not increase energy
expenditure or decrease appetite in response. They seem to be resistant to
the actions of leptin on the hypothalamus, but the mechanism of this ‘‘leptin
resistance’’ remains unclear. Attempts at using leptin as a treatment for obe-
sity have also been largely unsuccessful; a randomized controlled trial of this
demonstrated efficacy in only a small subset of obese patients [63].
Adiponectin is an adipokine that seems to be closely related to a number
of the components of MS. It is produced exclusively by adipocytes, in
greater quantities by subcutaneous than visceral adipose cells [64]. As
with leptin, levels are higher in females than males, but unlike leptin, levels
of adiponectin are generally inversely related to the degree of obesity. Over-
all, adiponectin is a beneficial hormone that acts to decrease insulin resis-
tance and inhibit atherogenesis [65]. Its concentrations are decreased in
patients with obesity; states of insulin resistance (eg, PCOS); T2DM; and
macrovascular disease. In addition, adiponectin levels correlate with insulin
sensitivity (by glucose disposal rate) [64], and low levels may be predictive of
future diabetes [66]. Adiponectin-deficient knockout mice fed a fat- and car-
bohydrate-rich diet develop insulin resistance, hyperglycemia, and have
a higher degree of atherogenesis than normal controls [64]. These effects
can be reversed by administration of adiponectin. A small number of hu-
mans with genetic adiponectin deficiencies have also been found and they
exhibit many of the components of MS [64].
In mice, resistin is an adipokine that is produced almost exclusively by
adipose cells. There is evidence that increased levels of resistin are associated
with insulin-resistant states (in mice) [67] and it seems likely that resistin is
involved in the pathogenesis of insulin resistance in these animals. In addi-
tion, there is considerable evidence that administration of exogenous resistin
can cause insulin resistance in mice [65]. Despite this, resistin does not seem
to be associated with states of obesity in these animals [67]. These findings
initially generated a great deal of excitement, but it turns out that in humans
most studies demonstrate that resistin is not produced by mature adipose
cells and has a relatively minor role in the pathogenesis of insulin resistance
[65]. Its main action seems to be as a proinflammatory agent.

Role of adipokines in polycystic ovary syndrome

PCOS confers insulin resistance independently of BMI. Several studies
have looked at adipokine levels in patients with PCOS to determine whether
 OBESITY AND THE POLYCYSTIC OVARY SYNDROME 1161

they may be involved in its pathogenesis. A case control study of 64 women

with PCOS demonstrated that these women had significantly lower adipo-
nectin levels than age- and BMI-matched nonhyperandrogenic controls (in-
dependently of BMI) [68]. Using a multiple regression analysis, the authors
demonstrated that free testosterone levels, waist-to-hip ratio, and age were
the major determinants of adiponectin concentrations in these women.
The finding that adiponectin levels are lower in patients with PCOS than
age- and BMI-matched controls was also confirmed in several other studies
[69,70]. In addition, adiponectin levels show a strong inverse correlation
with central adiposity [69]. Interestingly, several studies have also demon-
strated a positive correlation between free testosterone and adiponectin
levels [68,69]. This remains somewhat perplexing given the higher levels of
adiponectin found in females than males (despite lower free testosterone
levels in females) and the inverse relationship between PCOS and adiponec-
tin (despite higher androgen levels in these patients). The impact of this re-
lationship is likely to be minimal in patients with PCOS, however, because it
is overshadowed by the inverse correlation between adiponectin and both
central obesity and PCOS itself.
Despite the inverse correlation seen between insulin resistance and adipo-
nectin levels in control patients, most studies have not been able to demon-
strate a similar correlation in patients with PCOS. This may simply reflect
an inability accurately to measure insulin resistance, or it may suggest
that adiponectin is not involved in the pathogenesis of insulin resistance
in patients with PCOS. Conversely, it may indicate the involvement of mul-
tiple pathways in the pathogenesis of insulin resistance in the syndrome.
Levels of leptin correlate well with the amount of body fat in both pa-
tients with PCOS and controls. There is no significant difference in leptin
concentrations between these two groups after controlling for BMI
[69,70]. It seems unlikely that leptin has a significant role in the pathogenesis
of PCOS. Resistin levels were found to be higher, however, in patients with
PCOS than age- and BMI-matched controls [70]. Given the poor relation
between resistin and insulin resistance in humans, however, it seems unlikely
that this is responsible for the increased insulin resistance in these patients.
Nevertheless, it may play a contributory role in the proinflammatory state
associated with MS.
Ghrelin is another adipokine that is involved in the regulation of food in-
take and body weight. It is the endogenous ligand of the growth hormone
releasing factor receptor in the central nervous system, but its receptors
are also present in the periphery, including on the ovaries [71]. As with adi-
ponectin, its levels are reduced in patients with PCOS (independent of body
weight) and obesity [69]. There is conflicting evidence on ghrelin’s involve-
ment in insulin resistance and the pathogenesis of PCOS itself.
It is clear that adiponectin and resistin levels are altered in patients with
PCOS, but it is unclear whether they are involved in the pathophysiology of
the syndrome. Of all the adipokines presently known, adiponectin is most
1162 MAGNOTTI & FUTTERWEIT

