Volume 61, Number 2

OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright 2006
by Lippincott Williams & Wilkins

CME REVIEWARTICLE

CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a total
of 36 AMA/PRA category 1 credit hours can be earned in 2006. Instructions for how CME credits can be earned appear on
the last page of the Table of Contents.

Polycystic Ovary Syndrome and Its

Differential Diagnosis
Danielle E. Lane, MD
Director, Center for Reproductive Health, Kaiser Vacaville, Vacaville, California
Polycystic ovary syndrome (PCOS) is a common disorder of reproductive-aged women. It affects
between 3.46.8% of this population. Common clinical symptoms of PCOS include menstrual
irregularities, hirsutism, and often obesity. Long-term sequelae include anovulatory infertility,
endometrial carcinoma, and an increased risk for cardiovascular disease due to type II diabetes
mellitus, dyslipidemia, and systolic hypertension.
The diagnosis of PCOS is one of exclusion and is defined by the Rotterdam criteria which were
established in 2004. However, several other endocrine disorders can closely resemble PCOS. It is
important for practitioners to recognize and distinguish PCOS from other disorders in its differential.
Target Audience: Obstetricians & Gynecologists, Family Physicians
Learning Objectives: After completion of this article, the reader should be able to summarize the
short-term reproductive and long-term metabolic consequences of polycystic ovary syndrome (PCOS),
point out the importance of meeting the current criteria for diagnosis, and recall the recommended
treatment related to the clinical presentation of the patient.

DEFINITION AND PREVALENCE OF

POLYCYSTIC OVARY SYNDROME
In 1990, an National Institutes of Health/National
Institute of Child Health and Human Development
conference first defined standardized criteria for the
diagnosis of polycystic ovary syndrome (PCOS).
They defined PCOS as the presence of 1) chronic
anovulation, 2) clinical hyperandrogenism (hirsutism, acne, androgenic alopecia) and/or hyperandroThe author has disclosed that she has no financial relationships
with or interests in any commercial companies pertaining to this
educational activity.
The author has disclosed that combined oral contraceptives
and the levonorgestrel-releasing intrauterine device have not been
approved by the U.S. Food and Drug Administration for use in the
treatment of menorrhagia. Please consult product labeling for the
approved usage of this drug or device.
Wolters Kluwer Health has identified and resolved all faculty
conflicts of interest regarding this educational activity.
Reprint requests to: Danielle E. Lane, MD, Director, Center for
Reproductive Health, Kaiser Vacaville, 3700 Vaca Valley Parkway,
Vacaville, CA 95688. E-mail: Danielle.lane@kp.org.

genemia, and 3) the exclusion of secondary causes

such as hyperprolactinemia, thyroid dysfunction, and
adrenal disorders (1). However, over the next decade,
concerns developed regarding the marked heterogeneity of this disease state (48) (Table 1). Thus, in
2003, another consensus workshop was held in Rotterdam, and the criteria for PCOS were updated (2)
(Table 2). The result was to include the ultrasonographic appearance of polycystic-appearing ovaries
as part of the diagnostic criteria (Fig 1). The conference further recognized that patients with PCOS
were at increased risk for the development of insulin
resistance, hyperinsulinemia, and type II diabetes
mellitus in addition to other long-term sequelae, including obesity, infertility, cardiovascular risk (all
components of the metabolic syndrome), and endometrial carcinoma.
Given the potential public health risk suggested
by the long-term complications associated with
PCOS, it is somewhat surprising that limited information is available regarding its prevalence. In

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Obstetrical and Gynecological Survey

TABLE 1
Historical factors in self-selected women with polycystic ovary syndrome (PCOS) and control women. Adapted from Legro et al. (48)
Characteristic
Irregular menstrual cycles
Nulliparous
Use of fertility medications
in attempt to achieve
pregnancy
Hyperandrogenemia I
(T #58 ng/dL)
Hyperandrogenemia II
(T #58 ng/dL and/or uT
#16 ng/dL)

PCOS Women,
% (n)

Control Women,
% (n)

Odds Ratio

95% Confidence
Interval for Odds Ratio

P Value

96 (44)
84 (44)
59 (39)

0 (37)
43 (79)
6 (36)

Undefined
7
24

(0, 2, !)
(3, 21)
(5, 228)

"0.001
"0.001
"0.001

66 (35)

11 (80)

15

(6, 40)

"0.001

74 (35)

13 (80)

20

(7, 63)

"0.001

By Fisher exact test, all P for individual characteristic comparisons of the 2 groups were "0.001.

the United States, a single prospective study at the

University of Alabama defined the prevalence of
PCOS in their community as 4.0%. In that study,
277 unselected women of reproductive age (1845
year) seeking a preemployment physical were
evaluated. The prevalence was 4.7% among white
and 3.4% among black women (3). This study is
unique not only in its assessment of prevalence in
a general population, but also the heterogeneity of
the study population.
In several European studies, a higher prevalence of
PCOS has been reported. On the island of Lesbos,
Greece, Diamanti-Kandarakis and colleagues (4)
found a 6.8% prevalence of PCOS. They examined
192 women recruited through a free medical examination and excluded any women receiving hormonal
medications. Findings from a study conducted on
230 women aged 1825 years from university and
private practices in the United Kingdom indicated
that the prevalence of PCOS was 6.8% (5). Finally,
in a study by Asuncion and colleagues (6), 154 white
women in Madrid, Spain, were identified prospectively after reporting spontaneously for blood donation, and the prevalence of PCOS was 6.5%. These
studies suggest that PCOS is likely the most common
endocrinologic disorder of reproductive-age women.

