V

P O LY C Y S T I C O VA R Y S Y N D R O M E

Robert L. Barbieri, m.d., f.a.c.p.

The polycystic ovary syndrome (PCOS) is a reproductive and
metabolic disorder that is characterized by hyperandrogenism
and, in most cases, oligo-ovulation and oligomenorrhea. Many
women with PCOS are insulin resistant, obese, and at increased
risk for developing type 2 (noninsulin-dependent) diabetes
mellitus. The most common presenting problems of women
with PCOS are: irregular and infrequent menstrual cycles, hirsutism, anovulatory infertility, obesity, endometrial hyperplasia,
and endometrial cancer.
Definition
The definition of PCOS is controversial. The two most widely
utilized diagnostic criteria are the NIH criteria and the Rotterdam criteria. The 1990 NIH criteria for PCOS include the presence of both hyperandrogenism (diagnosed by clinical presentation, laboratory testing, or both) and oligo-ovulation (frequently
manifesting as oligomenorrhea) in the absence of other causes of
hyperandrogenism, such as nonclassic 21-hydroxylase deficiency or an androgen secreting tumor.1 Oligo-ovulation is defined
as a menstrual cycle length greater than 35 days. Most women
with PCOS have fewer than nine menses per year. The 2003 Rotterdam criteria for PCOS require the presence of two of the following three conditions: (1) hyperandrogenism, (2) oligo-ovulation, and (3) a multifollicular ovary consistent with PCOS morphology as demonstrated by pelvic ultrasound.2 The Rotterdam
criteria for PCOS morphology are: (1) 12 or more follicles in each
ovary measuring 2 to 9 mm in diameter, (2) an increased ovarian
volume (> 10 ml) in the absence of a dominant follicle or corpus
luteum, or (3) both. Follicle distribution and ovarian stromal
echogenicity are not included in the Rotterdam criteria. Both the
NIH criteria and the Rotterdam criteria were developed by expert panels; however, neither panel had the benefit of prospective research to determine the clinical and research impacts of
the criteria.
The Rotterdam criteria encompass a broader range of clinical
presentations than the NIH criteria, yet the Rotterdam criteria
have several weaknesses. For example, to fully apply the criteria,
all women with either hyperandrogenism alone or oligo-ovulation alone need to receive a transvaginal pelvic ultrasound by a
trained expert, which is a potentially expensive use of limited
healthcare resources with modest clinical benefit. In addition, as
many as 25% of normal ovulatory women without hyperandrogenism or oligo-ovulation have PCOS morphology, indicating
that this criterion has a high prevalence in the normal population.3 Another weakness of the Rotterdam criteria is the inclusion
of women who have very mild forms of PCOSa factor that
lessens the usefulness of the criteria in identifying clinically significant PCOS. For example, women with regular ovulatory
menses, hyperandrogenism, and PCOS morphology typically
have a good clinical prognosis with regards to both their reproductive and metabolic function; many clinicians would diagnose
these woman as having so-called idiopathic hirsutism.
The main weakness of the NIH criteria is that a small number of women with PCOS (e.g., women who have hirsutism,
multifollicular ovaries, and slightly elevated blood androgen
2006 WebMD, Inc. All rights reserved.
January 2007 Update

levels) are normo-ovulatory, yet the NIH criteria does not recognize this small group as having PCOS. Most endocrinologists and gynecologists in the United States use the NIH criteria for diagnosing PCOS, and this chapter will do so as well,
unless otherwise stated. When the term PCOS is used, it refers
to the combination of hyperandrogenism and oligomenorrhea;
it does not refer to an ovary with a polycystic appearance on
transvaginal ultrasound.
Epidemiology
PCOS is one of the most common endocrine disorders in
women. In three population-based studies, the average prevalence of PCOS in women of reproductive age was reported to be
about 6%.4-6 Among anovulatory women, the prevalence of
PCOS is approximately 30%.7 The menstrual irregularity associated with PCOS typically begins before age 18. Signs of clinically
significant androgen excess typically follow but may overlap the
onset of menstrual irregularity. Adolescents with irregular
menses at age 16 are at increased risk for developing PCOS, especially if they are obese or have elevated levels of luteinizing
hormone (LH).8 The peak incidence of PCOS is between 18 and
30 years of age. In the fourth and fifth decades of life, androgen
levels in women with PCOS decreased by about 50%, but these
levels remain elevated compared with the androgen levels of
age-matched normal women.9
Ethnic, racial, and other population factors may influence the
phenotype and prevalence of PCOS. In a large-cohort study
from Kaiser Permanente, the prevalence of PCOS among
women 25 to 34 years of age was 2.6%. Women with PCOS were
more likely to be obese and have dyslipidemia and diabetes.
Among the PCOS cohort, blacks and Hispanics were more likely
than whites to be obese, and Asians were less likely to be obese
than whites. In this same cohort, blacks were more likely and
Hispanics less likely to have hypertension than whites, and
Asians and Hispanics were more likely to have diabetes than
whites.10 In another study, Mexican-American women with
PCOS were reported to have higher body mass index (BMI) and
higher levels of fasting insulin than white women with PCOS.11
The risk of PCOS varies among countries. For example, the
prevalence of PCOS in Greece (6.8%) and in the Southeast United States (6.6%)12 appears to be greater than the prevalence in
Finland (3.5%).13 Populations with a low average BMI and a low
prevalence of diabetes are probably at reduced risk for developing PCOS.
Family history is a strong risk factor for PCOS. In addition,
among women with PCOS, a family history of diabetes is a
strong risk factor for the development of impaired glucose tolerance and diabetes. The impact of family history on risk suggests
that genetic factors play an important role in the etiology of
PCOS.14
Etiology and Genetics
The cause of PCOS is not known. PCOS is probably a complex, polygenic disorder whose phenotype is strongly influenced by environmental factors, including obesity. The first-degree relatives of women with PCOS appear to be at increased
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WOMENS HEALTH:V Polycystic Overy Syndrome1

risk for both hyperandrogenism and menstrual irregularity. In

one study, the sisters of 80 women with PCOS were examined
for the presence of hyperandrogenism and menstrual irregularity. Of the 115 sisters available for study, 22% fulfilled the NIH
criteria for PCOS, and 24% had hyperandrogenemia but regular
menstrual cycles.15 This finding suggests that all first-degree relatives of women diagnosed with PCOS should be screened for
the disorder.
There are rare single-gene mutations that are highly associated with hyperandrogenism and menstrual irregularity. For
example, women with functional mutations in the alpha or
beta subunit of the insulin receptor gene tend to develop severe insulin resistance, acanthosis nigricans, hyperandrogenism, and oligo-ovulation.16 Several genes have been reported to be associated or linked with the PCOS phenotype, including the insulin gene variable number tandem repeats
(VNTR), insulin receptor substrate-1 (IRS-1), insulin receptor
substrate-2 (IRS-2), androgen receptor (AR), sex hormone
binding globulin (SHBG), cytochrome P450 cyp17, and type 5
17 beta hydroxysteroid dehydrogenase (17 beta-HSD5).17 In addition, a marker on chromosome 19 near the insulin receptor
gene has been strongly associated with PCOS in multiple independent samples.18
Preliminary data indicates that the in utero environment of a
fetus, especially an environment leading to intrauterine growth
restriction or hyperandrogenemia, may increase the likelihood
that the newborn will develop hyperandrogenism and insulin
resistance as a child or adult.19-21
Pathophysiology
Women with PCOS have both reproductive and metabolic
abnormalities.
reproductive abnormalities
The reproductive abnormalities of PCOS include (1) an increase in the hypothalamic pulse frequency of gonadotropinreleasing hormone (GnRH); (2) an increase in pituitary LH secretion (an abnormality present in over 90% of women with
PCOS); (3) increased production of ovarian androgens, including testosterone and androstenedione, from the thecal and
stromal compartments; (4) dysfunction in ovarian follicle maturation resulting in lack of development of a dominant ovarian follicle, which is a necessary prerequisite to ovulation; and
(5) in the absence of ovulation, the accumulation in the ovary
of small follicles (2 to 9 mm in diameter). It is the elevated
androgen secretion that causes hirsutism in PCOS patients;
oligomenorrhea is the consequence of the absence of monthly
ovulation.
Women with PCOS show an abnormal increase in both the
amplitude and the frequency of LH pulses in the early follicular
phase of the menstrual cycle.22 The elevated LH pulse frequency
indicates an underlying increase in the pulse frequency of GnRH
secretion by the hypothalamus; this suggests that PCOS may result from a neuroendocrine disorder. The neuroendocrine mechanisms that raise GnRH pulse frequency are poorly characterized but may include alterations in hypothalamic opioid and catecholamine tone.
Ovarian tissue from women with PCOS will continue to oversecrete androgens when cultured in vitro over long periods of
time. This suggests that the ovarian tissue has developed a relative independence from stimuli such as LH and insulin.23
2006 WebMD, Inc. All rights reserved.
January 2007 Update