heavily correlated with PCOS (independently of BMI) and preliminary evi-

dence suggests that it may be involved in its pathogenesis. Resistin is also
positively correlated with PCOS, but its role in humans needs to be further
defined. Finally, leptin correlates well only with BMI. Given the relatively
recent recognition of the endocrine functions of adipose tissue and ghrelin,
it is likely that time will bring the discovery of new adipokines that may help
to explain better the complex relationships between obesity, PCOS, and MS.

Treatment
The treatment of PCOS must be individualized, taking into account the
patient’s major manifestations of the syndrome and her treatment goals. Be-
cause a thorough discussion of the treatment of PCOS requires its own
article, this section briefly explores the major treatment options available.
Table 1 lists the most commonly used agents in the treatment of PCOS.
In the case of the obese patient with PCOS, the first step in treatment
should be an attempt at weight loss. As little as a 7% weight loss can lead
to a significant reduction in hyperandrogenism and a restoration of fertility

Table 1
Major agents used in the treatment of the PCOS
Drug Name Common Brands Effective On Major Side Effects
Biguanides Glucophage Insulin resistance Gastrointestinal upset
Metformin Glumetza Metabolic syndrome (can be minimized
Riomet Ovulation induction by titrating dose
Fortamet Hyperandrogenic over a few weeks)
symptoms
Amenorrhea
Thiazolidenediones Avandia Insulin resistance Weight gain
Rosiglitazone Actos Metabolic syndrome Edema
Pioglitazone Ovulation induction Congestive heart
Hyperandrogenic failure (in
symptoms susceptible
Amenorrhea patients)
Oral contraceptive Yasmin/Yaz Hyperandrogenic Thromboembolism
agents Ortho-Cyclen/ symptoms (especially in
Ethinyl estradiol Tri-Cyclen Amenorrhea smokers O35)
plus drospirenone Desogen/ Hyperkalemia
Ethinyl estradiol Mircette (with drospirenone)
plus norgestimate
Ethinyl estradiol
plus desogestrel
Antiandrogens Aldactone Hyperandrogenic Hyperkalemia
Spironolactone symptoms Teratogenic
5a-Reductase Proscar Hyperandrogenic Teratogenic
inhibitors symptoms
Finasteride
 OBESITY AND THE POLYCYSTIC OVARY SYNDROME 1163