TABLE 2
Revised diagnostic criteria of polycystic ovary syndrome
Revised 2003 criteria (patients should have 2 of criteria 13)
1 Oligo- or anovulation
2 Clinical and/or biochemical signs of hyperandrogenism
3 Polycystic ovaries
4 Exclusion of other etiologies (congenital adrenal hyperplasia,
androgen-secreting tumors, Cushing syndrome)
Modified from The Rotterdam ESHRE/ASRM-Sponsored PCOS
Consensus Workshop Group (Group 2004) (2).

DIAGNOSIS OF POLYCYSTIC OVARY

SYNDROME: CLINICAL EXAMINATION
AND LABORATORY TESTING
The initial evaluation of patients suspected of having PCOS should include an evaluation of cycle
regularity, androgen elevation, ultrasonographic appearance of the ovaries, and the exclusion of any
other endocrinologic abnormalities. Normal menstrual cycles range from 25 to 35 days in duration.
Thus, women who report menstrual irregularity of
greater than 35 days are likely have oligo- or anovulation and are at increased risk for PCOS.
Elevations in androgens can be determined by either
clinical examination or laboratory testing. Clinical manifestations of hyperandrogenism include acne and/or
hirsutism. Hirsutism should be evaluated after patients
have had a hiatus from hormonal agents such as oral
contraceptives or antiandrogenic agents. The severity of
male-pattern hair growth should be quantitated using
the Ferriman-Gallwey scale (49) (Fig. 2). Biochemical
elevations in testosterone, free testosterone, androstenedione, or DHEAS are frequently seen in patients
with PCOS. Unfortunately, assays for these tests are
extremely inconsistent among individual laboratories,
making the diagnosis of elevated androgen levels difficult. It is unclear exactly how long patients should
remain off of hormonal agents before clinical and biochemical assessment of androgen elevation. However,
there are data showing that the average time to conception after discontinuing oral contraceptives containing
less than 50 !g estrogen averages 4.01 cycles. This
would suggest that normalization of the hormonal milieu has occurred by approximately 1 month before this
(approximately 3 months without oral contraceptives)
to achieve an ovulatory cycle (7).
In addition to the aforementioned clinical and biochemical evaluation, 2 groups of potential patients with

PCOS and Its Differential Diagnosis Y CME Review Article

TABLE 3
Differential diagnosis of polycystic ovary syndrome
Hypogonadotropic hypogonadism
Nutrition
Excessive exercise
Chronic disease
Hyperprolactinemia
Macroadenomas (#1 cm)
Microadenomas ("1 cm)
Idiopathic hyperprolactinemia (no visible lesion)
Hypothyroidism
Hyperadrenalism
Cushing syndrome
Cushing disease
Nonclassic congenital adrenal hyperplasia
Androgen-secreting tumors
Ovarian
Adrenal
Androgenic alopecia

PCOS deserve further evaluation. Patients who are either obese or who have a family history of noninsulindependent diabetes mellitus should be evaluated for
insulin resistance. Because nonobese women with
PCOS also may have insulin resistance, some investigators advise assessing insulin resistance in all women
with PCOS. There is controversy about the best manner
of assessing insulin sensitivity, but the most practical
evaluation involves a 2-hour glucose tolerance test with
insulin levels measured after a 75-g glucose load. The
test should be performed after an 8- to 12-hour fast and
serum levels of insulin and glucose should be collected
every 30 minutes from zero to 120 minutes.

Fig. 1. Appearance of a polycystic ovary on ultrasound. Note

multiple enlarged follicles with necklace-like appearance on
periphery.

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Although PCOS remains the most common cause

