P Managing the complications of polycystic ovarian syndrome

Managing the complications
of polycystic ovarian syndrome
Draion M. Burch, DO
Paige E. Paladino, DO
P
olycystic ovarian
syndrome (PCOS)
is the most
common endocrine abnormality
of reproductive-aged women.1
This chronic condition affects 5 million
to 6 million females in the United States.2
In addition, an estimated 50% to 75%
of cases remain undiagnosed.3
April 2011 DOs Against DIABETES
AOA Health Watch 19
PCOS is classified by the presence
of two of the following three criteria:
(a) oligo- and/or anovulation;
(b) clinical and/or biochemical signs
of hyperandrogenism; and (c) polycystic
ovaries, all in the absence of other
known etiologies.4 Women with
PCOS may seek care from physicians
in various medical specialties, including
endocrinology, internal medicine,
obstetrics and gynecology, dermatology
and family medicine. Therefore,
physicians in these specialties must
understand management of the
short- and long-term complications
associated with PCOS.
Short-term complications
Following are short-term
complications related to PCOS,
as well as treatment options.
䡲 Menstrual irregularities
The prevalence of menstrual dysfunction
in women with PCOS is 14.6%
to 22.8%, and irregularities range
from amenorrhea to menorrhagia
with a classic peripubertal onset.5,6
Recommendations: A modest
weight reduction of 5% can return
menses to normal.7 Combination
oral contraceptives (COCs) or
progestins are also effective at
regulating the menstrual cycle
in these patients. Metformin
has been shown to have positive
effects on ovulatory dysfunction
and hyperandrogenism, ultimately
restoring normal menstruation.8,9
added if acceptable results are not
achieved, but these medications
must be used in conjunction
with COCs due to known risk
of congenital anomalies.
Eflornithine, a topical medication,
has been shown to be effective in
hirsute women, and waxing, shaving,
depilatories, electrolysis and laser
treatments are alternative options for
hirsutism.10-12 Topical retinoids and
antimicrobials or oral antibiotics can
be effective in the treatment of
acne.13 Limited data support the use
of topical minoxidil in the treatment
of alopecia.14 Hyperandrogenism has
also been shown to improve with
dietary modification.15
䡲 Hyperandrogenism
Cutaneous hyperandrogenism
䡲 Infertility
manifests as hirsutism, acne and
Infertility due to anovulation affects
androgenic alopecia. Its prevalence
75% of women with PCOS.16
in the PCOS population in the form
of acne is 15% to 25%; hirsutism,
Recommendations: Lifestyle
65% to 75%; and alopecia, 5% to 50%.5
modifications, including weight
reduction, decreasing alcohol
Recommendations: COCs are
consumption, smoking cessation
beneficial for all forms of cutaneous
and limiting caffeine intake, are
hyperandrogenism; however, the
beneficial.17 Weight loss induces
selection of a low-androgenic
ovulation in overweight patients.
progestin component is essential.
Clomiphene citrate (CC) is
Anti-androgens, such as spironolactone,
a first-line pharmacologic treatment
flutamide or finasteride can then be
20 AOA Health Watch
in anovulatory women with PCOS.
Other agents used in ovulation
induction include metformin
and thiazolidinediones. Referral
to a reproductive endocrinologist
is appropriate if CC fails to
achieve pregnancy.
Treatment with exogenous
gonadotropins or laparoscopic
ovarian surgery such as ovarian
diathermy is second-line intervention.
The ovarian wedge resection has
been abandoned, secondary to
increased adhesion formation.
