413145_PGO03_sw 2/7/05 9:45 AM Page 1

POSTGRADUATE
OBSTETRICS & GYNECOLOGY
VOLUME 25 NUMBER 3
February 15, 2005

A BIWEEKLY PUBLICATION FOR CONTINUING MEDICAL

EDUCATION IN OBSTETRICS AND GYNECOLOGY

Polycystic Ovary Syndrome

Samuel Smith, M.D.
Learning Objectives: After reading this issue, the participant should be able to:
1. Explain how to diagnose, evaluate, and treat women with polycystic ovary syndrome.
2. Describe the pathophysiologic mechanisms that underlie polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) refers to a reproductive endocrine disorder characterized by chronic hyperandrogenism and/or chronic anovulation. Polycystic appearing ovaries are frequently, but not always, associated with
the syndrome. Since the sentinel report by Stein and
Leventhal in 1935,1 a variety of clinical, biochemical, histologic, and ultrasonographic criteria have been associated
with PCOS. There has never been universal agreement on
which criteria should be core components of its definition.
The 1990 International Consensus Conference organized
by the National Institute of Child Health and Development
(NICHD) exposed the lack of consensus among experts in
the field. Nevertheless, a practical definition of PCOS
emerged from that conference: women were defined as
having PCOS if they had chronic anovulation and clinical
or biochemical evidence of androgen excess after other
known causes had been excluded. PCOS was thus defined
as a condition of unexplained hyperandrogenic chronic
anovulation as specific diseases of the ovaries, adrenal, and
pituitary glands needed to be excluded.2
The NICHD conference criteria helped to standardize the
diagnosis of PCOS and facilitated clinical research of PCOS.
Since then, there has been increased understanding that the
clinical expression of PCOS may be broader than that
defined by the 1990 NICHD consensus criteria. The 2003
Rotterdam international consensus workshop,3 sponsored by

the American Society for Reproductive Medicine and the

European Society for Human Reproduction and Embryology,
concluded that PCOS is a syndrome characterized by at least
two of the following cardinal features: oligo-ovulation, hyperandrogenism, and polycystic ovary (PCO) morphology (Table
1). It is now recognized that women with regular menstrual
cycles who have hyperandrogenism and polycystic ovaries
may have the syndrome, as do women who demonstrate
oligo-ovulation and PCO morphology without hyperandrogenism. These two clinical presentations are now considered
part of the PCOS spectrum, an important departure from the
1990 criteria, which required both oligo-ovulation and hyperandrogenism to be present. The discussion that follows is
based on clinical research using the 1990 criteria for the diagnosis of PCOS.

Epidemiological Findings and Diagnosis

PCOS affects approximately 4% to 6% of reproductiveaged women according to most large studies, although
prevalence estimates of 10% have been reported.4,5 The best
prevalence studies are based on consecutive unselected samples of women and suggest that the prevalence of PCOS is
relatively uniform internationally. This makes PCOS one of
the most common endocrine disorders affecting women.
Table 1. Diagnostic Criteria for Polycystic Ovary Syndrome
1990 NICHD Criteria (requires all three)2
Chronic anovulation
Clinical and/or biochemical evidence of hyperandrogenism
Exclusion of other known etiologies

Dr. Smith is Chairman, Department of Obstetrics and Gynecology, Franklin

Square Hospital, and Associate Professor, Department of Gynecology and
Obstetrics, Johns Hopkins Medicine, 9105 Franklin Square Drive, Suite 316,
Baltimore, MD 21237; E-mail: samuel.smith@medstar.net.

2003 Rotterdam Criteria (requires two of the first three)3

Chronic oligo- or anovulation
Clinical and/or biochemical evidence of hyperandrogenism
Polycystic ovaries
Exclusion of other known etiologies

The author has disclosed that he has no significant relationships with or financial
interests in any commercial organizations pertaining to this educational activity. The
author has disclosed that the use of metformin, rosiglitazone, and pioglitazone for
ovulation induction in patients with polycystic ovary syndrome and the use of
spironolactone, flutamide, and finasteride for the treatment of hirsutism as discussed
in this article have not been approved by the U.S. Food and Drug Administration.

The continuing education activity in Postgraduate Obstetrics & Gynecology is intended for obstetricians, gynecologists, and
other health care professionals with an interest in the diagnosis and treatment of obstetric and gynecological conditions.
1

413145_PGO03_sw 2/7/05 9:45 AM Page 2

Postgraduate Obstetrics & Gynecology

EDITORS
Edward E. Wallach, M.D.*
Johns Hopkins University
Baltimore, Maryland
Roger D. Kempers, M.D.*
Mayo Clinic and Mayo
Foundation
Rochester, Minnesota