of anovulatory hyperandrogenism in the adolescent
and reproductive-age woman, a variety of other conditions need to be excluded before this diagnosis is
confirmed (Table 3). In general, the areas of focus in
investigating the etiology of menstrual irregularities
include the pituitary, thyroid, adrenal gland, and
ovary.
DIFFERENTIAL DIAGNOSIS OF
POLYCYSTIC OVARY SYNDROME:
DISORDERS AND TREATMENT
Hypogonadotrophic Hypogonadism
Nutritional and metabolic disturbances are the
most common causes of secondary hypogonadotrophic hypogonadism. Nutritional causes include
anorexia nervosa and bulimia and are marked by
decreased body weight over time. Other chronic
causes of malnutrition include celiac disease with its
associated gluten intolerance and chronic intestinal
disorders such as Crohn disease.
Metabolic disturbances may arise from intensive
physical training in athletes such as runners, swimmers, skaters, and ballet dancers and result in the
delay of sexual development. Fortunately, this metabolic cause of anovulation has a better prognosis for
recovery than nutritional disorders.
Tumors of the central nervous system such as
craniopharyngiomas, germinomas (including pinealomas, ectopic pinealomas, atypical teratomas, or
dysgerminomas), or other extrasellar germ cell tumors may interfere with follicle-stimulating hormone
(FSH) secretion and lead to the failure of ovulatory
function. Patients who have very low levels of all
pituitary hormones warrant radiologic evaluation.
In hypogonadotrophic hypogonadism, there is a deficiency of the pituitary gonadotropins, luteinizing hormone (LH), and FSH, leading to a relative estrogen
deficiency. This may result from disturbances of anterior pituitary secretions or may be secondary to chronic
disease or metabolic disturbance. In either case, measurement of serum LH and FSH will result in low to
undetectable levels with an FSH predominance.
Treatment of this disorder in adolescent females
should be limited to the use of sex steroids in cyclic
fashion. The main objective of therapy in this group
of patients is to protect bone mineral density. Use of
injectable human menopausal gonadotropins and human chorionic gonadotropins is typically avoided in
this age range as a result of the need for close
supervision. These agents are useful for induction of

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Obstetrical and Gynecological Survey

Fig. 2. Adaptation of Ferriman and Gallwey visual method of scoring hair growth in women. Points are assigned based on the amount
of hair visualized in each area of the body. A summary score of greater than 8 is considered indicative of hirsutism. Adapted from Hatch
et al. (49).

ovulation and fertility treatment for reproductive purposes (8). However, they will only induce ovulation
in the cycle(s) in which they are administered. In
addition to hormonal treatment, appropriate psychologic support and follow up must be added to hormonal treatment.
Hyperprolactinemia
Elevations in prolactin affect the breast, the gonads, and occasionally mood. Additionally, at least
one study suggests an association of hyperprolactinemia with insulin resistance in the patient with PCOS
(9). Prolactin directly stimulates breast secretions,
and as a result, approximately 90% of women with
hyperprolactinemia develop galactorrhea. The impact of elevated prolactin on the gonads is hypothesized to be the result of the disruption of normal
pulsatility of gonadotropin-releasing hormone (GnRH)
and consequent alterations in the secretion of FSH
and LH. Clinically, the end result is anovulation
with either amenorrhea or oligomenorrhea in most
women.
Hyperprolactinemia can be divided into pituitary
and nonpituitary causes. Pituitary causes include
prolactin-secreting microadenomas, nonsecreting pituitary tumors, craniopharyngiomas, Rathke cleft
cysts, altered forms of prolactin, and idiopathic hyperprolactinemia. Any disruption of the pituitary
stalk or macroadenomas can lead to failure of the

normal hypothalamic suppression of prolactin by

dopamine. Nonpituitary causes are common and
include pregnancy, hypothyroidism, and dopamine
antagonist drug therapy (phenothiazines and metoclopramide). Some women with PCOS have mild
hyperprolactinemia.
An elevated prolactin level should be repeated after
counseling the patient to avoid any nipple stimulation. Once confirmed, the prolactin level may guide
decisions regarding further evaluation. Hyperprolactinemia between 20 and 200 !g/L may be the
result of various causes, including stress, hypothyroidism, PCOS, microadenomas, and pituitary stalk
disruption. Prolactin elevations #200 !g/L are usually the result of macroadenomas; however, large
nonprolactin-secreting tumors may be seen with only
modest elevations of prolactin.
The initial evaluation of patients with hyperprolactinemia should include exclusion of nonpituitary
causes by a careful history of medications, evaluation
of the thyroid, pregnancy testing, and assessment of
whether the patient has PCOS. After these potential
causes have been excluded, the evaluation should focus
on the pituitary. Clinical examination for all patients
should include assessment of visual fields. Although
direct confrontation testing is acceptable as a screening
tool, any patients with a significant mass lesion should
undergo formal ophthalmologic examination.
In patients with sustained hyperprolactinemia, the
pituitary and hypothalamus must be evaluated for