The recommended third-line
intervention is in vitro fertilization.18
䡲 Obesity
Obesity in the PCOS patient
tends to be central (android)
or visceral in its distribution.19
The prevalence of obesity is
40% to 60% in this population.20
This epidemic exacerbates
insulin resistance, ovulatory and
menstrual dysfunction and pregnancy
outcome. Obesity is associated
with increased prevalence of
metabolic syndrome, glucose
intolerance, cardiovascular risk
factors and sleep apnea.21
DOs Against DIABETES April 2011
Recommendations: Lifestyle
higher concentrations of smallerand higher-density LDL particles.
modification is crucial. Modest
amounts of weight loss have been
Recommendations: Lifestyle
shown to restore spontaneous
modification with diet, exercise
ovulation and menstruation and to
and weight loss is essential.
improve insulin sensitivity.20 No
HMG-CoA, reductase inhibitors
particular type of dietary modification
(statins)
have been shown to
has been shown to be superior.22
effectively treat dyslipidemia
Anti-obesity medications, such as
and decrease levels of circulating
orlistat, sibutramine and rimonabant,
androgens. Other treatments include
and surgical weight loss have been
nicotinic acid and fibrates.31
found to be effective and even more
sustainable in the long term for
䡲 Obstructive sleep apnea (OSA)
weight loss.23,24 Metformin has also
Patients with PCOS have a higher
appeared to have some benefit.8
risk for obstructive sleep apnea, even
when compared with obese non䡲 Insulin resistance
PCOS control subjects.32 Insulin
and hyperinsulinemia
resistance seems to be a better
Insulin resistance and compensatory
predictor of sleep-disordered
hyperinsulinemia affect 40% to 70%
breathing. Glucose tolerance is
of women with PCOS independent
directly related to the severity of
of obesity.5,25 The strongest predictors
sleep apnea in these patients.33
of insulin resistance in a patient
with PCOS are body mass index,
Recommendations: Weight loss,
hyperandrogenemia, and hirsutism.26
avoidance of alcohol, sleep position
Insulin resistance is also associated
changes, avoidance of medications
with obstructive sleep apnea,
that inhibit the central nervous
nonalcoholic steatohepatitis
(or, nonalcoholic fatty liver disease)
and metabolic abnormalities such as
metabolic syndrome, dyslipidemia
and type 2 diabetes mellitus (T2DM),
which are all more prevalent in
these patients.5 Hyperinsulinemia
also exacerbates cutaneous
hyperandrogenism.
system and positive airway pressure
have been shown to be effective.34
䡲 Pregnancy loss
Pregnant women with PCOS have
a 30% to 50% increased risk of
early spontaneous abortion.35
Recommendations: Weight
reduction and medications such as
metformin have been shown to
reduce first trimester spontaneous
abortion (SAB) rates.35 The optimum
time to discontinue metformin has
yet to be elucidated.36
䡲 Pregnancy complications
Women with PCOS also have an
increased risk of preterm delivery,
hypertensive disorders, gestational
diabetes and perinatal mortality.37
Maternal and neonatal risk are
increased by iatrogenic multiple
gestation from infertility treatment.18
Recommendations: Metformin
continued during pregnancy decreases
rates of gestational diabetes.38
Recommendations: Weight
reduction and medications such as
metformin and thiazolidinediones
have all been shown to decrease
insulin resistance.27-29
䡲 Dyslipidemia
Lipid abnormalities, including
elevated low-density lipoprotein
cholesterol levels, triglyceride levels,
total cholesterol to high-density
lipoprotein cholesterol ratios, and
decreased high-density lipoprotein
cholesterol levels are found in women
with PCOS.5 The prevalence of
abnormal lipid levels, according
to National Cholesterol Education
Program criteria, approaches 70% in
these patients.30 PCOS patients have
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Long-term complications
Following are long-term
complications related to PCOS,
as well as treatment options.
䡲 Endometrial hyperplasia
and carcinoma
The chronic unopposed estrogen
exposure in PCOS increases the
risk of endometrial hyperplasia
and endometrial carcinoma.39
An increased incidence of
endometrial hyperplasia and atypia
in the obese PCOS patient has been
observed.40 Increased progression
to carcinoma, however, has not
been supported by epidemiologic
evidence.39 PCOS patients have
other risk factors for endometrial
cancer including chronic
hyperinsulinemia, increased
concentrations of serum insulin-like
growth factor, hyperandrogenemia
and obesity.41
Recommendations: To prevent
endometrial hyperplasia, the use
of COCs or the use of intermittent
progestins is warranted. For
women with oligomenorrhea
or amenorrhea, menstruation
is induced by the administration
of medroxyprogesterone acetate
prior to initiation of COCs.
