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Polycystic Ovarian Syndrome Treatment &

Updated: Aug 11, 2016

Author: Richard Scott Lucidi, MD, FACOG; Chief Editor: Richard Scott Lucidi, MD,
FACOG more...


Approach Considerations
Certain lifestyle changes, such as diet and exercise, are considered first-line treatment for
adolescent girls and women with polycystic ovarian syndrome (PCOS). [41] Pharmacologic
treatments are reserved for so-called metabolic derangements, such as anovulation, hirsutism,
and menstrual irregularities. Medications for such conditions include oral contraceptives,
metformin, prednisone, leuprolide, clomiphene, and spironolactone.

Mean platelet volume (MPV) is a marker associated with adverse cardiovascular events, and
women with newly diagnosed PCOS appear to have significantly elevated MPV levels. [47] Kabil
Kucur et al reported that use of ethinyl estradiol/cyproterone acetate or metformin for the
treatment of women with PCOS seemed to have similar beneficial effects in reducing MPV. [47]

Consultation with an endocrinologist is necessary for performing an adrenocorticotropic

hormone (ACTH) stimulation test or for other causes of menstrual irregularity such as thyroid
disease or pituitary adenoma. A reproductive endocrinologist should be consulted if the patient is
infertile and desires pregnancy. [48]

In October 2013, the Endocrine Society released practice guidelines for the diagnosis and
treatment of PCOS. The following were among their conclusions [49] :

Use the Rotterdam criteria for diagnosing PCOS (presence of 2 of the following:
androgen excess, ovulatory dysfunction, or polycystic ovaries).

In adolescents with PCOS, hyperandrogenism is central to the presentation; hormonal

contraceptives and metformin are treatment options in this population. [50]

Postmenopausal women do not have a consistent PCOS phenotype.

Exclude alternate androgen-excess disorders and risk factors for cardiovascular disease,
diabetes, endometrial cancer, mood disorders, and obstructive sleep apnea.

For menstrual abnormalities and hirsutism/acne, hormonal contraceptives are first-line


For infertility, clomiphene is first-line treatment.

For metabolic/glycemic abnormalities and for improving menstrual irregularities,

metformin is beneficial.
Metformin is of limited or no benefit for managing hirsutism, acne, or infertility.

Overall, thiazolidinediones have an unfavorable risk-benefit ratio.

More investigation is needed to determine the roles of weight loss and statins in PCOS.

Lifestyle Modifications
The American College of Obstetricians and Gynecologists (ACOG) and the Society of
Obstetricians and Gynaecologists of Canada (SOGC) indicate that lifestyle modifications such as
weight loss and increased exercise in conjunction with a change in diet consistently reduce the
risk of diabetes. This approach has been found to be comparable to or better than treatment with
medication and should therefore be considered first-line treatment in managing women with
polycystic ovarian syndrome (PCOS). [2, 3] These modifications have been effective in restoring
ovulatory cycles and achieving pregnancy in obese women with PCOS. Weight loss in obese
women with PCOS also improves hyperandrogenic features.

Drug Treatment
Medical management of PCOS is aimed at the treatment of metabolic derangements,
anovulation, hirsutism, and menstrual irregularity. The use of insulin-sensitizing drugs to
improve insulin sensitivity is associated with a reduction in circulating androgen levels, as well
as improvement in both the ovulation rate and glucose tolerance. [3] The Endocrine Society has
published a clinical practice guideline on hirsutism evaluation and treatment in premenopausal
women. [51] ACOG notes that eflornithine in conjunction with laser treatment is superior to laser
therapy alone in treating hirsutism. [3]

First-line medical therapy usually consists of an oral contraceptive to induce regular menses. The
contraceptive not only inhibits ovarian androgen production but also increases sex hormone-
binding globulin (SHBG) production. ACOG recommends use of combination low-dose
hormonal contraceptive agents for long-term management of menstrual dysfunction. [3] If
symptoms such as hirsutism are not sufficiently alleviated, an androgen-blocking agent may be
added. Pregnancy should be excluded before therapy with oral contraceptives or androgen-
blocking agents is started.

First-line treatment for ovulation induction when fertility is desired is clomiphene citrate. [2, 3, 5]
Second-line strategies may be equally effective in infertile women with clomiphene citrate
resistant PCOS.