PCOS and Its Differential Diagnosis Y CME Review Article

structural pathology. Radiologic evaluation should

be performed in any patient with sustained hyperprolactinemia and no obvious secondary cause (10).
Magnetic resonance imaging (MRI) or computed tomography (CT) scanning are the preferred imaging
modalities. Structural anomalies include pituitary
microadenomas ("10 mm diameter), pituitary macroadenomas (#10 mm diameter), pituitary stalk
lesions, hypothalamic tumors, and granulomas. MRI
is quickly becoming the modality of choice as a
result of its lack of radiation exposure, superior resolution, and ability to distinguish structures such as
the optic chiasm and carotid arteries. However, CT
scanning is acceptable if thin slice images are used in
conjunction with contrast material.
It is important to recognize that approximately
20% of the normal population has been found to have
pituitary microadenomas at autopsy. Thus, as more
small adenomas are being detected by imaging resulting from increased sensitivity and resolution, the finding of a small pituitary adenoma may not explain an
associated endocrinopathy. Conversely, some women
with sustained hyperprolactinemia and no evident nonpituitary cause may not have a demonstrable lesion.
These patients may have a lesion less than 2 mm in
diameter, lactotroph hyperplasia, nonsecreting pituitary
tumors, or nontumoral hyperprolactinemia.
Management of hyperprolactinemia depends on the
identified etiology. The goal of treatment is to restore
ovulatory function, to promote estrogen production,
and to prevent lactation. In patients with prolactinomas, tumor shrinkage may also be of significance.
With hyperprolactinemia of even 6 months duration,
patients are at significant risk for bone mineral density reduction. Thus, prevention of osteoporosis is of
paramount importance.
Pituitary adenomas can be approached surgically,
medically, or radiologically. Surgery plays a relatively small role in the treatment of prolactinomas
currently. Although surgical treatment has the potential to yield a long-term cure and obviate the need for
medication, in reality, long-term remission of the
hyperprolactinemia in larger tumors (macroadenomas) is uncommon.
Currently, medical management has become the
primary treatment of both pituitary prolactinomas
and idiopathic hyperprolactinemia. Dopamine agonists are the primary medications used in the treatment of hyperprolactinemia. D2 receptor agonists
have demonstrated prolactin suppression and even
tumor shrinkage in 80% to 90% of patients. Approximately 90% of women demonstrate restoration of
ovarian function. Furthermore, 80% of patients dem-

129

onstrate up to 25% tumor shrinkage in timeframes as

short as 48 hour. Bromocriptine was the initial medication used in the dopamine receptor agonist group.
Although it is still widely used in practice, it has a
side effect profile that includes nausea, postural hypotension, dizziness, headache, and constipation. Additionally, less common side effects include mild
depression and, on occasion, psychosis. Newer agents
with fewer side effects have been developed in place
of bromocriptine. These include cabergoline and
quinagolide, specific D2 receptor ligands. Both
agents have a longer half-life, with cabergoline being
administered one to 2 times per week and quniagolide given once each day. Although side effects such
as nausea and postural hypotension still exist with
these agents, they are significantly less common. All
3 agents require low initial doses with gradual increases to minimize side effects. Restoration of ovulation and normal menstrual cycles is generally
within weeks.
Given the impressive success rates with dopamine
agonists, the question of how long to continue therapy
has arisen. Historically, discontinuance of bromocriptine has been found to result in return of symptoms,
including headache, oligomenorrhea or amenorrhea, infertility, galactorrhea, and visual changes. The prolactinomas typically return to pretreatment size and the
prolactin levels again increase. However, a recent study
by Colao and colleagues evaluated the withdrawal of
cabergoline in patients treated for micro- or macroprolactinomas. That study indicates that 2 to 5 years
after withdrawal, recurrences occurred in 24% of patients with nontumoral hyperprolactinemia, 31% of patients with microprolactinomas, and 36% of patients
with macroprolactinomas. Renewed tumor growth was
not seen in any patients, and only 22% of women with
recurrent hyperprolactinemia demonstrated gonadal
dysfunction. Additionally, prolactin levels at the time of
recurrence were significantly lower in all groups. Thus,
it seems that some patients taking cabergoline can have
the medication safely withdrawn in patients with normalized prolactin levels and no evidence of tumor,
providing that they continue close follow up (11).
An additional alternative for patients with microadenomas or nontumoral hyperprolactinemia is to treat
them with estrogen replacement or oral contraceptive
pills. If there is no symptomatic galactorrhea, the
main concern for patients not actively trying to conceive is protection of bone density. Therefore, estrogen treatment may be considered a less expensive
and effective treatment to regulate cycles and protect
the patient from bone loss. Only rarely will tumor
growth be noted.

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Obstetrical and Gynecological Survey

Hypothyroidism
In reproductive-age women, hypothyroidism results
in changes in cycle length and amount of bleeding.
Therefore, menstrual disorders can include oligomenorrhea and amenorrhea, polymenorrhea, and menorrhagia (12). The excessive bleeding disorders may result
from estrogen breakthrough bleeding secondary to
anovulation. Additionally, defects in hemostasis such
as decreased levels of factors VII, VIII, IX, and XI
may be present in hypothyroidism and contribute to
the polymenorrhea and menorrhagia seen in these
patients (13).
Hypothyroidism should be excluded in all cases of
menstrual irregularity. On physical examination, the
clinician may see a delay in the onset of puberty with
respect to chronologic age or paradoxically precocious puberty and galactorrhea in juvenile hypothyroidism (14). Although overt hypothyroidism is
easily detected by measuring the level of serum thyroid stimulating hormone (TSH), subclinical disease
may require performance of a prolactin stimulation
test with metoclopramide. This becomes particularly
important as reproductive age is reached because
subclinical hypothyroidism is of greater clinical importance in infertile women with menstrual disorders
(15).
Adequate thyroid supplementation should resolve
the reproductive symptoms associated with hypothyroidism, including oligo- or amenorrhea, and allow
progression of delayed puberty. Additionally, in
cases of severe hypothyroidism with associated hyperprolactinemia, prolactin levels should return to
normal as the hypothalamic thyrotropin-releasing
hormone (TRH) level, which stimulates prolactin as
well as TSH, normalizes (14).
Hyperadrenalism
Cushing syndrome refers to chronic glucocorticoid
excess irrespective of the cause. It should be in the
differential diagnosis of PCOS, obesity, diabetes,
hirsutism, and menstrual disorders. The most common time for presentation is during the reproductive
years (ages 2040), and the disease occurs in women
more often than men in a ratio of 10:1. Furthermore,
of adults with Cushing syndrome, 70% have Cushing
disease.
Cushing disease refers to the presence of an
ACTH-hypersecreting pituitary adenoma that demonstrates partial resistance to the normal suppressive
effect of glucocorticoids. As a result of systemic
hypercortisolism, peripheral tissues manifest the