EDITORIAL BOARD
Jonathan S. Berek, M.D.
David Geffen School of Medicine
at UCLA
Los Angeles, California
Daniel L. ClarkePearson, M.D.
Duke University Medical Center
Durham, North Carolina
Harold Fox, M.D.
Johns Hopkins University School
of Medicine
Baltimore, Maryland
Charles B. Hammond, M.D.
Duke University Medical
Center
Durham, North Carolina
Timothy R.B. Johnson, M.D.
University of Michigan Medical
School
Ann Arbor, Michigan
Jack Ludmir, M.D.
Pennsylvania Hospital
Philadelphia, Pennsylvania
Kamran S. Moghissi, M.D.
Wayne State University School
of Medicine
Detroit, Michigan
Jennifer R. Niebyl, M.D.
University of Iowa
Iowa City, Iowa
Antonio Pellicer, M.D., Ph.D.
Associate Editor, Spanish Edition
University of Valencia (Ob/Gyn)
Valencia, Spain
John T. Repke, M.D.
Penn State College of
Medicine Milton S. Hershey
Medical Center
Hershey, Pennsylvania
Nikos Vlahos, M.D.
Johns Hopkins University
School of Medicine
Baltimore, Maryland
*The editors have disclosed that they have
no significant relationships with or financial
interests in any commercial organizations
pertaining to this educational activity.

February 15, 2005

In 1935, Stein and Leventhal1 described

seven women with amenorrhea and bilaterally enlarged polycystic ovaries. Four of the
seven women were hirsute; one of these four
women was virilized. Three of the women
were obese, and five were infertile. All seven
women were treated with bilateral ovarian
wedge resection, all resumed normal ovulation, and one woman conceived.1 Soon after
their report was published, the term SteinLeventhal syndrome was used to characterize
all young women who demonstrated amenorrhea, hirsutism, infertility, and bilaterally
enlarged ovaries. During the ensuing 30
years, Stein-Leventhal syndrome and PCOS
became synonymous.
Women with PCOS typically present to
their gynecologists with reports of menstrual
irregularity, hirsutism, and/or infertility.4,5
Treatment is generally directed at trying to
help patients with PCOS conceive if this is
their principal concern. Otherwise, treatment
is directed at controlling hyperandrogenism
and regulating menstruation. During the past
two decades, there has been a growing appreciation that women with PCOS are at significantly greater risk of developing medical
sequelae because of the pathophysiologic
abnormalities that underlie the syndrome.
Women with PCOS are at increased risk to
develop endometrial cancer, Type 2 diabetes
mellitus, hypercholesterolemia, hypertension,
and probably heart disease.35 Consequently,
long-term management of women with
PCOS is geared to reducing the risks that
develop from these medical events.

Pathophysiological
Characteristics
Inappropriate Gonadotropin Secretion

The most common pathophysiologic

mechanisms that account for the hyperandrogenism seen in PCOS are altered

gonadotropin secretion and insulin resistance.3,5,6 Both the absolute concentration of

circulating luteinizing hormone (LH) and its
relation to serum follicle-stimulating hormone (FSH) concentration are elevated in
women with PCOS compared with controls.
Approximately two-thirds of obese and
nonobese women with PCOS demonstrate
increased LH pulse frequency and amplitude,
which leads to an increased 24-hour mean
serum concentration. This generally correlates with an increased pulse frequency of the
hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator, and recent
data suggest that LH pulse frequency is 1.3 to
1.5-fold increased relative to women with
regular menstrual cycles.5 Because androgen
production by ovarian theca and stroma cells
is LH-dependent, inappropriate LH secretion
is believed to stimulate excess ovarian androgen production. Suppression of LH production and secretion by combination oral contraceptives or GnRH analogs results in
reduced serum testosterone and androstenedione concentrations.4,5
As the GnRH pulse frequency increases, LH is secreted preferentially to FSH.
Many women with PCOS have reduced
serum levels of FSH. Without exposure to
normal amounts of FSH, granulosa cells
within ovarian follicles of patients with
PCOS will fail to develop sufficient aromatase activity to convert the excess theca
cell-derived androgen to estrogen. Granulosa
cells may continue to produce estradiol in
amounts sufficient to suppress pituitary
FSH production, which reinforces the
inappropriate gonadotropin secretion.5 Up
to 95% of anovulatory women with PCOS
demonstrate an elevated LH:FSH ratio.
Interestingly, granulosa cells from patients
with PCOS retain their ability to respond
to exogenous FSH, suggesting that they
are functionally intact.3,5