A randomized study suggested that combined metformin/letrozole and bilateral ovarian drilling
are similarly effective as second-line treatment in infertile women with clomiphene citrate
resistant PCOS. [52] In this study, 146 patients were given metformin and letrozole, and 73
underwent bilateral ovarian drilling. There was significant reduction in testosterone, fasting
insulin, and ratio of fasting glucose to fasting insulin in the metformin/letrozole group. There
was significant reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and
ratio of LH to FSH in the bilateral drilling group. There was no significant difference between
the patients in the 2 groups regarding cycle regularity, ovulation, pregnancy rate, and abortion
rate. [52]

Another study, a double-blind trial by Legro et al, found that letrozole is more effective than
clomiphene in the treatment of infertility in PCOS. Based on treatment periods of up to five
cycles, the study, which involved 750 anovulatory women with PCOS, found that the birth rates
for letrozole and clomiphene were 27.5% and 19.1%, respectively. The rate of congenital
abnormalities and the risk of pregnancy loss in the letrozole and clomiphene groups were found
to be comparable, although the likelihood of twin births was lower with letrozole. [53, 54]


If the patient develops type 2 diabetes mellitus, consider treatment with oral antihyperglycemic
drugs, such as metformin. Metformin can also be considered in other women with PCOS who are
insulin resistant and therefore at risk of developing cardiovascular disease, even women without
type 2 diabetes.

Clinical trials have shown that metformin can effectively reduce androgen levels, improve
insulin sensitivity, and facilitate weight loss in patients with PCOS as early as adolescence. [55, 56,
57, 58]
One study concluded that the use of metformin throughout pregnancy was associated with a
9-fold decrease in gestational diabetes in women with PCOS. [59] In addition to having the
potential to reduce gestational diabetes in pregnant women with PCOS, metformin may also
reduce the risk of preeclampsia in this population. [60]

A long-term study suggested that metformin continued to improve the metabolic profile of
women with PCOS over a 36-month treatment course, particularly improving circulating high-
density lipoprotein cholesterol (HDL-C), diastolic blood pressure, and body mass index (BMI).
However, data are insufficient as yet to recommend metformin to all women with PCOS.

Other agents

If the patient has concomitant adrenal hyperandrogenism, treatment with low-dose prednisone or
dexamethasone may be considered.

Depot leuprolide acetate (Lupron) is effective in suppressing ovarian hormone production, which
effectively induces menopause; therefore, this drug must be accompanied by hormone
replacement therapy. This treatment approach has not gained widespread favor.

Several medications, including benzoyl peroxide, topical retinoids (Retin-A), and topical and
oral antibiotics, are effective for acne treatment. Systemic isotretinoin is used for severe or
refractory cases.

FDA Safety Alerts


On March 1, 2012, the US Food and Drug Administration (FDA) updated health care
professionals regarding changes to the prescribing information concerning interactions between
protease inhibitors (drugs for management of human immunodeficiency virus [HIV] and
hepatitis B infection) and certain statin drugs. The combination of these drugs may raise the
blood levels of statins and increase the risk for myopathy. Rhabdomyolysis, the most serious
form of myopathy, can cause kidney damage and lead to kidney failure, which is life threatening.

On February 28, 2012, the FDA approved important safety label changes for the class of
cholesterol-lowering drugs known as statins, including removal of routine monitoring of liver
enzymes. Information about the potential for generally nonserious and reversible cognitive side
effects and reports of increased blood glucose and glycosylated hemoglobin (HbA1c) levels was
added to the statin labels. In addition, extensive contraindication and dose-limitation updates
were added to the lovastatin label in situations when this drug is taken with certain medications
that can increase the risk for myopathy. [63]

On June 8, 2011, the FDA notified health care professionals of its recommendations for limiting
the use of the highest approved dose (80 mg) of the cholesterol-lowering medication simvastatin
(Zocor) because of increased risk of muscle damage. The FDA required changes to the
simvastatin label to add new contraindications (should not be used with certain medications) and
dose limitations for using simvastatin with certain medications. [64]


On October 8, 2010, Abbott Laboratories and the FDA notified health care professionals and
patients about the voluntary withdrawal of the obesity drug sibutramine (Meridia) from the US
market because of clinical trial data indicating an increased risk of heart attack and stroke. [65]

Metabolic Derangements
In patients with polycystic ovarian syndrome (PCOS) who are obese, endocrine-metabolic
parameters markedly improve after 4-12 weeks of dietary restriction. Their sex hormonebinding
globulin (SHBG) levels rise, and free testosterone levels fall by 2-fold. [66] Serum insulin and
insulin-like growth factor-1 (IGF-1) levels also decrease. In patients with PCOS who are obese,
weight loss is associated with a reduction of hirsutism and a return of ovulatory cycles in 30% of
women, thereby improving pregnancy rates, as well as improving glucose tolerance and lipid
levels. [12, 3]