[6,37]. A similar degree of weight loss can also bring about an improvement
in insulin resistance, lipid profiles, and T2DM. Although it is often difficult
to achieve and maintain, weight loss can be extremely gratifying for the pa-
tient, improving self-image and relieving many (or all) of the manifestations
of the syndrome.
An insulin-sensitizing agent, such as the biguanide metformin, can target
many of the problems seen in the obese PCOS patient. Metformin’s effects
are mainly on the liver, lowering insulin resistance and decreasing gluconeo-
genesis. It has obvious beneficial effects on the IGT or overt T2DM that is
often seen in obese patients with the syndrome. In addition, the resulting
increase in insulin sensitivity triggers a decrease in circulating insulin levels,
leading to a decrease in ovarian androgen production and an increase in he-
patic SHBG production. This combination leads to lower free androgen
levels, and can result in the resumption of spontaneous ovulation and regu-
lar menses. Because of this, metformin (with or without clomiphene citrate)
is often used to induce ovulation in women with PCOS who desire fertility
[72].
Although it remains controversial, a recent literature review of six pro-
spective trials demonstrated that adding metformin to patients who are re-
sistant to clomiphene citrate significantly increases the odds of ovulation
[73]. Because the proposed target of metformin is insulin resistance, it seems
logical that it should be most effective in patients with the highest degree of
resistance. A recent review of the evidence, however, showed that it is diffi-
cult to use measures of insulin resistance to predict which women will
respond to metformin [74], although this may be related to the present
lack of a reliable, noninvasive measure of insulin resistance.
Furthermore, women with PCOS have a significantly higher rate of mis-
carriage than normal controls [75]. There is evidence that metformin may
help to reduce the spontaneous abortion rate in these women if continued
through the first trimester or even the entire pregnancy [76]. Although this
approach is often used in practice, the safety of metformin in pregnancy
has not been validated with large prospective trials, so its routine use
throughout pregnancy cannot be recommended at this time. Because met-
formin targets one of the key pathologies present in PCOS (insulin resis-
tance), its use should be considered in most women with the syndrome
(especially those who also have MS).
In patients with PCOS who do not desire pregnancy, it is important to
remember that some form of birth control should be part of the treatment
regimen. This is because treatments, such as weight loss or insulin sensi-
tizers, can often result in resumption of fertility and unwanted pregnancies.
The combination oral contraceptive pill (OCP) is often used in this situation
both to prevent unwanted pregnancies and improve the symptoms of the
disorder. The exogenous estrogen in the OCP feeds back on the pituitary,
leading to decreased luteinizing hormone production and decreased ovarian
androgen production. In addition, estrogen causes increased SHBG
1164 MAGNOTTI & FUTTERWEIT

production by the liver, leading to further decreases in free androgen levels.

The progestin component is important to protect the endometrium from the
effects of unopposed estrogen. Because many of the synthetic progestins
used in OCPs can have proandrogenic effects, however, one must take
care in selecting an appropriate OCP for the patient with PCOS. The pro-
gestin drospirenone has some antiandrogen effects and should theoretically
be the ideal progestin for a mild to moderately hyperandrogenic patient.
Preliminary data suggest efficacy in reducing androgen levels and hirsutism
in many PCOS patients [77,78]. Parenthetically, any form of estrogen may
further increase insulin resistance and increase the risk of thromboembolism
and should be used only when deemed necessary [79].
Antiandrogens can also be effective in reducing many of the cosmetic ef-
fects of hyperandrogenism. The potassium-sparing diuretic spironolactone
is the most commonly used antiandrogen in the United States, although cy-
proterone acetate is also available in many other countries. It is important to
note that spironolactone is teratogenic and must be used with an effective
form of contraception, even in patients with reduced fertility. Because of
this, it is commonly given together with an OCP containing a progestin,
such as drospirenone, to combine the antiandrogen effects of both agents
and provide effective birth control. Careful monitoring of potassium levels
is especially important with this combination, although it is generally well
tolerated. The 5a-reductase inhibitor finasteride may also be useful in the
treatment of hirsutism, although it is often less effective than other antian-
drogens [80]. It too must be given together with an effective form of contra-
ception because of teratogenicity.