Progestins can be given every one
month to three months to induce a
withdrawal bleed. Endometrial biopsy
should be performed for all women
older than 35 years with abnormal
bleeding and women younger than 35
years with risk factors for endometrial
hyperplasia. PCOS patients have other
risk factors for endometrial cancer
including chronic hyperinsulinemia,
increased concentrations of
serum insulin-like growth factor,
hyperandrogenemia and obesity.41
䡲 Metabolic syndrome:
Metabolic syndrome is associated
with an increased risk of
cardiovascular disease (CVD)
and T2DM.43 Metabolic syndrome
occurs in up to 43.6% of women
with PCOS.42 Specifically for the
PCOS patient, the presence of
three of the following provides the
diagnosis of metabolic syndrome:
— abdominal obesity (waist
circumference, ⬎35 inches)
— triglycerides, ⬎150 mg/dL
— high-density lipoprotein
cholesterol, ⬎50 mg/dL
— blood pressure, ⬎130 systolic
and/or ⬎85 diastolic mm Hg
— fasting glucose level, 110 mg/dL
to 126 mg/dL, and/or two-hour
glucose tolerance test result,
140 mg/dL to 199 mg/dL
Recommendations: Treatment
starts with lifestyle modification such
as diet and exercise to reduce weight.
Prevention of T2DM is achieved by
administration of oral hypoglycemic
metformin and thiazolidinediones.
Use of lipid-lowering and
antihypertensive therapies is effective
in reducing cardiovascular risk.44
䡲 T2DM/Impaired
glucose intolerance
Fifty percent to 75% of women with
PCOS have T2DM or prediabetes.45
The conversion rate from impaired
glucose tolerance to frank diabetes is
fivefold to tenfold higher in women
with PCOS.45
Recommendations: Women should
be screened with a fasting glucose
test followed by a two-hour glucose
test after ingesting a 75-gram glucose
load.46 Management involving
lifestyle modification, including diet,
22 AOA Health Watch
exercise and weight reduction, and
an oral hypoglycemic and insulin
should be initiated. Lifestyle
modification has been shown to be
the superior treatment for improving
insulin sensitivity, reducing weight,
decreasing the incidence of T2DM
and metabolic syndrome and
improving risk factors for CVD.47
䡲 Cardiovascular disease
Insulin-resistant states are associated
with a greater susceptibility to
coronary artery disease.25 Women
with PCOS have increased CVD risk
factors such as obesity, metabolic
syndrome, hypertension, T2DM and
dyslipidemia.45 These women exhibit
greater endothelial dysfunction,
arterial stiffness in the internal and
external carotid arteries, presence
of carotid and aortic plaque,
increased thickness of intima media
layers of the carotid artery and
coronary artery and cerebrovascular
artery calcification.48-50 Increased
early left ventricular diastolic
dysfunction, lower ejection fraction
and a 7.1-times-higher risk than a
non-PCOS patient for developing
a myocardial infarction.50 Death
from CVD is more common in
women with PCOS.48 These risk
factors could be the result of
inflammation because C-reactive
protein levels are elevated
in PCOS patients.45
Recommendations: Women
with PCOS should be screened
for cardiovascular risk by determination
of body mass index, fasting lipid and
lipoprotein levels, and metabolic
syndrome risk factors. Management
focuses on modifying the CVD
risk factors.51
䡲 Nonalcoholic steatohepatitis
(NASH)
The prevalence of nonalcoholic
steatohepatitis is increased
in the PCOS patient and is
associated with obesity, T2DM,
and hyperlipidemia.52 Insulin
resistance may be the key mechanism
leading to hepatic steatosis.