Postgraduate Obstetrics & Gynecology (ISSN 0194-3898) is published biweekly by Lippincott Williams & Wilkins, Inc., 16522
Hunters Green Parkway, Hagerstown, MD 21740-2116. Customer Service Manager, Audrey Dyson: Phone (800) 787-8981
or call (410) 528-8572. 24-Hour Fax (410) 528-4105 or E-mail adyson@lww.com. Visit our website at LWW.com. Publisher,
Daniel E. Schwartz: Phone (410) 528-4020, Fax (410) 528-4105.
Copyright 2005 Lippincott Williams & Wilkins. Priority Postage paid at Hagerstown, MD, and at additional mailing offices. POSTMASTER: Send address changes to Postgraduate Obstetrics & Gynecology, Subscription Dept., Lippincott Williams & Wilkins,
P.O. Box 1600, 16522 Hunters Green Parkway, Hagerstown, MD 21740-2116.
PAID SUBSCRIBERS: Current issue and archives from 2004 on are now available FREE online at www.lwwnewsletters.com.
Subscription rates: Personal: $299 US, $343 Foreign. Institutional: $499 US, $553 Foreign. In-training: $99 resident non-scored, US and
Foreign. GST Registration Number: 895524239. Send bulk pricing requests to Publisher. Single copies: $15. COPYING: Contents of
Postgraduate Obstetrics & Gynecology are protected by copyright. Reproduction, photocopying, and storage or transmission by magnetic
or electronic means are strictly prohibited. Violation of copyright will result in legal action, including civil and/or criminal penalties.
Permission to reproduce in any way must be secured in writing from: Permissions Dept., Lippincott Williams & Wilkins, 351 West Camden
Street, Baltimore, MD 21201; Fax: (410) 528-8550; E-mail: permissions@lww.com. For commercial reprints, contact Carol Bak: Phone
(410) 528-4163 or E-mail cbak@lww.com.
Opinions expressed do not necessarily reflect the views of the Publisher, Editor, or Editorial Board. A mention of products or services does
not constitute endorsement. All comments are for general guidance only; professional counsel should be sought for specific situations.

413145_PGO03_sw 2/7/05 9:45 AM Page 3

February 15, 2005

Postgraduate Obstetrics & Gynecology

The findings of altered gonadotropin secretion suggest

that PCOS is in part attributable to a neuroendocrine abnormality that results in acceleration of the hypothalamic
GnRH pulse frequency. In research studies, nearly all
patients with PCOS can be shown to demonstrate increased
secretion of LH. In clinical practice, however, a single or
several measurements of LH and FSH may not identify
abnormalities.3,5 The 1990 National Institutes of Health
panel and the 2003 Rotterdam panel agreed that measurement of serum LH levels is not necessary for the diagnosis
of PCOS but is useful as a secondary parameter, particularly in lean women and those participating in research trials.2,3

G:I ratio, several simple indices that use basal fasting glucose and insulin values are being evaluated as tools to
detect insulin resistance, including the homeostasis model
assessment and the quantitative sensitivity check index.6,10

Differential Diagnosis
The differential diagnosis of PCOS includes other
causes of chronic anovulation and hyperandrogenism
(Table 2). PCOS is a clinical diagnosis, and both features
are usually present. When either anovulation or hyperandrogenism is absent, polycystic ovaries must be seen on
ultrasound. Women with PCOS typically give a history of
irregular menstrual cycles that date back to menarche.
Generally, six or fewer menstrual flows occur per year.
Women who have history of regular menstrual cycle
intervals who subsequently develop amenorrhea should
be suspected of having a disorder other than PCOS.35
PCOS is still a clinical diagnosis of exclusion. Laboratory
testing should be geared toward documenting hyperandrogenism and excluding nonclassic adrenal hyperplasia
(NCAH). A serum 17-hydroxyprogesterone (17OHP) level
below 200 ng/dL effectively excludes NCAH. An ACTH
stimulation test is advised if the basal level of 17OHP exceeds
this level, and stimulated values exceeding 1000 ng/dL are
diagnostic. Serum levels of total and free/bioavailable testosterone and dehydroepiandrosterone sulfate (DHEAS) help to
document the extent of hyperandrogenism. If Cushing syndrome is suspected because of clinical stigmata, assessment
of 24-hour urinary free cortisol is a practical screening test.
Androgen-secreting tumors may be suspected by rapid progression of clinical symptoms such as hirsutism or virilization, the so-called short history. Serum levels of testosterone
and DHEAS are neither sensitive nor specific in excluding
ovarian or adrenal tumors, which rarely cause hirsutism.
Imaging studies would be diagnostic of these tumors. The
HAIR-AN syndrome7 is associated with very severe symptoms of hirsutism. Fasting and glucose-stimulated insulin
levels are markedly elevated in the HAIR-AN syndrome.
Testosterone levels are also markedly elevated. Idiopathic
hirsutism is associated with regular menstrual cycles, normalappearing ovaries, and normal serum androgen levels and
should not be confused with PCOS.35
The Rotterdam conference participants thought that
polycystic ovaries should be considered as a possible criterion for PCOS. This was a clear departure from the 1990