Summary
PCOS is extremely common among reproductive-aged women, but often
goes undiagnosed. Although considerable controversy exists as to the pre-
cise criteria for defining the syndrome, it is generally agreed on that hyper-
androgenism is a cardinal feature and that polycystic ovarian morphology
on ultrasonography is not required for the diagnosis. PCOS is often associ-
ated with obesity and it imparts a degree of insulin resistance in excess of
that conferred by obesity alone. It is associated with MS and carries a greatly
increased risk of IGT and T2DM and cardiovascular risks. Treatment of
PCOS may provide relief of cosmetic problems and depression by improving
patient self-esteem. In addition, because of its association with MS, T2DM,
and CVD, its recognition and treatment can potentially be life saving.
A number of treatment options exist, but an attempt at weight loss
should be the first step in the obese patient. Insulin sensitizers, such as met-
formin, or a thiazolidinedione, such as pioglitazone or rosiglitazone, can di-
rectly target the insulin resistance associated with the syndrome and may
lead to a restoration of fertility. OCPs and antiandrogens are useful in
 OBESITY AND THE POLYCYSTIC OVARY SYNDROME 1165

women who do not desire pregnancy and have a preponderance of hyperan-

drogenic symptoms.

References
[1] Azziz R, Woods KS, Reyna R, et al. The prevalence and features of the polycystic ovary syn-
drome in an unselected population. J Clin Endocrinol Metab 2004;89:2745–9.
[2] Hart R, Hickey M, Franks S. Definitions, prevalence and symptoms of polycystic ovaries
and polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2004;18:671–83.
[3] Asuncion M, Calvo RM, San Millan JL, et al. A prospective study of the prevalence of the
polycystic ovary syndrome in unselected caucasian women from Spain. J Clin Endocrinol
Metab 2000;85:2434–8.
[4] Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853–61.
[5] Alvarez-Blasco F, Botella-Carretero JI, San Milan JL, et al. Prevalence and characteristics
of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med 2006;
166:2081–6.
[6] Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese
amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab
1989;68:173–9.
[7] Moran LJ, Brinkworth G, Noakes M, et al. Effects of lifestyle modification in polycystic
ovarian syndrome. Reprod Biomed Online 2006;12:569–78.
[8] Moghetti F, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and
metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, dou-
ble-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.
J Clin Endocrinol Metab 2000;85:139–46.
[9] Baillargeon JP, Iuorno MJ, Nestler JE. Insulin sensitizers for polycystic ovary syndrome.
Clin Obstet Gynecol 2003;46:325–40.
[10] Kitzinger K, Willmott J. ‘‘The thief of womanhood’’: women’s experience of polycystic ovar-
ian syndrome. Soc Sci Med 2002;54:349–61.
[11] Zawadsky JK, Dunaif A, et al. Polycystic ovary syndrome. In: Dunaif A, Givens JR, Hasel-
tine FP, editors. Diagnostic criteria for polycystic ovary syndrome: towards a rational
approach. Boston: Blackwell Scientific Publications; 1992. p. 377–84.
[12] Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003
consensus on diagnostic criteria and long-term health risks related to polycystic ovary syn-
drome. Fertil Steril 2004;81:19–25.
[13] Azziz R, Carmina E, Dewailly D, et al. Position statement: criteria for defining polycystic
ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Soci-
ety guideline. J Clin Endocrinol Metab 2006;91:4237–45.
[14] Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in women: experience with
over 1000 consecutive patients. J Clin Endocrinol Metab 2004;89:453–62.
[15] Carmina E, Lobo RA. Polycystic ovaries in hirsute women with normal menses. Am J Med
2001;111:602–6.
[16] Kahsar-Miller MD, Nixon C, Boots LR, et al. Prevalence of polycystic ovary syndrome
(PCOS) in first-degree relatives of patients with PCOS. Fertil Steril 2001;75:35–8.
[17] Yildiz BO, Yarali H, Oguz H, et al. Glucose intolerance, insulin resistance, and hyperandro-
genemia in first degree relatives of women with polycystic ovary syndrome. J Clin Endocrinol
Metab 2003;88:2031–6.
[18] Sam S, Legro RS, Essah P, et al. Evidence for metabolic and reproductive phenotypes in
mothers of women with polycystic ovary syndrome. Proc Natl Acad Sci USA 2006;103:
7030–5.
[19] Escobar-Morreale HF, Luque-Ramirez M, San Millan JL. The molecular-genetic basis of
functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev 2005;26:
251–82.
1166 MAGNOTTI & FUTTERWEIT