classic features of Cushing syndrome. The classic

symptom complex includes obesity, amenorrhea, hypertension, glucose intolerance or diabetes, hirsutism, striae, weakness, osteoporosis, purpura and easy
bruisability, and psychiatric disorders. The distribution of adipose tissue in Cushing disease tends to be
facial and truncal with apparent sparing of the limbs
resulting from muscle wasting. There is elevation of
both the systolic and diastolic blood pressures, and
70% to 80% of patients have evidence of decreased
glucose tolerance. Menstrual irregularities are common and may even develop into complete amenorrhea. Excessive hair growth may be noted in the
sideburn region, the forehead, the limbs, and the
trunk. There can also be temporal hairline recession
and a deepening of the voice when androgen excess
is present. Purple striae are present in the hip and
abdominal regions, as well as the shoulders and the
breast regions. Muscle weakness is extremely common, affecting the upper legs and arms and occurring
secondary to a reduction in muscle mass. Finally,
40% to 80% of patients are affected by osteoporosis.
In the setting of hypercortisolism, there is both a
decrease in bone formation as well as an increase in
bone resorption.
Treatment of Cushing disease resulting from an
ACTH-producing tumor with bilateral adrenal hyperplasia has varied with time. Historically, bilateral
adrenalectomy was performed, which corrected the
hypercortisolism but produced adrenal insufficiency.
This secondary endocrinopathy requires lifetime glucocorticoid and mineralocorticoid replacement and
may result in the development of a pituitary tumor.
Current management options of the pituitary tumor
include primarily transsphenoidal surgery, followed
by radiation and medical therapy in the cases of
incomplete surgical removal or recurrent tumor. In
the case of persistent disease, surgical bilateral adrenalectomy can be life-saving.
Several medications have been used in the treatment of Cushing disease. Cyproheptadine, a serotonin antagonist, can be useful in suppressing ACTH.
However, its use is short-term and it does not result
in normal serum cortisol levels. Bromocriptine, a
dopamine agonist, although useful for the treatment
of prolactin- and sometimes growth-hormone secreting tumors, is of little use in ACTH-secreting pituitary tumors.
Treatment of ectopic ACTH syndrome requires
localization and removal of the ACTH-secreting tumor. In cases of iatrogenic Cushing syndrome, cessation of excess exogenous glucocorticoid treatment
should be sufficient.

PCOS and Its Differential Diagnosis Y CME Review Article

Adrenal adenomas and carcinomas are infrequent

findings in the female. When present, they generally
produce large amounts of 17-ketosteroids such as
DHEA and androstenedione as well as cortisol (16).
The majority of these tumors are not responsive to
dexamethasone suppression, and systemically low
but persistent levels of ACTH are found.
A variety of tests may be useful in assessing adrenocortical function. It is common to begin preliminary
investigation with an 8:00 AM plasma cortisol concentration. The timing of this test is critical as a result of the
diurnal variation in the secretion of cortisol normally.
Nonetheless, this single value is only of limited significance. Urinary 17-hydroxycorticosteroids (17-OHCS)
and urinary-free cortisol may be useful, particularly in
combination to rule out Cushing disease. Finally, the
CRH test is used to assess the source of a cortisol
excess. It involves the intravenous administration of
CRH (100 !g/dose) and leads to an exaggerated increase in both plasma cortisol and ACTH in Cushing
disease, but no change in ectopic ACTH syndrome.
Using a combination of these tests, it should be
possible to determine the presence and cause of
hyperadrenalism.
Nonclassic (cryptic, peripubertal, adult-onset) adrenal hyperplasia (CAH) results in a spectrum of
clinical manifestations of postnatal androgen excess
(17). The disorders are autosomal-recessive in inheritance pattern and reflect problems in the adrenal
steroid synthesis pathway. Approximately 95% of patients with CAH have disorders of 21-hydroxylation as
a result of a deficiency of the 21-hydroxylase enzyme
(21"OH, P450c21). Other enzyme deficiencies that
present a similar clinical picture include the much less
common 11" hydroxylase (11"OH, P450c11) and 3"hydroxysteroid dehydrogenaseisomerase deficiency
(3"HSD).
The prevalence of nonclassic CAH varies according to the population in question. The frequency of
21"OH deficiency in women with suspected PCOS
has been reported to be anywhere from 1% to 19%
(18,19). Another study by Sahin et al (20) found that
8.4% of women with PCOS in Turkey had 11-" OH
deficiency. Thus, this is clearly an important consideration when evaluating reproductive-age women for
PCOS.
A common clinical presentation of the reproductiveage woman with nonclassic CAH is hirsutism, menstrual irregularity, and infertility (21). Furthermore,
studies have suggested that polycystic-appearing
ovaries are not uncommon in patients with nonclassic
CAH resulting from 21"OH, 11"OH, or 3"HSD
(2225). This profile is difficult to distinguish clini-