metabolic abnormalities
The metabolic abnormalities of PCOS include: (1) insulin resistance in both lean and obese women with PCOS, with a higher
prevalence in obese women; (2) an increased prevalence of impaired glucose tolerance and impaired fasting glucose; (3) an increased prevalence of diabetes mellitus, especially in obese women
with PCOS; and (4) an increased prevalence of the metabolic syndrome as characterized by decreased levels of high-density
lipoprotein cholesterol (HDL-C), increased levels of triglycerides,
and increased prevalence of hypertension and abdominal obesity.
The pathophysiology of insulin resistance associated with obesity, diabetes, or PCOS is not completely characterized at a molecular level. Disorders of oxidative phosphorylation,24 insulin receptor defects, and intracellular postreceptor binding defects all
appear to contribute to insulin resistance. In women with PCOS,
genetic mutations in the insulin receptor and autoantibodies to
the insulin receptor are two specific and rare causes of insulin resistance. The most common cause of insulin resistance in PCOS is
probably a post-binding defect in insulin signaling that is exacerbated by the development of obesity.25,26 Another potential mechanism involves a defect in serine phosphorylation of the insulin
receptor in women with PCOS; this defect may cause a decrease
in receptor function, resulting in insulin resistance.27 An intriguing hypothesis is that PCOS is a gender-specific form of the metabolic syndrome (i.e., syndrome XX).28 When pancreatic function
is normal, resistance to the action of insulin in the liver, adipose
tissue, muscle, and other insulin-sensitive tissues results in a compensatory and chronic hypersecretion of insulin. Laboratory
studies suggest that insulin, especially in high concentrations, can
stimulate ovarian androgen secretion when combined with LH.
Why insulin resistance develops in muscle and fat but not in the
ovary remains unclear.29
other abnormalities
In addition to reproductive and metabolic abnormalities, numerous other abnormalities are present in women with PCOS.
For example, the levels of SHBG are reduced, as a direct result of
the impact of hyperandrogenism and hyperinsulinemia on the
livers production of SHBG. Decreased SHBG and increased androgen secretion result in increased concentrations of bioavailable testosterone. In turn, increased levels of circulating bioavailable testosterone and other androgens stimulate the growth of
terminal hairs at androgen-dependent sites. Many women with
PCOS have increased adrenal production of androgens such as
dehydroepiandrosterone sulfate (DHEAS) and androstenedione. The mechanisms that cause adrenal androgen overproduction in women with PCOS are not fully characterized, but
may include mild steroidogenic enzyme defects, such as mildly
reduced 21-hydroxylase activity (heterozygotes) or 3-beta hydroxysteroid dehydrogenase activity, increased activity of P450
cyp17, and adrenal overresponsiveness to adrenocorticotropic
hormone (ACTH).30,31
Diagnosis
The NIH definition of PCOS (see above) requires the presence
of both hyperandrogenism and oligo-ovulation and the absence
of evidence for another cause of hyperandrogenism, such as
nonclassic adrenal hyperplasia resulting from either a 21-hydroxylase deficiency or an androgen-secreting tumor.
The presence of hyperandrogenism is the hallmark of PCOS.
Most women with PCOS will show both clinical and biochemiACP Medicine
WOMENS HEALTH:V Polycystic Overy Syndrome2

Table 1 Characteristics of Common Causes of Androgen Excess

Cause

Diagnosis

Testosterone Level

Ovulation Status

8 A.M. Follicular-Phase
17-Hydroxyprogesterone Level

PCOS

Elevated LH, serum insulin,

or both

Anovulation or oligoovulation

Elevated (0.752 ng/ml) or

upper limits of normal

Normal (< 2 ng/ml)

Idiopathic hirsutism

Elevated production of androgen in the pilosebaceous unit, or a mild form

of PCOS

Regular ovulation

Normal (< 0.75 ng/ml)

Normal (< 2 ng/ml)

Adrenal hyperplasia

Decrease in 21-hydroxylase
activity because of a gene
mutation

Anovulation or oligoovulation

Elevated (0.752 ng/ml)

Elevated (> 2 ng/ml)

Ovarian or adrenal tumor

Disorder of cell growth

Anovulation

Markedly elevated
(> 2 ng/ml)

May be elevated

LH luteinizing hormone PCOSpolycystic ovary syndrome

cal manifestations. The common clinical signs of hyperandrogenism are hirsutism, acne, and male-pattern baldness. Most
women with PCOS do not have signs of virilization, such as clitoromegaly or deepening of the voice. The presence of signs of
virilization or the rapid progression of hirsutism should alert the
clinician to search for an androgen-secreting tumor or other
causes of virilization.
Oligomenorrhea is defined as menstrual cycle lengths greater
than 35 days. Most women with PCOS have fewer than nine cycles per year.
history
The history can provide key information in the differential diagnosis of androgen excess (and heightened androgen sensitivity) in women [see Table 1].

Age of Onset
In PCOS, oligomenorrhea, hirsutism, and acne typically begin
in the perimenarchal or teenage years. The onset of severe hirsutism in menopause suggests an ovarian neoplasm.

Menstrual History
Patients with PCOS typically experience irregular menstrual
cycles starting at menarche. Regular cycles are more consistent
with familial or idiopathic hirsutism. A history of initially regular periods followed by onset of oligomenorrhea or amenorrhea
and hirsutism with virilization in adult life suggests an androgen-secreting tumor.

Pace of Progression of Hirsutism

In PCOS, hirsutism tends to progress slowly, over many
years. Rapid progression to severe hirsutism suggests a virilizing
disorder from an androgen-secreting tumor. Patients with androgen-secreting tumors typically report other manifestations of
virilization, such as deepening of the voice and secondary amenorrhea. Virilization will be evident on the physical examination
(see below).

Family History
Approximately 50% of women with PCOS have a family history of PCOS, type 2 diabetes mellitus, or both.