[20] Urbanek M, Woodroffe A, Ewens KG, et al. Candidate gene region for polycystic ovary syn-
drome on chromosome 19p13.2. J Clin Endocrinol Metab 2005;90:6623–9.
[21] Tucci S, Futterweit W, Concepcion ES, et al. Evidence for association of polycystic ovary
syndrome in caucasian women with a marker at the insulin receptor gene locus. J Clin En-
docrinol Metab 2001;86:446–9.
[22] Futterweit W. Pathophysiology of polycystic ovarian syndrome. In: Redmond GP, editor.
Androgenic disorders. New York: Raven Press; 1995. p. 77–166.
[23] Polson DW, Adams J, Wadsworth J, et al. Polycystic ovaries: a common finding in normal
women. Lancet 1988;1:870–2.
[24] Michelmore KE, Balen AH, Douglas DB, et al. Polycystic ovaries and associated clinical and
biochemical features in young women. Clin Endocrinol (Oxf) 1999;51:779–86.
[25] Futterweit W, Diamanti-Kandarakis E, Azziz R. Clinical features of the polycystic ovary
syndrome. In: Azziz R, Nestler JE, Dewailly D, editors. Androgen excess disorders in
women: polycystic ovary syndrome and other disorders. 2nd edition. Totowa (NJ): Humana
Press Inc.; 2006. p. 155–67.
[26] Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223–36.
[27] Balen AH, Conway GS, Kaltsas G, et al. Polycystic ovary syndrome: the spectrum of the dis-
order in 1741 patients. Hum Reprod 1995;10:2107–11.
[28] Yeh HC, Futterweit W, Thornton JC. Polycystic ovarian disease: US features in 104
patients. Radiology 1987;163:11–6.
[29] van Hooff MH, Voorhorst FJ, Kapstein MB, et al. Predictive value of menstrual cycle
pattern, body mass index, hormone levels and polycystic ovaries at age 15 years for oligo-
amenorrhoea at age 18 years. Hum Reprod 2004;19:383–92.
[30] Legro RS. The genetics of obesity: lessons for polycystic ovary syndrome. Ann N Y Acad Sci
2000;900:193–202.
[31] Carmina E, Legro RS, Stamets K, et al. Difference in body weight between American and
Italian women with polycystic ovary syndrome: influence of the diet. Hum Reprod 2003;
18:2289–93.
[32] Dunaif A, Segal KR, Futterweit W, et al. Profound peripheral insulin resistance, indepen-
dent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165–74.
[33] Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implica-
tions for pathogenesis. Endocr Rev 1997;18:774–800.
[34] Venkatesan AM, Dunaif A, Corbould A. Insulin resistance in polycystic ovary syndrome:
progress and paradoxes. Recent Prog Horm Res 2001;56:295–308.
[35] Gambeneri A, Pelusi C, Vicennati V, et al. Obesity and the polycystic ovary syndrome. Int
J Obes Relat Metab Disord 2002;26:883–9.
[36] Futterweit W, et al. An endocrine approach to obesity. In: Simopoulos AP, VanItallie TB,
Gullo SP, editors. Obesity: new directions in assessment and management. New York:
Charles Press; 1994. p. 96–121.
[37] Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian func-
tion during dietary treatment of obese women with polycystic ovary syndrome. Clin Endo-
crinol (Oxf) 1992;36:105–11.
[38] Harborne L, Fleming R, Lyall H, et al. Metformin or antiandrogen in the treatment of hir-
sutism in polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:4116–23.
[39] Jakubowicz DJ, Nestler JE. 17 alpha-hydroxyprogesterone responses to leuprolide and
serum androgens in obese women with and without polycystic ovary syndrome after dietary
weight loss. J Clin Endocrinol Metab 1997;82:556–60.
[40] Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes defining their role in the
development of insulin resistance and b-cell dysfunction. Eur J Clin Invest 2002;32(Suppl 3):
14–23.
[41] Vildirim B, Sadir N, Kaleli B. Relation of intra-abdominal fat distribution to metabolic
disorders in nonobese patients with polycystic ovary syndrome. Fertil Steril 2003;79:
1358–64.
 OBESITY AND THE POLYCYSTIC OVARY SYNDROME 1167