131

cally from PCOS. Most patients with either PCOS or

nonclassic CAH as their diagnosis will demonstrate
elevations of DHEAS, androstenedione, and testosterone levels on baseline laboratory evaluations.
In general, a basal 17-hydroxyprogesterone (17OHP) measurement should be obtained as a screening test in women suspected of having PCOS. Levels
"200 ng/dL (6.0 nmol/L) effectively rule out patients with 21-OH-deficient nonclassic CAH. Additionally, a study by Dewailly et al (26) suggested that
in patients with a basal 17-OHP level #500 ng/dL
(15.1 nmol/L), the diagnosis of nonclassic CAH is
certain and there is no reason for further adrenal
testing. For patients with basal 17-OHP levels between 200 and 500 ng/dL (6.015.1 nmol/L), an
ACTH stimulation test should be performed to confirm the diagnosis of 21-OH-deficient nonclassic
CAH. After the administration of ACTH (25 USP
units) or #-corticotropin (250 !g), levels of 17-OH
P, 11-DOC, and DHEAS are measured to determine
the presence of 21-OH, 11-" OH, or 3-" HSD
deficiencies (27). In a recent study in which the
prevalence of nonclassic 21-OH CAH in a Turkish
population was determined, a 17-OHP cutoff of 13.4
ng/mL (1340 ng/dL) after ACTH stimulation was
used as the diagnostic criterion, because this value
was greater than the 95th percentile (17). Other authors have suggested that a poststimulation 17-OHP
level exceeding 1000 ng/dL (30 nmol/L) is consistent
with at least a carrier status for CAH (28).
Treatment of nonclassic CAH in females involves
replacement of cortisol and in patients who are
also salt-wasters, the mineralocorticoid 9# fluorohydrocortisone (29). This results in normalization of
adrenal progestin and androgen secretion, renin, and
electrolyte imbalance. In adolescent or reproductiveage females, who have essentially completed growth,
a long-acting glucocorticoid such as prednisone,
prednisolone, or dexamethasone is preferred. The
maintenance dose of prednisone is 10 mg per day in
divided doses in classic 21-hydroxylase-deficient patients or 5 to 7.5 mg per day in nonclassic patients in
2 divided doses. Treatment should be titrated according to the patients clinical signs (hirsutism score,
menstrual history, weight changes, blood pressure,
and cushingoid features) (29) Additionally, periodic
review of biochemical findings (progesterone, 17OHP, androstenedione, testosterone, and renin levels) is
important. Of note, use of spironolactone for the treatment of hirsutism in women with 21-hydroxylase deficiency CAH is not recommended as a result of the
potentially salt-wasting complication of the drug even
in the nonclassic form of CAH (30,31). Of note, earlier

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Obstetrical and Gynecological Survey

work by Azziz and colleagues has suggested that

very low doses of 0.25 to 0.5 mg dexamethasone
nightly or every other night are adequate for the
management of nonclassic CAH (28). The goal of
treatment using this regimen is to reduce adrenal
hyperandrogenism without any attempt to normalize
17-OHP levels. No study has compared the effectiveness of these 2 approaches.
Androgenic Alopecia
Androgenic alopecia (AGA) is the most common
cause of hair loss in women, affecting up to 40%
by the end of the reproductive years (32). In
women, the hair loss resulting from AGA typically
involves the central portions of the scalp, but not
the frontotemporal hairline. Rarely is the hair loss
complete. However, after the menopausal transition, women may develop a male hair pattern. The
development of AGA is a function of both genetic
and hormonal factors with androgens playing a
significant role. Dihydrotestosterone (DHT), a potent metabolite of testosterone, is thought to be the
dominant androgen in the development of AGA.
From puberty onward, androgens interact with androgen-sensitive hair follicles triggering a series of
events that include the gradual miniaturization of
the follicles, alteration of the hair growth cycle
and, ultimately, progressive thinning and loss of
hair. Hair follicle responses to androgens are a
genetically predetermined event. Clinical presentation of AGA in women is less prominent, likely
as a result of lower levels of 5#- reductase (which
converts testosterone to DHT) and higher levels of
aromatase (which converts testosterone to estradiol). Additionally, the distribution of androgensensitive hair follicles differs in women compared
with men resulting in a different balding pattern. In
addition, premenopausal women benefit from the antiandrogenic effect of estradiol that occurs because estradiol increases sex hormone-binding globulin (SHBG).
The diagnosis of AGA is a clinical one based
predominantly on history and physical examination. The classic pattern is one of diffuse thinning
that is greatest over the central scalp without obvious recession of the frontal hairline. The presence of a central parting often appears both wider
and more prominent as a result of the overall
sparseness of the hair. Further criteria for diagnosis include the onset of hair loss after puberty, the
aforementioned pattern of hair loss, visible miniaturization of hairs, and a family history of hair loss
or thinning in first- or second-degree relatives.