Medication Use
Some medications appear to cause increased LH secretion
and ovarian androgen production; such medication can promote
2006 WebMD, Inc. All rights reserved.
January 2007 Update

the development of PCOS. In particular, long-term use of the anticonvulsant valproate is strongly associated with the onset of
PCOS (see below).32

Cigarette Smoking
Women who smoke have higher concentrations of androstenedione and testosterone than do nonsmoking women.
Hence, smoking may contribute to hyperandrogenism.33

Sleep Apnea
Many women with PCOS are obese and have obstructive
sleep apnea (see below). Women with PCOS should be questioned about symptoms of sleep apnea and daytime sleepiness.
physical examination

Hirsutism
Hirsutism can be assessed objectively with the Ferriman-Gallwey scoring system [see Figure 1] [see 16:XVIII Hirsutism].34 Along
with providing a baseline measurement of hirsutism, this system
can also be used to follow the efficacy of treatment. A FerrimanGallwey score of 6 or greater and 8 or greater have both been
proposed as criteria for defining hirsutism.

Insulin Resistance
Various physical findings point to insulin resistance [see
Table 2]. Excess weight is a major determinant of insulin resistance and hyperinsulinemia. Relative weight is best assessed
by means of the BMI, which is calculated by dividing the patients weight in kilograms by the square of the patients height
in meters. Women with a BMI of greater than 25 (i.e., those
who are overweight) are often insulin resistant and may
demonstrate hyperinsulinemia in response to a glucose stimulus. Women with a BMI of greater than 30 (i.e., those who are
obese) are almost always insulin resistant. Women with a BMI
of less than 22 are unlikely to be insulin resistant unless they
have one of a relatively rare group of acquired or inherited
lipodystrophic disorders.
Other physical findings that suggest insulin resistance are a
waist-to-hip ratio greater than 0.85 and a waist circumference
greater than 89 cm (35 in). The presence of acanthosis nigricans
or acrochordons (skin tags) suggests the presence of insulin resistance. The syndrome of hyperandrogenism, insulin resistance,
and acanthosis nigricans (HAIR-AN syndrome) is the most severe form of the insulin-resistant phenotype of PCOS.
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WOMENS HEALTH:V Polycystic Overy Syndrome3

Grade

Site
1. Upper Lip

1
2

2. Chin

4
5

3. Chest

6
7

4. Upper Back

5. Lower Back

6. Upper Abdomen

7. Lower Abdomen

10
8. Arm

1
2
3
4
1
2
3 and 4
1
2
3
4
1
2
3 and 4
1
2
3
4
1
2
3 and 4
1
2
3
4
1
2

11

9. Forearm

3 and 4
1, 2, 3, and 4

10. Thigh
11. Leg

1, 2, 3, and 4
1, 2, 3, and 4

Definition
Few hairs at outer margin
Small mustache at outer margin
Mustache extending halfway from
outer margin
Mustache extending to midline
Few scattered hairs
Scattered hairs with small
concentrations
Complete cover, light and heavy
Circumareolar hairs
With midline hair in addition
Fusion of these areas, with threequarters cover
Complete cover
Few scattered hairs
Rather more, still scattered
Complete cover, light and heavy
Sacral tuft of hair
With some lateral extension
Three-quarters cover
Complete cover
Few midline hairs
Rather more, still midline
Half and full cover
Few midline hairs
Midline streak of hair
Midline band of hair
Inverted V-shaped growth
Sparse growth affecting not more
than one quarter of limb surface
More than this; cover still
incomplete
Complete cover, light and heavy
Complete cover of dorsal surface; 2
grades of light and 2 of heavy
growth
As for arm
As for arm

Figure 1 Ferriman-Gallwey scoring system for quantifying hirsutism. The 11 sites are graded from 0 (no terminal hair) to 4 (severe
hirsutism). Women with a total score greater than 8 are considered hirsute.34

Unfortunately, the physical findings that are associated with

insulin resistance tend to be specific but not sensitive. For example, patients with acanthosis nigricans are almost always insulin
resistant, but many women with insulin resistance do not have
acanthosis nigricans. Although the identification of severe insulin
resistance on the basis of clinical manifestations may be relatively
simple, the detection of mild insulin resistance may be difficult.

Metabolic Syndrome
Compared to the general population, women with PCOS are
at a twofold greater risk for being diagnosed with the metabolic
syndrome.35 Many authorities recommend that women with
PCOS be screened for the presence of the metabolic syndrome.
The physical exam findings that are components of the diagnosis
of the metabolic syndrome include a waist circumference greater
than 35 inches in women and a blood pressure greater than
130/85 mm Hg. The diagnosis of metabolic syndrome requires
testing for fasting serum glucose levels, triglyceride levels, and
HDL-C levels [see Laboratory Tests, below].36

Virilization
A key aspect of the physical examination is a search for signs
of virilization, such as clitoromegaly, increased upper-body mus 2006 WebMD, Inc. All rights reserved.
January 2007 Update

cle mass, and male pattern baldness. These may indicate the presence of an androgen-secreting tumor.
Women with PCOS have enlarged ovaries, although the
ovaries typically are not palpable on pelvic examination, especially in obese women. If pelvic examination discloses a large, complex mass, the patient may have an adrenal or ovarian tumor.
laboratory tests
The goals of the laboratory evaluation of hyperandrogenism
are to rule out an adrenal and ovarian tumor, assess the severity
of the androgen excess, determine whether the source of the hy-

Table 2 Physical Findings Associated with

Insulin Resistance
Body mass index* > 25
Waist-to-hip ratio > 0.85
Waist > 90 cm

Acanthosis nigricans
Numerous acrochordons
(skin tags)

*Calculated by dividing the patients weight in kilograms by the square

of her height in meters.

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WOMENS HEALTH:V Polycystic Overy Syndrome4

perandrogenism is adrenal (nonclassic adrenal hyperplasia resulting from a 21-hydroxylase deficiency) and screen for the
presence of the metabolic syndrome.
There are few consensus guidelines on laboratory testing for
women with PCOS. In one survey of 176 pediatric endocrinologists, more than 50% of the clinicians recommended testing for
the following analytes: testosterone, 17-hydroxyprogesterone,
prolactin, DHEAS, LH, follicle-stimulating hormone (FSH), fasting glucose, and fasting insulin.37 In addition, assessment for the
metabolic syndrome is recommended by most authorities.

Testosterone
Serum testosterone concentration provides the best laboratory
estimate of the severity of androgen overproduction. Measurement can be taken of total serum testosterone, free serum testosterone, or both. Total serum testosterone measurement is performed by all clinical laboratories; these tests are reasonably well
standardized, especially in the range greater than 1.5 ng/ml, and
are less expensive than free serum testosterone measurement.
Many women with PCOS have a total testosterone concentration
in the upper end of the normal range (about 0.60 to 0.80 ng/ml);
this range is not well standardized among clinical laboratories. If
the total testosterone level is greater than 2 ng/ml (200 ng/dl),
the patient probably has ovarian stromal hyperthecosis or an
adrenal or ovarian tumor; such a patient needs a detailed evaluation, which should include imaging studies of the ovary and
adrenal glands.
Measurement of free serum testosterone concentration is
more sensitive than total testosterone measurement in detecting
mild androgen overproduction; however, the free serum testosterone assay is not well standardized among laboratories, and is
more expensive than a total testosterone assay.

17-Hydroxyprogesterone
Approximately 2% of women who present with hyperandrogenism and oligo-ovulation or anovulation have nonclassic

DHEAS
DHEAS, an androgen prohormone that can be converted to
testosterone in the periphery, is secreted almost exclusively by
the adrenal glands. The normal DHEAS level in premenopausal
women is 0.12 to 5.35 g/dl. A DHEAS level above 10.70
g/dlthat is, more than twice the upper limit of normal
should raise concern over a possible adrenal tumor.

Serum Prolactin and Thyroid-stimulating Hormone

If the patient has amenorrhea, the laboratory workup should
include an assessment of the serum prolactin level to rule out a
prolactin-secreting pituitary tumor [see 16:I Amenorrhea]. Many
clinicians also routinely measure serum FSH and serum thyroidstimulating hormone (TSH) levels in amenorrheic patients.