Insulin Resistance

Insulin resistance with compensatory hyperinsulinemia

is the second important pathophysiologic feature of
PCOS.36 The causeeffect relationship between insulin
resistance and hyperandrogenism was first proposed in
1983 and is best demonstrated in women with the syndrome of hyperandrogenism, insulin resistance, and
acanthosis nigricans (HAIR-AN).6,7 In vitro experiments
document that insulin synergizes with LH to stimulate
theca cell production of androgen. Clinical trials have
demonstrated that treating insulin resistance and reducing circulating insulin levels leads to reductions in circulating serum androgens. This is consistent with a
causeeffect relationship between insulin resistance and
ovarian hyperandrogenism. Insulin can potently stimulate
ovarian androgen production in patients with PCOS,
although there is insulin resistance in peripheral tissues
involved with glucose homeostasis.3,5,6
Obesity is also associated with insulin resistance.
However, the extent of insulin resistance seen in women
with PCOS is not totally explained by obesity. Nonobese
patients with PCOS have lower insulin sensitivity than
nonobese controls, and obese patients with PCOS have
lower insulin sensitivity than obese patients without PCOS.
Overall, 25% to 50% of women who have PCOS are obese.5
There are no consensus criteria for the definition of
insulin resistance. Laboratory criteria that suggest the
presence of insulin resistance include elevated fasting
insulin level, a reduced fasting glucose:insulin (G:I) ratio
(<4.5), impaired glucose tolerance as demonstrated by a
2-hour oral glucose tolerance test (OGTT), and/or elevated serum insulin levels during an OGTT.6 Clinically, however, the measurement of fasting insulin concentration is
limited by the fact that there is considerable overlap
between normal subjects and women with insulin resistance. The use of serum insulin levels is further hindered
by a lack of standardization of insulin assays; replicate
patient samples assayed in different laboratories may
demonstrate great variability.6,8 In contrast, in research
settings, the sensitivity of a fasting G:I ratio as a screening test for insulin resistance is 95%, and its specificity is
84%.9 Clinical findings that suggest the presence of
insulin resistance include a body mass index greater than
27 kg/m2, a waist:hip ratio greater than 0.85, and the presence of acanthosis nigricans.6 In addition to the fasting

Table 2. Differential Diagnosis of Polycystic Ovary Syndrome

Polycystic ovary syndrome
Nonclassic (late onset) adrenal hyperplasia
Hyperandrogenism insulin resistance, acanthosis nigricans syndrome
Androgen-secreting tumors of the ovary or adrenal gland
Cushing syndrome
Idiopathic hirsutism
Hyperprolactinemia
Menopause
Medications

413145_PGO03_sw 2/7/05 9:45 AM Page 4

Postgraduate Obstetrics & Gynecology

February 15, 2005

NICHD conference participants. Ultrasound criteria consistent with polycystic ovaries include the presence of 12
or more 2 to 9 mm antral follicles, and/or increased ovarian volume (>10 mL). The follicle distribution around the
periphery (string-of-pearls appearance) and an increase in
stroma volume or echogenicity are not criteria for polycystic ovaries. A single ovary that meets these criteria is
sufficient to diagnose a polycystic ovary. The use of oral
contraceptives will modify ovarian ultrasound appearance
and confound the use of this diagnostic criterion. If a
dominant follicle greater than 10 mm in diameter is identified in an ovary or a corpus luteum, the ultrasound examination should be repeated during the early follicular
phase of the next cycle.3 Women who have polycystic
ovaries without chronic anovulation and/or hyperandrogenism do not have PCOS. Thus, the presence of a polycystic ovary is not a stand-alone criterion for PCOS.

Table 3. Criteria for the Metabolic Syndrome in Women With PCOS3*

Abdominal obesity (waist circumference 35 inches)
Triglyceride levels >150 mg/dL
HDL-cholesterol levels <50 mg/dL
Hypertension
Impaired glucose tolerance (fasting glucose 100125 mg/dL and/or
2-hour glucose 140199 mg/dL)
*Three of five criteria are required to diagnose.

noted to improve with weight loss, and the risk of developing diabetes is reduced.36 Weight loss and exercise are
thus considered a primary treatment for all obese women
who have PCOS.
Infertility

Infertile patients with PCOS will require ovulation

induction to conceive. The most physiologic approach to
ovulation induction is weight loss.4,5 If this fails, however, clomiphene citrate is an excellent initial ovulation
induction medication. Most women with PCOS will ovulate in response to clomiphene citrate doses of 50 mg/day
for 5 days or 100 mg/day for 5 days. Most pregnancies
will occur at these dosages and generally within the first
five or six ovulatory cycles.4,5
Some women with PCOS will be resistant to clomiphene
citrate and will require alternative treatments. Among these
women, many will have insulin resistance. Insulin-sensitizing agents used alone or in combination with clomiphene
will stimulate ovulation in many women who do not respond
to clomiphene alone.46 Metformin, a biguanide, is the best
studied of these agents. Studies suggest that most patients
with PCOS will require 4 to 6 months of therapy with metformin as a single agent before cyclic ovulation is restored.
Its effect is more rapid when used in combination with
clomiphene.5,6,11 The clinically effective dose of metformin is
1500 to 2550 mg/day.
Gastrointestinal side effects are common with metformin, particularly with initiation of therapy. Therefore,
metformin therapy is initiated at a low dose, which is
titrated to the therapeutic dosage over several weeks.
Metformin therapy may be complicated by hepatic toxicity, and rarely, lactic acidosis; thus liver and renal function tests must be assessed before treatment and periodically thereafter. In addition, metformin should be temporarily stopped before surgical procedures that require
restriction of fluid intake and radiologic procedures such
as hysterosalpingogram, in which the iodinated contrast
agent combined with metformin is associated with an
increased risk of lactic acidosis.5,6
Some authors advocate metformin as a primary therapy in
anovulatory, infertile patients with PCOS, while others
reserve its use for women who are resistant to clomiphene
citrate alone.46 Rosiglitazone and pioglitazone are thiazolidinediones that are being researched as alternatives to metformin. Their mechanism of action is different from that of
metformin, which acts primarily to reduce hepatic glucose
output, decrease intestinal absorption of glucose, and