Treatments for mild to moderate AGA include

topical agents, antiandrogens, and estrogens. Minoxidil (2%) is a topical agent that is more effective in women than in men. Stronger preparations
(5%) are not advised as a result of resultant localized or diffuse hypertrichosis in a large proportion
of patients.
Antiandrogens such as cyproterone acetate and
spironolactone have been used for the treatment of
AGA for many years. Their use in the reproductive-age population requires concomitant contraceptive use because of the risk of feminization of
the developing male fetus. As a result, antiandrogens such as finasteride are not U.S. Food and
Drug Administration-approved for use in women
with AGA. No studies have been conducted in
premenopausal women, and in a double-blind,
placebo-controlled trial of AGA in postmenopausal women, finasteride was not found to be
effective. Nonetheless, these agents are widely
used in treating women with a variety of hyperandrogenic conditions, including hirsutism, acne, and
AGA.
Cyproterone acetate (CPA) is an androgen receptor
antagonist. Recommended dosages for the treatment of
hirsutism, acne, and AGA in women range from 25 to
100 mg per day for 10 days during the follicular phase
of the menstrual cycle. In addition, estrogen is used in
combination with CPA, and therefore combination
drugs such as Diane/Dianette (2 mg CPA and 35 !g
ethinyl estradiol) plus 50 mg CPA are used for the first
10 days. Although the contraceptive alone is insufficient to provide efficacy for hirsutism or acne, it is often
prescribed as the sole antiandrogen. Hepatotoxicity has
been demonstrated at doses of 100 mg and above. It is
not approved for use in the United States.
Spironolactone is another antiandrogen that is
available in the United States. It prevents the interaction between androgens and their receptor. In
addition, it decreases enzymes necessary for the synthesis of androgens. Spironolactone administered in
doses of 200 mg per day for women with AGA has
been shown to retard hair loss (33).

Androgen-Producing Tumors
These tumors can be either ovarian or adrenal in
origin. In the presence of ovarian androgen-secreting
tumors, autonomous androgen production may result in
chronic anovulation and virilization. The tumor types
include hilus cell tumors, arrhenoblastomas (SertoliLeydig cell tumors), benign cystic teratomas, luteinized

PCOS and Its Differential Diagnosis Y CME Review Article

thecomas, gynandroblastomas (Leydig and granulosa

cell elements), and ovarian sex cord tumors (granulosa
and Sertoli cells). Tumor markers may be helpful
in differentiating the various tumors. Inhibin and
mullerian-inhibiting substance are markers for sex cord
tumors, germ cell tumors in XY individuals, and occasionally in granulosa and Leydig cell tumors. Isolated
androgen secreting tumors are possible.
The workup for ovarian or adrenal androgenproducing tumors in suspected cases should include MRI, CT, or ultrasonography. Further localization may necessitate the use of retrograde venous catheterization to clarify both location (ovary
vs adrenal) and site (left vs right) of the excess
hormone production (16).
MANAGEMENT OF POLYCYSTIC OVARY
SYNDROME
Lifestyle Modification
Currently, the best recommendation for the management of PCOS is lifestyle modification. Much of
the support for this recommendation comes from
the Diabetes Prevention Program (DPP) Research
Group, which conducted a large National Institutes
of Health-sponsored trial. In the DPP, over 3000
nondiabetic, insulin-resistant subjects greater than 25
years of age were followed for an average of 2.8
years. They were randomized to placebo, lifestyle
modification, or metformin use. At the end of the
trial, the incidence of new-onset diabetes was 11.0
cases per 100-person years in the placebo group, 7.8
cases per 100 person-years in the metformin group
and only 4.8 cases per 100 person-years in the lifestyle modification group (34). Although the study
population does not completely replicate the PCOS
population, the overlap is likely close enough that the
recommendations should be the same.
With this in mind, goals of modification should be
to decrease weight by approximately 7% and to perform an average of 150 minutes of physical activity
per week. Although this should certainly be the goal
for all patients with PCOS, there are cases when
more directed therapy may be required.
Menstrual Irregularities
Chronic anovulation is a prevalent symptom of
PCOS and results in menstrual irregularities as well
as an increased risk of endometrial hyperplasia and
carcinoma. Menstrual irregularities can be addressed
with the addition of a progestin either alone or in