Serum Luteinizing Hormone and Follicle

Stimulating Hormone
The measurement of serum LH presents a special problem in
the laboratory evaluation of PCOS. In the research settingusing multiple serum LH measurements (every 10 minutes for at
least 8 hours) and a precise and reliable LH assayelevated LH
levels can be documented in more than 90% of women with
PCOS. However, because LH secretion is pulsatile and the standard commercial assays are not as precise as research assays,
measurement of LH in clinical practice is of only modest utility.
An elevated LH level is reasonably specific for PCOS, provided
the sample was not taken during a preovulatory LH surge. A
normal LH value does not necessarily exclude PCOS, however,
because the test sample may have been drawn when the patient
was at the nadir of an LH pulse. Another important point is that
as BMI increases, the normal range for LH decreases [see Figure
2].38,39 Nomograms that control serum LH for BMI are not widely
available. Many women with PCOS have an LH:FSH ratio
greater than 2. The ratio of LH:FSH may be a better test for PCOS
than a single LH measurement.

Geometric Mean LH Level (U/L)

adrenal hyperplasia resulting from a 21-hydroxylase deficiency.

The prevalence of this congenital disorder varies markedly
among different ethnic groups, from below 1% in Hispanic populations to as high as 5% to 8% in Ashkenazi Jewish populations.
The decision to screen for the disorder depends on the cost-benefit assessment of detection and the baseline prevalence of the
disorder in the patients ethnic group.
If the 17-hydroxyprogesterone level at 8 A.M. (measured in
the follicular phase of the menstrual cycle) is greater than 2
ng/ml, the patient probably has nonclassic adrenal hyperplasia
resulting from a 21-hydroxylase deficiency. This diagnosis can
be confirmed by a 60-minute ACTH stimulation test. The test
utilizes a form of synthetic ACTH (cosyntropin) that contains the
first 24 of the 39 amino acids of natural ACTH; 0.25 mg ACTH is
given intravenously or intramuscularly, and the 17-hydroxyprogesterone level is measured 60 minutes later. An ACTH 17hydroxyprogesterone level greater than 10 ng/ml after the stimulation test confirms the diagnosis of nonclassic adrenal hyperplasia resulting from a 21-hydroxylase deficiency.

0
20.4

20.521.8

21.922.9

23.027.1

> 27.1

Body Mass Index

Figure 2 Relationship between body mass index (BMI) and basal

luteinizing hormone (LH) levels in women in the follicular phase of
the menstrual cycle.38

2006 WebMD, Inc. All rights reserved.

January 2007 Update

Antimullerian Hormone (Mullerian Inhibiting Substance)

Antimullerian hormone (AMH) concentration in the circulation of women with PCOS is elevated to two to three times that
of ovulatory women.40 The number of small antral follicles detected on transvaginal imaging is correlated with serum AMH
concentration. Some authorities have recommended replacing
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WOMENS HEALTH:V Polycystic Overy Syndrome5

160

140

100

Insulin ( U/ml)

Glucose (mg/dl)

120

80

60

40

20

0
-30

30

60

90

120

-30

180

30

60

90

120

180

Minutes
PCOS

Normal

PCOS

Normal

Figure 3 In response to an oral glucose challenge, nonobese women with PCOS experience an exaggerated
increase in circulating insulin compared with weight-matched control subjects; the increase persists for over
3 hours.103

the Rotterdam criterias method of counting the number of small

antral follicles with a serum measurement of AMH.41

Pelvic Imaging
Using the NIH criteria, demonstration of polycystic ovaries
on pelvic ultrasonography is not essential for the diagnosis of
PCOS; however, pelvic imaging is necessary if the Rotterdam
criteria are used for the diagnosis of PCOS. Pelvic imaging is
clinically indicated if the ovaries are palpable and enlarged on
physical examination or the total testosterone concentration is
greater than 2.0 ng/ml.

Tests for Detection of the Metabolic Syndrome

The diagnosis of metabolic syndrome requires laboratory testing for HDL-C levels (abnormal, < 50 mg/dl), fasting serum glucose levels (abnormal, > 100 mg/dl), and serum triglyceride levels (abnormal, >150 mg/dl) [see 9:II Diabetes Mellitus Type 2].

Screening and Testing for Diabetes Mellitus

The American Diabetes Association recommends screening
for type 2 diabetes in women with PCOS.42 In a population of
women with PCOS, approximately 4% have undiagnosed diabetes and 23% have impaired glucose tolerance. There are no
clear national guidelines specifying the best method by which to
screen and test for diabetes mellitus in women with PCOS. Data
suggest that the oral glucose tolerance test may be more sensitive
than the fasting serum glucose assay or the hemoglobin A1c assay for the detection of diabetes mellitus in women with PCOS.
In one study that compared the oral glucose tolerance test with
the fasting serum glucose test, 254 women with PCOS took both
tests; 3.2% of women had diabetes on the basis of the fasting
2006 WebMD, Inc. All rights reserved.
January 2007 Update

serum glucose test, and 7.5% had diabetes on the basis of the oral
glucose tolerance test.43 Similar findings have been reported in
adolescents.44 The Rotterdam consensus conference recommended screening all obese women with PCOS using an oral glucose
tolerance test. Most cases of undiagnosed diabetes occur in obese
women with PCOS, not in lean women with PCOS.

Tests for Detection of Insulin Resistance and

Hyperinsulinemia
At least 50% of women with PCOS have insulin resistance
and hyperinsulinemia. There is no clear consensus on how to
detect these two conditions. A major problem is that the least
resource-intensive laboratory techniques for diagnosing insulin resistance and hyperinsulinemia are specific but not sensitive. Elevation of the fasting serum insulin level or a fasting
serum insulin-to-glucose ratio of less than 4.5 is almost always
associated with insulin resistance, but many insulin-resistant
women do not have fasting hyperinsulinemia. Laboratory
techniques that are both specific and sensitive for detecting insulin resistance, such as euglycemic hyperinsulinemic clamp
studies, are too complex and expensive for application in general clinical practice. Until laboratory tests that are both specific
and sensitive become widely available for clinical practice, clinicians should determine insulin resistance on the basis of clinical findings and, if necessary, simple laboratory testssuch as
assessment of fasting insulin levels or assessment of insulin response to an oral glucose challenge. Even nonobese women
with PCOS have marked increases in circulating insulin after a
glucose challenge [see Figure 3].
The Rotterdam consensus conference concluded that, given
limited resources and time, it is preferable to screen for the metaACP Medicine
WOMENS HEALTH:V Polycystic Overy Syndrome6

bolic syndrome than to screen for insulin resistance using laboratory tests.
Differential Diagnosis

ovarian androgen production in women with hyperthecotic

ovaries. Low-dose estrogen-progestin contraceptives alone do
not suppress pituitary LH secretion as completely as they do in
combination with a GnRH agonist analogue.
cushing syndrome

idiopathic hirsutism
Idiopathic hirsutism is defined as hirsutism in a woman with
regular, ovulatory menstrual cycles. Women with idiopathic hirsutism have circulating testosterone and androstenedione concentrations at the upper limit of the normal range; however, in
these patients, such levels are lower than the levels observed in
women with PCOS [see Table 1]. Women with idiopathic hirsutism often have sisters with PCOS, and they tend to have a
lower BMI than their sisters with PCOS.45 Many authorities believe that idiopathic hirsutism is a mild form of PCOS in which
hyperandrogenism is present but has not progressed to the point
at which ovulatory menses have become disrupted. Other authorities believe that idiopathic hirsutism is the result of overactive skin conversion of weak precursor androgens (e.g., androstenedione) to potent androgens (e.g., dihydrotestosterone)
directly in the pilosebaceous unit. Regardless of the etiology, idiopathic hirsutism is best treated using the same approach as
that used for hirsutism in women with PCOS (see below).