DOs Against DIABETES April 2011
Recommendations: There is
no proven effective therapy for
nonalcoholic steatohepatitis,
although modification of risk
factors is recommended.53
䡲 Psychological disorders
The prevalence of depression in
PCOS patients is reported to be as
high as 40%.44 Depression has been
associated with insulin resistance,
impaired glucose intolerance and
obesity. Patients with PCOS may
have low self-esteem and poor selfimage.53 They can suffer from social
withdrawal, eating disorders, and
anxiety and may attempt suicide.
Recommendations: Treatment
should include behavioral and
psychological interventions adjunctive
to standard medical care.45
Final notes
PCOS is a complex medical condition
that requires a multidisciplinary team
approach for optimal treatment. It is
important to understand that PCOS
is a syndrome, not a disease, reflecting
multiple potential etiologies with
variable clinical expression of these
and other features in adolescents
and adults with this syndrome.
PCOS treatments must be directed
at addressing the immediate goals of
patients and preventing short- and
long-term complications. By addressing
these complications and making
lifestyle changes that are supported by
appropriate pharmacologic interventions
with continuous surveillance, patients’
quality of life can be improved.
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AOA Health Watch 23
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For more information
You can find out more about PCOS
by contacting womenshealth.gov
at (800) 994-9662 or the following
organizations:
Women’s Health Research,
National Institute of Child Health
and Human Development, NIH, HHS
Telephone: (800) 370-2943
http://www.nichd.nih.gov/
womenshealth
American Association
of Clinical Endocrinologists
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Impaired glucose tolerance, type 2 diabetes
and metabolic syndrome in polycystic ovary
syndrome: a systematic review and meta-analysis.
Hum Reprod Update. 2010;16(4):347-363.
Telephone: (904) 353-7878
http://www.aace.com
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Markham S, Vanvoorhis B, Jagasia DH.
Screening women with polycystic ovary
syndrome for metabolic syndrome.
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Telephone: (202) 638-5577
http://www.acog.org
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Carmina E. Long-term consequences
of polycystic ovary syndrome on cardiovascular
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Telephone: (205) 978-5000
http://www.asrm.org
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diabetes and cardiovascular disease in women
with PCOS: treatment with insulin sensitizers.
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2006;20(2): 245-260.
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American College of
Obstetricians and Gynecologists
American Society
for Reproductive Medicine
Center for Applied
Reproductive Science
Telephone: (423) 461-8880
http://www.ivf-et.com
InterNational Council on Infertility
Information Dissemination, Inc.
Telephone: (703) 379-9178
http://www.inciid.org
Polycystic Ovarian
Syndrome Association, Inc.
http://www.pcosupport.org
The Hormone Foundation
Telephone: (800) 467-6663
http://www.hormone.org
Draion M. Burch, DO, an obstetrics and gynecology resident from Detroit, serves as the intern and resident representative to the American
Osteopathic Association Board of Trustees. Dr. Burch also serves as an intern/resident trustee to the Michigan Osteopathic Association Board
of Trustees. He also serves as the chief resident of the obstetrics and gynecology residency program for the Statewide Campus System Michigan
State University College of Osteopathic Medicine/St. John Providence Health System Osteopathic Division Macomb-Oakland Hospital, Macomb
Center, in Warren, Michigan.
Dr. Burch received the 2009 St. John Osteopathic Division OBGYN Resident of the Year award and has been very active at state and national
levels. He can be reached at dr.draionmburch@gmail.com.
Paige Paladino, DO, is a first year resident in obstetrics and gynecology at St. John Macomb-Oakland Hospital, Macomb Center in Warren, Michigan.
She graduated from Kansas City University of Medicine and Biosciences, College of Osteopathic Medicine in 2010. Dr. Paladino can be reached
at paigepaladino@hotmail.com.
24 AOA Health Watch
DOs Against DIABETES April 2011