133

combination oral contraceptives. The recommended

interval of use is no less than every 3 months. Medroxyprogesterone acetate may be dosed at 10 mg
per day for 7 to 10 days duration. If this does not
result in control of the dysfunctional uterine bleeding
often associated with PCOS, then use of the combination estrogenprogestin preparation may be used
on a cyclic schedule.
Hyperandrogenism and Hirsutism
Similar to the treatment of androgenic alopecia
(discussed previously), the goal of treatment in hyperandrogenism and hirsutism is to interrupt the steps
leading to increased androgen expression. Although
mechanical hair removal methods such as shaving,
electrolysis, tweezing, waxing, and depilatory creams
can provide some improvement in hirsutism, a combination of medical treatments and mechanical methods provides the best prospect for improvement.
Suppression of circulating ovarian androgens with
low-dose oral contraceptives has resulted in moderate improvement in hirsutism (35,36). Combination
oral contraceptives continue to represent the first-line
approach to the treatment of hirsutism and acne. The
mechanism of action is thought to be a combination
of suppression of gonadotropin secretion, thereby
reducing ovarian androgen secretion, increasing SHBG
synthesis, inhibiting DHT receptor binding, and enhancing antiandrogen effectiveness (3537).
Gonadotropin-releasing hormone (GnRH) agonist
therapy such as with leuprolide acetate has also been
successful in improving hirsutism. However, longterm use with this therapy requires the addition of
estrogen and progestin to prevent the associated hypoestrogenism seen with this therapy (3840). The need
for an injection and additional medication make this a
challenging option, particularly for adolescents.
In addition to these options, a more direct approach
is the use of agents to block the effects of androgens
at their receptors. A variety of antiandrogenic agents,
including cyproterone acetate (not available in the
United States), spironolactone, flutamide, and finasteride, have been used in the treatment of PCOS-related
hirsutism and acne. The use of these medications is
discussed previously in the treatment of androgenic
alopecia.
Insulin Resistance and Hyperinsulinemia
Although adolescent patients with PCOS typically
present for cosmetic reasons relating to hirsutism and
acne or as a result of menstrual irregularities, meta-

134

Obstetrical and Gynecological Survey

bolic abnormalities represent the most serious longterm risk factors for patients with PCOS. Legro and
colleagues (41) have demonstrated that by their
fourth decade of life, as many as 40% of patients with
PCOS have impaired glucose tolerance and up to 10%
go on to develop type II diabetes mellitus. Given these
risks, the attenuation of hyperinsulinemia may have a
beneficial effect on the long-term sequelae thought to
develop in patients with PCOS. Currently, the use of
metformin, an insulin-sensitizing agent, provides the
opportunity to treat hyperinsulinemic patients with
PCOS with the goals of improving insulin resistance
and lowering insulin levels, thereby improving associated metabolic sequelae, including dyslipidemia,
glucose intolerance, and hyperandrogenism.
A study by Palmert and colleagues (42) concluded
that adolescents with PCOS are at increased risk for
both impaired glucose tolerance and diabetes mellitus. Additionally, they found that a 2-hour glucose
tolerance test after a 75-g oral load was the most
sensitive test to screen for insulin resistance in this
population.
Metformin (dimethylbiguanide) is an oral agent
used in the treatment of noninsulin-dependent diabetes mellitus (NIDDM). It maintains glucose homeostasis through suppression of hepatic glucose
output. Additionally, it improves insulin sensitivity
and decreases insulin levels. Overall, the use of metformin leads to a decrease in serum insulin and
androgen levels, as well as an improvement in ovulatory function (43). Metformin should be given to
reach maximum combined doses of 1500 to 2000 mg
per day divided over 2 to 3 daily doses. The goal of
treatment should be to improve insulin resistance and
hyperinsulinemia while encouraging the use of diet
and exercise for long-term therapy. Assessment of
insulin sensitivity should occur at no less than yearly
intervals. Treatment with metformin requires that
renal and liver function be assessed on an annual
basis.
In addition to metformin, thiazolidinediones continue to be under investigation for use in the management of PCOS-related metabolic abnormalities.
Early work with troglitazone before its withdrawal
from the market indicated that daily treatment with
400 mg for 12 weeks resulted in a decrease in insulin
and androgen levels in patients with PCOS (44). As
a family of compounds, thiazolidinediones are selective ligands for PPAR$, a nuclear receptor that regulates the transcription of multiple insulin-responsive
genes crucial to the control of glucose and lipid
metabolism and plays a central role in the regulation
of adipocyte gene expression and regulation (4547).

Although troglitazone is no longer available for use,

several other compounds in the thiazolidindione family, including pioglitazone, have been suggested for
use in the treatment of PCOS. Definitive studies have
not yet been performed.
SUMMARY
PCOS is a common but heterogeneous disorder.
The goal of management in adolescence should focus
on addressing the concerns of the patient while providing education regarding the long-term sequelae of
the syndrome. Further studies are needed to clarify
the extent of excess cardiovascular disease in patients
with PCOS and to determine the best course of
short-term and long-term management. Current studies suggest that diet and exercise, perhaps with use of
insulin-sensitizing agents, provide the best opportunity for long-term improvement of dyslipidemia, impaired glucose tolerance, and hyperandrogenemia in
adolescents with PCOS.
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