Some women with ACTH-secreting pituitary tumors present

with signs of androgen excess and menstrual irregularity. Physical findings such as violaceous abdominal striae larger than 2 cm
in diameter and proximal muscle weakness, together with laboratory findings such as hypokalemia, should lead the clinician to
consider a diagnosis of Cushing syndrome rather than PCOS [see
3:IV The Adrenal].
valproic acid treatment
Epilepsy and bipolar disorder can be associated with
oligomenorrhea and hirsutism.48,49 But treatment with valproic
acid appears to be associated with an increased prevalence of
PCOS above that present for the underlying condition. Valproic
acid increases both pituitary secretion of LH and ovarian secretion of testosterone.50 This may result in the onset of oligomenorrhea and hirsutism in many women.
Syndromes and Diseases Associated with PCOS

virilization syndromes
Women with a rapid onset of virilization or a serum testosterone
level greater than 2 ng/ml (200 ng/dl) should be evaluated for the
presence of an adrenal or ovarian tumor. Magnetic resonance
imaging can be used to screen for an adrenal tumor, whereas
pelvic sonography may be helpful in detecting an ovarian tumor.
Adrenal carcinoma often presents with rapid-onset virilization; it is often associated with systemic symptoms such as fatigue, weakness, and weight loss. In patients with adrenal carcinoma, the DHEAS concentration is often greater than 8 g/ml,
and 24-hour urinary 17-ketosteroid excretion is markedly increased, to about 30 mg/dl.
ovarian hyperthecosis
Careful histologic examination of ovaries from women with
PCOS often reveals islands of luteinized, steroid-secreting stromal cells (stromal hyperthecosis) in the medullary portion of the
ovary that are not associated with follicular structures.46 Severely
hyperthecotic ovaries may contain only a small number of follicles, each 4 to 8 mm in diameter. PCOS patients with more severe
hyperinsulinemia seem to be at highest risk for hyperthecosis.
Only a small subset of women with hyperandrogenism have
stromal hyperthecosis. The diagnosis should be considered in a
patient who presents with virilization, a total serum testosterone
concentration of greater than 2 ng/ml, a normal LH level, and
marked insulin resistance and hyperinsulinemia. Pathologic
confirmation of the diagnosis, which requires removal of the
ovaries, is not necessary.
Differentiation of ovarian hyperthecosis from PCOS is important because women with ovarian hyperthecosis often do not
have significant suppression of circulating testosterone when
treated with estrogen-progestin contraceptive alone. Instead,
treatment with a GnRH analogue (e.g., leuprolide acetate depot,
3.75 mg intramuscularly every 4 weeks) plus an estrogen-progestin contraceptive, often results in the normalization of circulating androgens.47A possible interpretation of this observation is
that LH must be profoundly suppressed in order to decrease
2006 WebMD, Inc. All rights reserved.
January 2007 Update

metabolic syndrome
Many studies report that women with PCOS, especially those
who are obese, are at high risk for developing the metabolic syndrome. In the NHANES III cohort, the population-wide risk for
metabolic syndrome among women 20 to 29 years of age was
6%; in women with PCOS, it was 45%.35 In women with PCOS,
the most prevalent factors for metabolic syndrome were increased waist circumference (67%) and decreased serum HDL-C
(68%). The least prevalent factor was an elevated fasting glucose
(4%). Increased levels of triglyceride and low-density lipoprotein
cholesterol (LDL-C) and decreased levels of HDL-C are commonly observed in women with PCOS.51,52
cardiovascular disease
The risk for coronary heart disease among women with
PCOS is not precisely characterized. Many surrogate and intermediate markers for coronary heart disease are abnormal in
women with PCOS. For example, C-reactive protein53,54 and endothelin-155 are increased in the serum of women with PCOS.
In one series, women with PCOS were reported to have more
extensive coronary artery disease as demonstrated by cardiac
catheterization than ovulatory women.56 In women older than
45 years of age who have PCOS, the mean thickness of the
carotid intima-media was significantly greater than in control
subjects, but it was below that observed in women with established carotid artery disease.57 Women with PCOS appear to
have increased coronary artery calcium as shown by computed
tomography; however, obesity appears to account for much of
the observed association between PCOS and coronary artery
calcification.58 In the Nurses Health Study II cohort, menstrual
cycle irregularity was associated with a small and significant
increase in the risk for cardiovascular events.59
sleep apnea
Obese individuals are at increased risk for sleep apnea. Insulin resistance and the PCOS phenotype appear to increase the
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WOMENS HEALTH:V Polycystic Overy Syndrome7

Table 3 Treatment of Hirsutism, Anovulatory Infertility, and Endometrial

Hyperplasia in Women with PCOS
Standard Treatment

Presenting Problem

Alternative Treatment

Hirsutism

Oral contraceptive plus spironolactone

Weight loss

Oral contraceptive used in a long-cycle

regimen, plus spironolactone
Oral contraceptive plus GnRH analogue
Insulin sensitizer, preferably metformin
Finasteride

Acne

Oral contraceptive

Topical agents, oral antibiotics

Infertility

Weight loss
Clomiphene
Metformin plus clomiphene
Clomiphene plus glucocorticoids
Low-dose FSH injections
Low-dose FSH injections plus metformin

Ovarian surgery
IVF-ET

Endometrial hyperplasia

Oral contraceptives
High-dose progestins

Weight loss

FSHfollicle-stimulating hormone GnRHgonadotropin-releasing hormone IVF-ETin vitro fertilization with embryo transfer

risk for sleep apnea more than obesity alone. Women with PCOS
should be screened for the presence of sleep apnea.60
nonalcoholic steatohepatitis
Obese individuals are at increased risk for nonalcoholic
steatohepatitis. In one study, 15% of women with PCOS had elevated concentrations of aspartate aminotransferase, elevated alanine aminotransferase, or both. Of the women with elevated liver function tests who underwent liver biopsy, all had nonalcoholic steatohepatitis with fibrosis.61
Treatment
Treatment for PCOS can be directed at the chief complaint(s)
as well as the other common problems faced by women with the
disorder. The most common complaints of women with PCOS
are irregular and infrequent menses, hirsutism, and anovulatory
infertility [see Table 3]. PCOS should be treated, because it poses
long-term risks of endometrial cancer, diabetes mellitus, and
possibly cardiovascular disease.
Treatment of PCOS in a woman who smokes cigarettes includes smoking cessation. Discontinuance of smoking may result in a reduction in circulating androgens; also, smoking is a
contraindication to the use of oral contraceptives, which are often prescribed for patients with PCOS.
Women with PCOS are frequently overweight or obese. Given the long-term morbidity and mortality associated with excess
BMI, weight reduction should be a focus of the treatment plan.62
treatment of irregular and infrequent menses
The first-line treatment of irregular and infrequent menses,
which is the chief complaint of women with PCOS, is a cyclic estrogen-progestin contraceptive. An estrogen-progestin contraceptive can be prescribed as an oral pill, a transvaginal ring, or a
transdermal patch. Cyclic estrogen-progestin oral contraceptives
produce multiple beneficial effects in patients with PCOS. These
effects include the following: (1) decreased LH secretion, which
suppresses ovarian androgen production; (2) increased liver pro 2006 WebMD, Inc. All rights reserved.
January 2007 Update