[42] Carey DG, Jenkins AB, Campbell LV, et al. Abdominal fat and insulin resistance in normal
and overweight women: direct measurements reveal a strong relationship in subjects at both
low and high risk of IDDM. Diabetes 1996;45:633–8.
[43] DeNino WF, Tchernof A, Dionne IJ, et al. Contribution of abdominal adiposity to age-
related differences in insulin sensitivity and plasma lipids in healthy nonobese women. Dia-
betes Care 2001;24:925–32.
[44] Puder JJ, Varga S, Kraenzlin M, et al. Central fat excess in polycystic ovary syndrome:
relation to low-grade inflammation and insulin resistance. J Clin Endocrinol Metab 2005;
90:6014–21.
[45] Hermanns-Le T, Scheen A, Pierard GE. Acanthosis nigricans associated with insulin resis-
tance: pathophysiology and management. Am J Clin Dermatol 2004;5:199–203.
[46] Dunaif A, Green G, Phelps RG, et al. Acanthosis nigricans, insulin action, and hyperandro-
genism: clinical, histological and biochemical findings. J Clin Endocrinol Metab 1991;73:
590–5.
[47] Glueck CJ, Papanna R, Wang P, et al. Incidence and treatment of the metabolic syndrome in
newly referred women with confirmed polycystic ovarian syndrome. Metabolism 2003;52:
908–15.
[48] Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an
increased risk of the metabolic syndrome associated with increased androgen levels indepen-
dent of obesity and insulin resistance. J Clin Endocrinol Metab 2006;91:492–7.
[49] Apridonidze T, Essah PA, Iuorno MJ, et al. Prevalence and characteristics of the metabolic
syndrome in women with polycystic ovary syndrome. J Clin Endocrinol 2005;90:1929–35.
[50] Cobin RH, Futterweit W, Nestler JE, et al. American association of clinical endocrinologists
position statement on metabolic and cardiovascular consequences of polycystic ovary syn-
drome. Polycystic Ovary Writing Committee. Endocr Pract 2005;11:125–34.
[51] Nestler JE. Insulin resistance syndrome and polycystic ovary syndrome. Endocr Pract 2003;
9(Suppl 2):86–9.
[52] Diamanti-Kandarakis E, Kouli C, Alexandraki K, et al. Failure of mathematical indices to
accurately assess insulin resistance in lean, overweight, or obese women with polycystic
ovary syndrome. J Clin Endocrinol Metab 2004;89:1273–6.
[53] Ehrmann DA, Barnes RB, Rosenfeld RL, et al. Prevalence of impaired glucose tolerance and
diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22:141–6.
[54] Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2
diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective,
controlled study in 264 affected women. J Clin Endocrinol Metab 1999;84:165–9.
[55] Tominaga M, Eguchi H, Manaka H, et al. Impaired glucose tolerance is a risk factor for car-
diovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabe-
tes Care 1999;22:920–4.
[56] Norman RJ, Masters L, Milner CR, et al. Relative risk of conversion from normoglycemia to
impaired glucose tolerance of non-insulin dependent diabetes mellitus in polycystic ovarian
syndrome. Hum Reprod 2001;16:1995–8.
[57] Golland IM, Vaughan Williams CA, Shalet SM, et al. Lack of predictive value of HbA1C for
impaired glucose tolerance in polycystic ovary syndrome. Gynecol Endocrinol 1989;3:
229–35.
[58] Legro RS, Gnatuk CL, Kunselman AR, et al. Changes in glucose tolerance over time in
women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab
2005;90:3236–42.
[59] Peppard HR, Marfori J, Iuorno MJ, et al. Prevalence of polycystic ovary syndrome among
premenopausal women with type 2 diabetes mellitus. Diabetes Care 2001;24:1050–2.
[60] Conn JJ, Jacobs HS, Conway GS. The prevalence of polycystic ovaries in women with type 2
diabetes mellitus. Clin Endocrinol (Oxf) 2000;52:81–6.
[61] Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations
in normal weight and obese humans. N Engl J Med 1996;334:292–5.
1168 MAGNOTTI & FUTTERWEIT