Medical Consequences of PCOS

An evaluation of metabolic abnormalities should be performed in women with PCOS. Patients should be evaluated
for impaired glucose tolerance and Type 2 diabetes mellitus.
Because of the greater sensitivity of a 2-hour OGTT compared with fasting glucose concentration, it is justified to
screen women with PCOS with an OGTT. An assessment of
fasting lipid and lipoprotein levels also should be obtained
in an effort to identify patients with PCOS who have the
metabolic syndrome, which is associated with insulin resistance, hypertension, fasting hyperglycemia, abdominal obesity, and dyslipidemia35 (Table 3). Measurement of height,
weight, body mass index, blood pressure, and waist and hip
ratio should be obtained in women with PCOS, as well as a
fasting lipid panel and blood glucose.4
Women with PCOS have multiple risk factors for Type 2
diabetes mellitus and are three to seven times more likely
to develop diabetes than women without PCOS. Women
with PCOS are also at increased risk of developing cardiovascular disease due to the insulin resistance, dyslipidemia, obesity, and abnormal vascular function associated
with the syndrome. The chronic anovulation that many
women with PCOS experience places them at increased
risk for endometrial carcinoma, infertility, and abnormal
uterine bleeding.35 Treatment of patients who have PCOS
should be directed toward reducing the risks of developing
these medical consequences of the syndrome.

Treatment of PCOS
Weight Loss

Women who are overweight or obese should be encouraged to lose weight. Obesity clearly impacts upon the
reproductive and metabolic consequences of PCOS, and
multiple studies have documented that weight loss of
greater than 5% favorably influences PCOS by decreasing androgen concentrations and improving ovulation
frequency. Circulating insulin levels decrease, sex hormone-binding globulin (SHBG) levels increase, and free
testosterone levels decrease. Hirsutism also has been
4

413145_PGO03_sw 2/7/05 9:45 AM Page 5

February 15, 2005

Postgraduate Obstetrics & Gynecology

increase the uptake and utilization of glucose in peripheral

tissues. The thiazolidinediones are agonists of peroxisome
proliferator-activating receptor- and work through postreceptor mechanisms to increase insulin sensitivity in fat, muscle and peripheral tissues.46
The insulin-sensitizing medications reduce fasting
insulin values, normalize fasting G:I ratios, increase
SHBG, and reduce serum total and bioavailable/free
testosterone levels in women who have PCOS.46
Although insulin-sensitizing medications are approved
for diabetes management, they are not FDA approved for
the treatment of PCOS. PCOS and insulin resistance are
also associated with an increased risk of miscarriage. It is
theorized, but yet unproven, that use of insulin sensitizers
may reduce the risk of miscarriage in women with
PCOS.5,6 Metformin is a category B drug in pregnancy,
whereas the thiazolidinediones are category C.4
Gonadotropins are fertility medications that contain FSH
and LH alone or in combination. A variety of gonadotropins
are commercially available, and others are in various stages
of research and development. Gonadotropins are frequently
used to induce ovulation in patients with PCOS who fail to
conceive with clomiphene. Careful monitoring of patients is
required when gonadotropins are used to minimize the risk
of side effects, most importantly multiple gestation and
ovarian hyperstimulation syndrome.
Women with PCOS are at increased risk for both of these
complications of gonadotropin therapy. Up to 30% of pregnancies that result from gonadotropin cycles are multiple,
in contrast to a rate of 1% to 2% without fertility medications and 5% to 10% with clomiphene. While most of these
pregnancies are twins, up to 5% are triplets or higher-order
multiple gestations. Multiple-gestation pregnancies are
associated with increased risk of pregnancy loss, premature
delivery, morbidity due to the consequences of prematurity,
pregnancy-induced hypertension, hemorrhage, and other
significant maternal and fetal complications.
The most serious side effect of gonadotropin therapy is
ovarian hyperstimulation syndrome, which represents an
exaggerated response to gonadotropins. The cardinal pathophysiologic feature of ovarian hyperstimulation syndrome
is increased capillary permeability, which results in fluid
shifting from the intravascular compartment to third-space
compartments, particularly the abdominal cavity. Although
most cases of ovarian hyperstimulation syndrome are of
mild to moderate severity and can be managed on an outpatient basis, hospitalization may be required for severe
cases. Low doses of gonadotropins are preferable to reduce
these risks, which are elevated in women with PCOS, particularly thin patients with PCOS.4,5,12