duction of sex hormonebinding globulin, which decreases free

testosterone concentration; (3) decreased adrenal androgen production, through an unidentified pathway; (4) prevention of endometrial hyperplasia; and (5) regular uterine withdrawal bleeding. Of course, oral contraceptives also prevent pregnancy. The
choice of agent does not seem important; it appears that any oral
contraceptive, regardless of the estrogen dose or the progestin employed, can be effective in the treatment of hirsutism. However,
most authorities avoid using an androgenic progestin such as norgestrel in treating women with PCOS. Drosperinone, which is a new
progestin that has antiandrogenic and antimineralocorticoid properties, may have modest relative benefits in women with PCOS.
The most common regimen of cyclic estrogen-progestin therapy comprises 21 hormone pills and seven placebo pills; however, alternative regimens are available. One such regimen uses 24
hormone pills and three placebo pills. Other regimens use 84
hormone pills and 7 placebo pills; these are referred to as longcycle regimens. Long-cycle regimens may be associated with
better suppression of ovarian testosterone secretion than are
standard-cycle regimens, especially in the first few months of
treatment.
Many women with PCOS are obese and have multiple risk
factors for cardiovascular disease. Some authorities have noted
that the risk of cardiovascular complications (e.g., myocardial infarction and stroke) associated with estrogen-progestin contraceptives are approximately twofold greater for women with
PCOS than for normo-ovulatory women.63 However, the attributable risk of the cardiovascular complications is very low (less
than one event/10,000 women-years of use) in both groups.
In specific situations where estrogen-progestin therapy is relatively contraindicated, such as in women with PCOS and hypertension, metformin can be used for the induction of regular
menses64; however, it may take up to 6 months of treatment before metformin induces regular cycles. In one study, after 3 and 6
months of metformin treatment, 55% and 70% of women respectively reported regular menstrual cycles.65 Metformin induces
ovulation, which may increase the risk of pregnancy in women
with PCOS using this treatment. Consequently, if the patient is
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WOMENS HEALTH:V Polycystic Overy Syndrome8

having sexual intercourse and does not desire to become pregnant, a contraceptive is required.
An alternative treatment for irregular menses is to use cyclic
progestin, such as medroxyprogesterone acetate (10 mg daily for
14 days each month) to induce a regular cycle. However, this
regimen does not provide contraception; in fact, medroxyprogesterone acetate may trigger ovulation by suppressing the elevated GnRH pulse frequency observed in women with PCOS.66
No high-quality studies directly compare estrogen-progestin
versus progestin-only treatment for irregular menses.67
treatment of hirsutism
Recommended treatment of hirsutism combines a hormonal
therapy with a nonhormonal therapy [see 16:XVIII Hirsutism].
The mainstay of the hormonal treatment of hirsutism resulting from androgen excess is the combination of an estrogenprogestin oral contraceptive (used in regular or long cycles) and
an antiandrogen (e.g., spironolactone, 100 mg daily). For patients
who prefer monotherapy, estrogen-progestin can be used alone.
In a meta-analysis of seven studies, spironolactone, 100 mg daily, was demonstrated to be superior to placebo for subjective improvement of hair overgrowth. In addition, spironolactone, 100
mg daily, was demonstrated to be superior to finasteride, 5 mg
daily; finasteride is a blocker of androgen synthesis.68 Patients
should be advised that response to spironolactone tends to be
slow; for more immediate results, patients may prefer the use of
techniques that directly destroy the hair follicle. The options for
nonhormonal therapy of hirsutism include shaving, electrolysis,
laser treatment, and the prescription medication eflornithine
(Vaniqa),which is an inhibitor of hair growth that is applied
topically.69
treatment of anovulatory or oligoovulatory infertility
Ovulation induction in PCOS follows a stepwise approach,
beginning with interventions that require nominal resources
(e.g., behavior modification and medical therapy) and escalating
to resource-intensive surgical interventions [see Table 4]. If the
BMI is greater than 25, weight loss is an important goal. If normalization of the BMI cannot be achieved, clomiphene is often
prescribed because it is relatively inexpensive and has an excellent safety profile. Hyperandrogenic, insulin-resistant women
are more likely to fail to ovulate and become pregnant with

Table 4 A Stepwise Approach to the Induction

of Ovulation in Infertile Women with PCOS*
Step 1: if BMI is > 27, weight loss of at least 10%
Step 2: clomiphene
Step 3: if DHEAS > 2 g/ml (200 g/dl), clomiphene plus glucocorticoid therapy
Step 4: metformin for 8 to 12 wk
Step 5: metformin plus clomiphene
Step 6: low-dose FSH therapy
Step 7: metformin plus low-dose FSH therapy
Step 8: in vitro fertilization
Step 9: laparoscopic ovarian surgery to reduce ovarian androgen
production
*Steps proceed in order of increasing resource intensity.

2006 WebMD, Inc. All rights reserved.

January 2007 Update

clomiphene than are women who are not insulin resistant. If

both weight loss and clomiphene do not induce ovulation and
result in pregnancy, the currently available choices for ovulation
induction include insulin-sensitizing agents such as metformin,
FSH injections, ovarian surgery, and in vitro fertilization with
embryo transfer (IVF-ET).
Before initiating ovulation induction for anovulatory infertility, a basic infertility examination should be completed. This should
include a semen analysis and possibly a hysterosalpingogram to
document tubal patency and a normal uterine contour.

Weight Loss
Many women with PCOS are overweight or obese. In such
women, weight loss in the range of 10% of body mass is associated with a decrease in insulin secretion, a decrease in LH secretion, and a decrease in androgen production. The result is
often a resumption of regular ovulation and, in some women,
pregnancy.70,71

Clomiphene
Clomiphene is the most widely used agent for ovulation induction in women with PCOS. Clomiphene is an antiestrogen (or
more precisely, a selective estrogen receptor modulator) that
blocks estrogen action in the hypothalamus and pituitary, resulting in an increase in pituitary secretion of LH and FSH. In turn,
the increased FSH secretion from the pituitary can remove the
presence of an intraovarian block prohibiting the development of
a dominant follicle, an issue that is often observed in women with
PCOS. If clomiphene-induced pituitary secretion of FSH can
cause a dominant follicle(s) to grow, that follicle will trigger the
pituitary release of LH, and subsequently ovulation will occur.
A meta-analysis of four randomized trials indicates that
clomiphene is an effective first-line agent for induction of ovulation in women with PCOS.72
The FDA-approved dosage of clomiphene for the induction of
ovulation is 50 or 100 mg daily for a maximum of 5 days during
each menstrual cycle. After a spontaneous menses or the induction of menses with a progestin withdrawal maneuver (e.g.,
medroxyprogesterone acetate, 10 mg p.o. daily for 5 days),
clomiphene (50 mg daily for 5 days) is started on cycle day 3, 4,
or 5. In properly selected women, 50% will ovulate through the
use of this clomiphene regimen. Another 25% will ovulate if the
dosage of clomiphene is increased to 100 mg daily. During each
cycle, determination of ovulation should be attempted by use of
basal body temperature charts, ultrasound monitoring of follicle
growth and rupture, or luteal-phase progesterone measurements. Some clinicians use endometrial biopsies to document
ovulation in cycles where conception is not attempted. In most
women, ovulation occurs approximately 5 to 12 days after the
last dose of clomiphene. Measurement of the urinary LH surge is
recommended to assist the patient in prospectively determining
the periovulatory interval.
Although the FDA has approved 100 mg as the maximum
daily dosage of clomiphene, many clinicians prescribe clomiphene at doses of 150 mg daily for 5 days, and some give doses
of 250 mg daily for 5 days. Women who fail to ovulate after taking clomiphene in doses of 100 mg daily for 5 days may ovulate
if they are treated with clomiphene at doses of 150 mg daily for 5
days. Some authorities advocate use of clomiphene at doses up
to 250 mg daily for up to 14 days. As many as 70% of the women
who fail to ovulate with doses of 100 mg daily will ovulate with
higher doses, but fewer than 30% of those become pregnant. In
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WOMENS HEALTH:V Polycystic Overy Syndrome9