[62] Havel PJ, Kasim-Karakas S, Dubuc GR, et al. Gender differences in plasma leptin concen-
trations. Nat Med 1996;2:949–50.
[63] Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese
and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999;283:1567–8.
[64] Matsuzawa Y, Funahashi T, Kihara S, et al. Adiponectin and metabolic syndrome. Arterios-
cler Thromb Vasc Biol 2004;24:29–33.
[65] Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptindthe classical, resistindthe contro-
versial, adiponectindthe promising, and more to come. Best Pract Res Clin Endocrinol
Metab 2005;19:525–46.
[66] Yamamoto Y, Hirose H, Saito I, et al. Adiponectin, an adipocyte-derived protein, predicts
future insulin resistance: two-year follow-up study in Japanese population. J Clin Endocrinol
Metab 2004;89:87–90.
[67] Rea R, Donnelly R. Resistin: an adipocyte-derived hormone. Has it a role in diabetes and
obesity? Diabetes Obes Metab 2004;6:163–70.
[68] Escobar-Morreale HF, Villuendas G, Botella-Carretero JI, et al. Adiponectin and resistin in
PCOS: a clinical, biochemical and molecular genetic study. Hum Reprod 2006;21:2257–65.
[69] Glintborg D, Andersen M, Hagen C, et al. Evaluation of metabolic risk markers in polycystic
ovary syndrome (PCOS). Adiponectin, ghrelin, leptin and body composition in hirsute
PCOS patients and controls. Eur J Endocrinol 2006;155:337–45.
[70] Carmina E, Orio F, Palomba S, et al. Evidence for altered adipocyte function in polycystic
ovary syndrome. Eur J Endocrinol 2005;152:389–94.
[71] Skommer J, Katulski K, Poreba E, et al. Gherlin expression in women with polycystic ovary
syndrome: a preliminary study. Eur J Gynaecol Oncol 2005;26:553–6.
[72] Neveu N, Granger L, St-Michel P, et al. Comparison of clomiphene citrate, metformin, or
the combination of both for first-line ovulation induction and achievement of pregnancy
in 154 women with polycystic ovary syndrome. Fertil Steril 2007;87:113–20.
[73] Liu KE, Tataryn IV, Sagle M. Use of metformin for ovulation induction in women who have
polycystic ovary syndrome with or without evidence of insulin resistance. J Obstet Gynaecol
Can 2006;28:595–9.
[74] Siebert TI, Kruger TF, Steyn DW, et al. Is the addition of metformin efficacious in the treat-
ment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured
literature review. Fertil Steril 2006;86:1432–7.
[75] Homburg R. Pregnancy complications in PCOS. Best Pract Res Clin Endocrinol Metab
2006;20:281–92.
[76] Khattab S, Mohsen IA, Foutouh IA, et al. Metformin reduces abortion in pregnant women
with polycystic ovary syndrome. Gynecol Endocrinol 2006;22:680–4.
[77] Guido M, Romualdi D, Giuliani M, et al. Drospirenone for the treatment of hirsute women
with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin
Endocrinol Metab 2004;89:2817–23.
[78] Batukan C, Muderris II. Efficacy of a new oral contraceptive containing drospirenone and
ethinyl estradiol in the long-term treatment of hirsutism. Fertil Steril 2006;85:436–40.
[79] Shulman LP. Oral contraceptives: risks. Obstet Gynecol Clin North Am 2000;27:695–704.
[80] Azziz R. The evaluation and management of hirsutism. Obstet Gynecol 2003;101:995–1007.