betes mellitus and other long-term metabolic sequelae is

the third main goal.4,5
Lifestyle Modification

Addressing the importance of long-term management first,

the importance of lifestyle modifications on future risks of
diabetes and cardiovascular disease cannot be overlooked.
Women with PCOS have a three- to sevenfold increased risk
of developing Type 2 diabetes mellitus. There is believed to
be an increased risk of coronary heart disease, as PCOS is
associated with dyslipidemia and metabolic syndrome,
markers of abnormal vascular function, and insulin resistance, which independently increases susceptibility to coronary heart disease. The precise risk of cardiovascular disease
is uncertain, however, as the limited epidemiological data
have not shown an increase in cardiovascular events in
younger cohorts.36 Nevertheless, lifestyle modification, diet,
and exercise should be strongly advised to reduce the risk of
both Type 2 diabetes mellitus and cardiovascular disease.
In the Diabetes Prevention Project, 3234 participants with
impaired glucose tolerance were randomized to placebo,
metformin, or a lifestyle modification program with a goal
of preventing or delaying the development of diabetes. The
intensive lifestyle intervention program focused on a low-fat
diet and exercise program that enabled participants to lose
approximately 5% to 7% percent of their body weight and
exercise approximately 30 minutes per day. This level of
weight loss and increased exercise reduced the risk of developing Type 2 diabetes mellitus by 58% compared with the
placebo arm. Metformin, 850 mg twice per day, reduced the
risk of developing diabetes by 31%. Overall, 29% of the
placebo group, 22% of the metformin group, and 14% of the
lifestyle intervention group developed Type 2 diabetes mellitus during an average of 3 years of follow-up. The incidence of newly diagnosed Type 2 diabetes mellitus was
11.0, 7.8, and 4.8 cases per 100 person years in the placebo,
metformin, and lifestyle groups, respectively.13 Independent
research has demonstrated that supervised weight loss and
exercise regimens lead to reduced insulin resistance,
reduced hyperandrogenism, and in some cases, resumption
of ovulation in obese patients with PCOS.14 Thus, in women
with PCOS, lifestyle modification and metformin provide
two options to reduce their future risk of developing Type 2
diabetes. Current data are insufficient, however, to warrant
the routine use of insulin-sensitizing agents as first-line prophylaxis to prevent Type 2 diabetes mellitus in all women
with PCOS.4
Menstrual Cycle Regulation

Menstrual cycle regulation and the prevention of endometrial carcinoma can be achieved by cyclically administering
progestogens to induce menstruation or by the use of combination oral contraceptive pills. Endometrial biopsy should be
considered as part of the evaluation of patients with PCOS to
determine whether endometrial abnormalities are preexistent. The regimen of cyclic oral progestogen therapy that
most effectively prevents endometrial carcinoma in women
with PCOS is unknown. Progestin-only oral contraceptives

Long-Term Management
There are several goals of therapy in patients with
PCOS who do not plan to conceive. Menstrual cycle regulation and the prevention of endometrial hyperplasia is
a primary goal. Control of hyperandrogenism is a secondary goal. Improving the metabolic state of the patient
with an aim at reducing the future risks of Type 2 dia5

413145_PGO03_sw 2/7/05 9:45 AM Page 6

Postgraduate Obstetrics & Gynecology

February 15, 2005

and depot-medroxyprogesterone acetate are alternatives to

cyclic progestogens for endometrial protection; however,
they do not induce cyclic menstruation, and many women
experience undesirable breakthrough bleeding.4,5
Oral contraceptives. The mainstay of long-term therapy
for patients with PCOS is combination oral contraceptive
pills. Oral contraceptives induce regular withdrawal bleeding and afford protection against endometrial carcinoma.
They are generally well tolerated. In addition to their benefit for menstrual cycle regulation, oral contraceptives favorably affect the hyperandrogenism associated with PCOS by
a variety of mechanisms. Oral contraceptives reduce pituitary secretion of LH, thereby reducing ovarian androgen
production. They also increase circulating levels of SHBG,
which serves to reduce free testosterone levels.4,5 The best
oral contraceptive for patients with PCOS is unknown. Oral
contraceptives have no clinically adverse effect on glucose
homeostasis. Oral contraceptives will slow the rate of hair
growth in women reporting hirsutism, and there is a measurable decline in hirsutism scores during a 6-month period.
In contrast, insulin-sensitizing agents less consistently
induce cyclic menstruation or improvement in hirsutism.15
Antiandrogens. For the treatment of hirsutism, blocking androgen action with an antiandrogen is often used in
combination with oral contraceptives. None of the antiandrogen medications used to treat women with PCOS are
approved by the FDA for this indication.
Randomized clinical trials have demonstrated that
spironolactone, flutamide, and finasteride all have similar
efficacy in treating hirsutism, and the best choice for
PCOS is unknown.16 Antiandrogens are potentially teratogenic if a patient conceives while taking them; they
can result in ambiguous genitalia in a male fetus.
Spironolactone is a diuretic and aldosterone antagonist
that also competitively binds to the androgen receptor as
an antagonist. It has several additional mechanisms of
antiandrogen action including inhibition of ovarian and
adrenal steroidogenesis and inhibition of 5-reductase
activity. Its main mechanism of action is to compete with
dihydrotestosterone for the androgen receptor in the hair
follicle.4,16 The usual dose is 25 to 100 mg twice daily,
and the dose is titrated slowly to balance therapeutic benefits and side effects, which include headaches, fatigue,
diuresis, and gastritis. Spironolactone is generally combined with an oral contraceptive and is the standard firstline antiandrogen in the United States.5,16
Flutamide is an androgen receptor-blocker that is approved
by the FDA as adjunctive therapy for prostate cancer to be
used in conjunction with a GnRH agonist. The usual dose is
250 mg per day. Side effects include dry skin, greenish urine,
and rare hepatotoxicity. Contraception should be used with
flutamide because it is linked to a high risk of teratogenicity.4
Finasteride inhibits 5-reductase. The 1-mg dose is FDA
approved for the treatment of male baldness, and the 5-mg
dose is approved for the treatment of benign prostatic
hypertrophy. Finasteride is well tolerated, with minimal risk
of hepatic or renal toxicity. Side effects include dry skin and