my opinion, there are few data to support the use of clomiphene

at doses greater than 150 mg daily. Women who do not become
pregnant while taking clomiphene at 150 mg daily should consider other approaches to ovulation induction (see below).
Clomiphene treatment can be associated with adverse changes
in the reproductive tract, including induction of a luteal-phase
defect (delay of endometrial maturation) and the creation of a
hostile cervical environment resulting from a low quantity and
poor quality of cervical mucus. Some clinicians recommend endometrial biopsy during a test cycle of clomiphene treatment to
assess whether clomiphene induces luteal-phase deficiency.
Many clinicians recommend that a postcoital test be performed
during the first cycle of clomiphene treatment to screen for poor
cervical mucus properties.
Multiple pregnancy is a well known outcome of clomiphene
use. The absolute risk of high-order multiple gestation with
clomiphene treatment was shown to be low in a manufacturers
study of 2,369 clomiphene-induced pregnancies: 7% resulted in
twins, 0.5% triplets, 0.3% quadruplets, and 0.13% quintuplets.
However, because clomiphene is a heavily prescribed medication, the number of triplets resulting from clomiphene is substantial. The rate of spontaneous abortion after clomiphene-induced ovulation and pregnancy is approximately 15%. The most
common side effects of clomiphene include vasomotor symptoms (20%), adnexal tenderness (5%), nausea (3%), headache
(1%), and, rarely, blurring of vision or scotomata. Most clinicians
permanently discontinue clomiphene in women who experience
changes in vision resulting from the drug.

Clomiphene plus Glucocorticoid

Anovulatory women with PCOS who do not ovulate with
clomiphene may ovulate if treated with the combination of a
short course of dexamethasone followed by clomiphene.73

Insulin Sensitizers
A major advance in reproductive endocrinology is the discovery that insulin sensitizers can induce ovulation in infertile
women with oligo-ovulation, hyperandrogenism, and insulin resistance. Insulin sensitizers that have been approved for the treatment of diabetes include metformin, rosiglitazone, and pioglitazone. The insulin sensitizer D-chiro-inositol has been demonstrated to induce ovulation in hyperandrogenic insulin-resistant
women, but it is currently available for use in research trials only.74
Metformin Metformin is an oral biguanide antihyperglycemic agent approved for the treatment of type 2 diabetes
mellitus. In women with PCOS, metformin restores regular
menstrual cycles, improves hirsutism, increases insulin sensitivity, and improves the lipid profile. In women with PCOS and
anovulatory infertility, metformin often restores ovulatory
menses, and pregnancy may result.75,76
Metformin decreases blood glucose by inhibiting hepatic glucose production and enhancing peripheral glucose uptake. It increases insulin sensitivity at the postreceptor level and stimulates
insulin-mediated glucose disposal. Metformin may work
through LKB1 (the Peutz-Jegher syndrome tumor suppressor
protein) to stimulate adenosine monophosphate-activated protein kinase in the liver.77 Unlike the sulfonylureas, metformins
mechanism of action does not involve increased insulin secretion.
Metformin is available in immediate-release tablets (500 mg,
850 mg, and 1,000 mg) and extended-release (ER) tablets (500 mg
and 750 mg). The typical target dose is approximately 1,500 mg
2006 WebMD, Inc. All rights reserved.
January 2007 Update

daily; however, doses up to 2,500 mg daily have been utilized. In

adolescents, doses as low as 500 mg to 850 mg daily may be effective. The immediate-release formulation is taken in divided doses
with breakfast, lunch, and dinner. The ER formulation is taken
with dinner (or the largest meal of the day). Many clinicians believe that the ER formulation is associated with fewer gastrointestinal side effects. To minimize gastrointestinal side effects, such
as nausea, many clinicians start metformin at 500 mg daily for the
first week, then increase the dosage to 500 mg twice daily for the
second week, and then increase the dosage again to 500 mg three
times daily. Although metformin is not approved by the FDA for
the treatment of PCOS, it may be significantly less expensive than
FSH injections, ovarian surgery, and IVF-ET; metformin may also
have fewer serious side effects than these treatments.
The most common side effects associated with metformin are
GI disturbances, including diarrhea, nausea, vomiting, and abdominal bloating. In rare cases, metformin treatment has caused
fatal lactic acidosis, but most of these patients had some degree
of renal insufficiency or were hypoxic. Before starting treatment
with metformin, it is advisable to confirm that the patients
serum creatinine level is less than 1.4 mg/dl.
Metformin increases the number of ovulatory cycles in infertile women with hyperandrogenism and insulin resistance. When
used together with clomiphene, metformin significantly increases the rate of ovulation and of pregnancy resulting in live-born
singleton births.78 Metformin has also been shown to enhance the
effectiveness of FSH injections to induce ovulation in oligo-ovulatory, hyperandrogenic, and insulin-resistant women.79
If a patient has not ovulated after 5 to 10 weeks of metformin
treatment, clomiphene can be added (see above). If the patient
becomes pregnant, metformin can be discontinued, although it
is a category B drug for pregnant women and has been used by
some clinicians to treat diabetes in pregnant women.80
Metformin versus clomiphene Clomiphene and metformin
are both effective first-line agents in the treatment of anovulatory
infertility. There is insufficient literature to definitively identify
the superior therapy. However, there is concern that clomiphene
treatment is associated with a greater risk of spontaneous abortion than metformin.81 Clomiphene, but not metformin, is approved by the FDA for ovulation induction.
Metformin plus clomiphene In a meta-analysis of 13 clinical
trials, the ovulation rates were 46% with metformin alone and 76%
with the combination of metformin plus clomiphene.82 For women who have not ovulated with metformin or clomiphene monotherapy, the combination of the two drugs appears to be effective.
Thiazolidinediones The thiazolidinediones increase cellular sensitivity to the effects of insulin. Agents in this category include pioglitazone, rosiglitazone, and troglitazone. Several studies of troglitazone in women with PCOS reported a decrease in
fasting insulin, LH, and testosterone levels, along with an increase in ovulatory cycles.83,84 Troglitazone was removed from
the market because of its association with the risk of death from
liver failure. The risk was very small, affecting approximately 1
in 25,000 patients treated with the drug.
Pioglitazone and rosiglitazone, widely used in the treatment
of diabetes mellitus, have not been extensively studied for their
impact on ovulation. Pilot studies indicate that like troglitazone,
both pioglitazone and rosiglitazone are effective for inducing
ovulation as monotherapy or in combination with clomiphene.
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They are not approved by the FDA for this indication.85,86 In one
study of women with PCOS and anovulatory infertility who had
not conceived with clomiphene monotherapy, rosiglitazone plus
clomiphene was reported to be associated with a per-cycle pregnancy rate of 21%.87

Clomiphene plus Gonadotropin Injection

In women who fail to ovulate after therapy with clomiphene
alone, gonadotropin injections can be added to clomiphene treatment to induce ovulation. Typically, the injections are started after clomiphene, 100 to 200 mg daily, has been given for 5 days.
The main benefit of this combination is that it tends to reduce the
quantity of gonadotropins (an expensive medication) needed to
induce ovulation during each cycle, because the rise in endogenous LH and FSH levels induced by clomiphene increases the
sensitivity of the follicles to the injected gonadotropins. This regimen has been associated with a 50% decrease in the dosage of
gonadotropin required to induce ovulation.88

Gonadotropins
The gonadotropins currently available for ovulation induction include (1) FSH produced by recombinant DNA technology
and immunopurification and (2) LH plus FSH derived from
menopausal urine. The recombinant FSH preparations can be
given as subcutaneous injections and are available in ampules of
37.5 or 75 IU. FSH is the primary hormone responsible for follicular recruitment and growth in humans; it can be used as a single agent to induce ovulation in most anovulatory women.
Women with PCOS generally do not require exogenous LH to
induce follicular development, because their levels of LH secretion are already increased.
In women with PCOS, induction of ovulation with long-term,
low-dose FSH treatment appears to result in a high pregnancy
rate with a low rate of complications, including high-order multiple gestation and ovarian hyperstimulation.89 In this approach,
75 units of FSH are given daily for the first 14 days; the dose is
then raised by 37.5 units every 7 days until follicular ripening is
complete. If FSH treatment fails to result in pregnancy, consideration should be given to the combination of metformin and FSH,
ovarian surgery, or IVF-ET.
During gonadotropin induction of ovulation, as many as 20%
of patients experience mild to moderate enlargement of the
ovaries. Some women treated with gonadotropins develop increased vascular permeability and accumulation of fluid in the
peritoneal cavity and pleural space, a condition termed the ovarian hyperstimulation syndrome (OHSS). Clinical manifestations
of OHSS include abdominal pain, abdominal distention, nausea,
vomiting, diarrhea, and dyspnea. Other physical and laboratory
findings of OHSS include weight gain, ovarian enlargement, ascites, pleural effusion, hemoconcentration, electrolyte imbalances, renal dysfunction, and thrombosis.90 Treatment includes
bed rest, maintenance of intravascular volume, prophylaxis
against thrombosis, and surgical correction of ovarian torsion.
Before the utilization of repetitive estradiol measurements
and sonographic evaluation of follicular development, OHSS
occurred in as many as 5% of women receiving gonadotropin
treatment. In recent series that employed intense monitoring
with these techniques, the rate of OHSS was approximately
0.5%.91 OHSS may be more severe and have a longer course if a
successful pregnancy occurs. Multiple births occur in approximately 15% of pregnancies that take place after ovulation induction with gonadotropins.
2006 WebMD, Inc. All rights reserved.
January 2007 Update

Ovarian Surgery
Laparoscopic drilling of the ovary is the most widely studied
surgical treatment for ovulation in PCOS92; approximately 1,000
cases have been reported. These reports demonstrate that
surgery to induce ovulation causes a decrease in circulating LH
(50% decline) and testosterone (30% decline) and an increase in
FSH (30% increase). The pregnancy rate is in the range of 50% at
12 months and 70% at 24 months. The surgical techniques used
for ovarian drilling vary between centers. However, all use a
laser or electrosurgery to make multiple millimeter-size punctures in each ovary.
In one randomized, controlled study, 50 women with PCOS
and anovulatory infertility were randomized to receive either
ovarian surgery for ovulation induction or injections of FSH; at 6
months the cumulative pregnancy rate was 28% in the surgical
group and 33% in the FSH injection group (no significant difference).93 A meta-analysis of six trials concluded that ovarian surgery and FSH injections had similar efficacy for ovulation induction in women with PCOS94; however, the long-term effects of
ovarian surgery on ovarian function were not well characterized.

In Vitro Fertilization with Embryo Transfer

IVF-ET has been demonstrated to be effective in the treatment
of infertile women with PCOS who fail to become pregnant with
gonadotropin injections. In preliminary reports, IVF-ET treatment of infertile women with PCOS has been associated with a
per-cycle live birth rate of 25% to 35%.95
treatment of obesity
Numerous studies have demonstrated the benefits of weight
loss in hyperandrogenic, insulin-resistant women.96 In these
studies, mean weight loss ranging from about 10 to 20 kg has
been associated with a decrease in insulin levels and testosterone
concentration and with ovulation and subsequent pregnancy in
many women.97
Weight loss is difficult to achieve. A structured program that
includes consultation with a nutritionist, encouragement by the
physician, a low-calorie diet, and initiation of an exercise program may be the most effective nonsurgical approach in these
patients [see CE:IV Diet and Exercise]. In select cases, pharmacological adjuvants may be of benefit. Surgical methods of weight
reduction can be very effective, especially in women whose BMI
is greater than 40 [see 3:X Obesity].98
reduction of risk for endometrial
hyperplasia and cancer
Women who are anovulatory, especially those with obesity
and insulin resistance, are at increased risk for developing endometrial hyperplasia and cancer. In these women, treatment
with cyclic progestin therapy either in the form of an estrogenprogestin contraceptive or as regular cycles of progestin-only
therapy can reduce the risk of both endometrial hyperplasia and
cancer. For women with PCOS and menorrhagia, an endometrial biopsy is needed to assess the status of the endometrium.99,100
treatments not recommended

Glucocorticoid Therapy for Hirsutism

Treatment with glucocorticoids may be appropriate in women
with ACTH-dependent adrenal androgen overproduction, such
as those with nonclassic adrenal hyperplasia resulting from 21hydroxylase deficiency101,102; however, it is not appropriate for the
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treatment of hirsutism in PCOS. A major problem with glucocorticoid therapy is that the complete suppression of ACTH production often requires giving more glucocorticoid than would normally be produced by the adrenal glands. As a result, patients receiving long-term glucocorticoid treatment are at increased risk
for iatrogenic Cushing syndrome, osteoporosis, and diabetes
mellitus. In addition, the corticotropin-releasing hormone
ACTHcortisol axis may become so suppressed that the adrenal
response to stress is blunted. For these reasons, it is advisable to
avoid using glucocorticoids in the treatment of hirsutism. If the
clinician does decide to use glucocorticoid therapy, use of lowdose glucocorticoids (5 or 7.5 mg of prednisone daily) or an alternate-day regimen of glucocorticoids may minimize these risks.
Because almost all women treated with glucocorticoids gain
weight and many develop osteoporosis, the clinician should carefully monitor weight and bone density in these patients.

Ovarian Surgery for Irregular Menses or Hirsutism

Ovarian surgery can be used to decrease the mass of androgen-secreting thecal and stromal tissue. No randomized, controlled trials have been published concerning the benefits and
risks of ovarian surgery for the treatment of irregular menses or
hirsutism. In my opinion, the risks of ovarian surgery, such as
anesthetic complications, major adhesion formation and ovarian
failure are greater than the potential benefits for women with irregular menses or hirsutism. I recommend ovarian surgery only
for women with PCOS and anovulatory infertility in whom standard approaches to induction of ovulation such as weight loss,
clomiphene, metformin and FSH therapy have failed.
The author has no commercial relationships with manufacturers of products or
providers of services discussed in this chapter.
Metformin and rosiglitazone have not been approved by the FDA for uses described in this chapter.

References
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2. Revised 2003 consensus on diagnostic criteria and long-term health risks related to
polycystic ovary syndrome (PCOS). The Rotterdam ESHRE/ASRM-sponsored PCOS
Consensus Workshop Group. Hum Reprod 19:41, 2004
3. Murphy MK, Hall JE, Adams JM, et al: Polycystic ovarian morphology in normal
women does not predict the development of PCOS. J Clin Endocrinol Metab Aug 1
(epub ahead of print), 2006
4. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al: Prevalence of PCOS in unselected
black and white women of the southeastern United States: a prospective study. J Clin
Endocrinol Metab 83:3078, 1998
5. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al: A survey of the polycystic ovary
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