reduced libido. Because of its teratogenic potential, finasteride should be used with an effective contraceptive agent.4
Cyproterone acetate is a derivative of 17OHP with
strong progestational activity. It also competes with dihydrotestosterone for the androgen receptor. It is not available in the United States. In other countries, cyproterone
acetate is a component of oral contraceptives as well as a
single agent for the treatment of hirsutism.16
Gonadotropin-releasing hormone agonists. GnRH agonists are the most effective agents for suppressing excess ovarian androgen production. They will suppress pituitary secretion of LH as well as its biologic activity of LH. GnRH agonists lead to improvement in hirsutism scores in patients with
PCOS even when the primary pathophysiologic mechanism is
insulin resistance. When the immunologic and biologic activity of LH is suppressed to below a critical threshold, insulin
loses its capacity to stimulate ovarian steroidogenesis. GnRH
agonists are associated with hypoestrogenic side effects, such
as hot flashes and genitourinary atrophy, and their potential for
inducing bone loss is a limiting factor for GnRH agonist use
unless prescribed in combination with oral contraceptives or
other hormone add-back regimens. GnRH agonists are most
useful for severe ovarian androgen excess states, such as
HAIR-AN syndrome, which is associated with relatively low
levels of LH and very high testosterone levels, because they
induce a greater suppression of LH secretion than oral contraceptives. It may take several months to maximally suppress
gonadotropin secretion, at which time GnRH agonists are
generally combined with oral contraceptives or hormone therapy and possibly antiandrogens as well.17
Cosmetic Therapies

When treating symptoms of androgen excess, improvement in acne may be noted within 1 to 2 months, whereas
improvement in hirsutism generally is not observed for 3 to
8 months. Topical eflornithine cream is an adjunct to the
medical management of hirsutism. Eflornithine inhibits
ornithine decarboxylase, an enzyme involved with hair
growth. Chemical depilatories, shaving, electrolysis, and
laser hair removal are additional cosmetic adjuvants.

Surgical Treatment
Surgical treatment of PCOS is of unconfirmed value.
Although ovarian wedge resection is rarely performed today, it
can induce long-term cyclic menstrual function in a majority of
patients.18 More recently, laparoscopic ovarian drilling with
cautery, diathermy, or laser has been suggested as a treatment
for patients with PCOS who are resistant to ovulation induction.
These procedures have greater usefulness for restoring ovulation than for treating hirsutism. Laparoscopic ovarian drilling is
associated with pregnancy rates that are equivalent to three
cycles of gonadotropin therapy.19 There is no difference in miscarriage rates, and the rate of multiple pregnancies is reduced
after laparoscopic ovarian drilling. The fertility benefits of ovarian drilling appear to be temporary, and the procedure does not
improve the metabolic abnormalities associated with PCOS.4
Oophorectomy may be an option for women approaching
menopause who have severe ovarian hyperandrogenism.
6

413145_PGO03_sw 2/7/05 9:45 AM Page 7

February 15, 2005

Postgraduate Obstetrics & Gynecology

Conclusion

2.

PCOS is a common reproductive endocrine disorder

characterized by chronic anovulation, chronic hyperandrogenism, and/or polycystic appearing ovaries. The
diagnosis is made after other causes of anovulation and
androgen excess have been excluded.
Altered gonadotropin secretion and insulin resistance are
important pathophysiologic mechanisms that underlie the
clinical syndrome. Many patients with PCOS are obese, but
obesity is not a diagnostic criterion nor does PCOS cause
obesity. The most common symptoms of PCOS are irregular menstruation, infertility, and hirsutism. Long-term medical consequences of PCOS include an increased risk of
endometrial cancer, Type 2 diabetes mellitus, dyslipidemia,
and possible heart disease.
Weight loss and exercise are key components of the
long-term management of PCOS. Ovulation induction
with clomiphene citrate is frequently a successful treatment for infertility. Insulin-sensitizing agents, such as
metformin, may improve ovulatory frequency as single
agents and also may improve responsiveness to clomiphene
citrate. Gonadotropins may also be used for ovulation
induction. Cyclic administration of progestogens and the
use of oral contraceptive pills both provide regulation of
the menstrual cycle and protect against endometrial carcinoma. Oral contraceptives have the added benefit of
suppressing ovarian androgen production and reducing
the percentage of free testosterone. Antiandrogens, such
as spironolactone, often are used in combination with
oral contraceptives. GnRH agonist therapy is usually
reserved for very severely affected patients. Long-term
management of patients with PCOS is required to reduce
their future risks of Type 2 diabetes mellitus and other
medical sequelae.

3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.

15.

16.
17.
18.
19.

REFERENCES
1.

Stein IF, Levanthal ML. Amenorrhea associated with bilateral polycystic

ovaries. Am J Obstet Gynecol 1935;29:181191.

Zawadski J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome:

towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, eds. Polycystic
Ovary Syndrome. Boston, MA: Blackwell Scientific; 1992, pp 377384.
Revised 2003 consensus on diagnostic criteria and long-term health risks
related to polycystic ovary syndrome. Fertil Steril 2004;81:1925.
ACOG Practice Bulletin. Polycystic Ovary Syndrome. Clinical
Management Guidelines for Obstetrician-Gynecologists: number 41,
December 2002. Obstet Gynecol 2002;100:13891402.
Guzick DS. Polycystic ovary syndrome. Obstet Gynecol 2004;103:181193.
Barbieri RL. Metformin for the treatment of polycystic ovary syndrome.
Obstet Gynecol 2003;101:785793.
Barbieri RL, Ryan KJ. Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 1983;147:90101.
American Diabetes Association. Consensus Development Conference on
Insulin Resistance, 56 November 1997. Diabetes Care 1998;21:
310314.
Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a
useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:26942698.
Carmina E, Lobo RA. Use of fasting blood to assess the prevalence of
insulin resistance in women with polycystic ovary syndrome. Fertil Steril
2004;82:661665.
Nestler JE, Jakubowicz DJ, Evans WS, et al. Effects of metformin on
spontaneous and clomiphene-induced ovulation in the polycystic ovary
syndrome. N Engl J Med 1998;338:18761880.
Whelan JG, 3rd, Vlahos NF. The ovarian hyperstimulation syndrome.
Fertil Steril 2000;73:883896.
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl
J Med 2002;346:393403.
Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive
potential by lifestyle modification in obese polycystic ovary syndrome:
role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol
Metab 1999;84:14701474.
Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and
metabolic effects of metformin versus ethinyl estradiol-cyproterone
acetate in obese women with polycystic ovary syndrome: a randomized
study. J Clin Endocrinol Metab 2000;85:31613168.
Moghetti P, Tosi F, Tosti A, et al. Comparison of spironolactone, flutamide,
and finasteride efficacy in the treatment of hirsutism: a randomized, double
blind, placebo-controlled trial. J Clin Endocrinol Metab 2000;85:8994.
Azziz R. The hyperandrogenic-insulin-resistant acanthosis nigricans syndrome: therapeutic response. Fertil Steril 1994;61:570572.
Lunde O, Djoseland O, Grottum P. Polycystic ovarian syndrome: a followup study on fertility and menstrual pattern in 149 patients 1525 years
after ovarian wedge resection. Hum Reprod 2001;16:14791485.
Farquhar CM, Williamson K, Gudex G, et al. A randomized controlled
trial of laparoscopic ovarian diathermy versus gonadotropin therapy for
women with clomiphene citrate-resistant polycystic ovary syndrome.
Fertil Steril 2002;78:404411.

View past*, current, and future issues of your paid subscription to Postgraduate Obstetrics &
Gynecology online for free! Follow these instructions to log-on to your account.
1.
2.
3.
4.

Locate your 12-digit account number on the mailing label of your current issue.
Go to: www.lwwnewsletters.com.
From the choices on the top yellow toolbar, select Sign On.
In the spaces provided, enter your Username and Password. Your username will be the letters LWW (case
sensitive) followed by the 12-digit account number on your address label. We have provided an easy-to-remember default password for you: Simply type the numbers 1234. (This password cannot be changed.)
5. Click Sign On.
6. Click Access My Account.
7. Click View or Renew Subscriptions. Click on Postgraduate Obstetrics & Gynecology, and select the current
or archive issue you wish to view. All issues are posted in PDF format. You will need Adobe Acrobat Reader
installed on your computer to view the issues. To download your free copy of the Acrobat Reader, visit
www.Adobe.com.
If you have any questions or problems regarding your print or electronic account, please call 1-800-787-8981.
*Archive issues are available as far back as January 2004.
7