The Androgen Excess and Polycystic Ovary Syndrome Society recommends lifestyle
management as the primary therapy for metabolic complications in overweight and obese women
with PCOS. [67] A moderate amount of daily exercise increases levels of IGF-1 binding protein
and decreases levels of IGF-1 by 20%. Modest weight loss of 2-5% of total body weight can help
restore ovulatory menstrual periods in obese patients with PCOS. A decrease of 500-1000
calories daily, along with 150 minutes of exercise per week, can cause ovulation.
Metformin, an antidiabetic drug, improves insulin resistance and decreases hyperinsulinemia in
patients with PCOS. [68] This drug also has a small but beneficial effect on metabolic syndrome,
as well as potentially causing a modest reduction in androgen levels (11%). [4] Note that women
with a body mass index (BMI) greater than 37 kg/m2 may not have a good response to
metformin. [4] An Italian study of 33 patients with PCOS demonstrated that metformin affected
thyroid hormone by lowering thyroid-stimulating hormone (TSH) in hypothyroid patients with
PCOS, regardless of whether these individuals received levothyroxine or were untreated. [69]

Ascertain that kidney and liver function are normal and that the patient does not have advanced
congestive heart failure before starting metformin therapy. The usual starting dose is 500 mg
given orally twice a day. Because common adverse effects are nausea, vomiting, and diarrhea,
metformin should be taken with meals. Patients who develop these adverse effects can be
instructed to decrease the dosage to once a day for a week and then gradually increase the
dosage. Also, inform patients that there is a high likelihood that they will have ovulatory cycles
while taking metformin. The US Food and Drug Administration (FDA) has not approved
metformin for this indication.

The American College of Obstetricians and Gynecologists (ACOG) and Society of Obstetricians
and Gynaecologists of Canada (SOGC) recommend clomiphene citrate as first-line therapy to
stimulate ovulation when fertility is desired. [2, 3, 5]

An alternative first line therapy to stimulate ovulation is letrozole. [54]

Second-line therapy, when clomiphene citrate fails to lead to pregnancy, is either exogenous
gonadotropins or laparoscopic ovarian surgery. [2, 3] If gonadotropins are used, a low-dose regimen
is recommended, [3] and patients must be monitored with ultrasonography and laboratory studies.
Note that gonadotropin therapy is expensive and is associated with an increased risk of
multiple pregnancy and ovarian hyperstimulation syndrome. [2]

Evidence suggests that metformin frequently, but not universally, improves ovulation rates and
pregnancy rates in women with polycystic ovarian syndrome (PCOS), especially in obese
women. [2, 3, 70] In addition, pretreatment with metformin has been shown to enhance the efficacy
of clomiphene for inducing ovulation. [71] Consider the combination of metformin and clomiphene
in older women with visceral obesity and clomiphene resistance. [2] However, this combination
doesnt significantly improve the live birth rate relative to clomiphene monotherapy. [2] Whether
short-course metformin pretreatment (less than 4 weeks) is as effective as conventional long-
course metformin remains uncertain. [5, 72]

A study found that N-acetylcysteine may enhance the effect of clomiphene citrate in inducing
ovulation in patients with PCOS. [73]

Patients with PCOS who are infertile but desire pregnancy should be referred to a reproductive
endocrinologist for further evaluation and management of infertility. Morbidly obese women
with PCOS should also be referred for pregnancy risk [2] ; metabolic surgery may be considered in
morbidly obese women with PCOS, because many features of this syndrome are reversible with
successful weight loss. In vitro fertilization (IVF) is reserved for women with PCOS and
unsuccessful gonadotropin therapy or those with other indications for this procedure. [2]

A study by Chen et al found that among infertile women with PCOS, frozen-embryo transfer was
associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome,
and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer. [74, 75]

A clear primary treatment for hirsutism in women with polycystic ovarian syndrome (PCOS)
remains lacking. [3] However, short-term, nonpharmacologic treatments of hirsutism include
shaving and the use of chemical depilatories and/or bleaching cream. [76] Plucking or waxing
unwanted hair can result in folliculitis and ingrown hairs. Long-term, more permanent measures
for unwanted hairs include electrolysis and laser treatment.

Adjunctive eflornithine with laser treatment is superior to laser therapy alone in treating
hirsutism. [3] Eflornithine (Vaniqa) is a topical cream that can be used to slow hair growth. This
agent works by inhibiting ornithine decarboxylase, which is essential for the rapidly dividing
cells of hair follicles.

Weight reduction decreases androgen production in women who are obese; therefore, losing
weight can slow hair growth.

Women who do not wish to become pregnant can be effectively treated for hirsutism with oral
contraceptives. [77] Oral contraceptives slow hair growth in 60-100% of women with
hyperandrogenemia. Therapy can be started with a preparation that has a low dose of estrogen
and a nonandrogenic progestin. Preparations that have norgestrel and levonorgestrel should be
avoided because of their androgenic activity. There is also a risk of thrombotic events in obese
women who use oral contraceptives; therefore, the proper precautions should be exercised to
prevent such events. Oral contraceptives containing cyproterone acetate are also very effective in
the treatment of more severe hirsutism [78] ; however, this combination of agents has not been
approved by the FDA for use in the United States.

Antiandrogens, such as spironolactone, are effective for hirsutism. [79] Spironolactone (50-100 mg
twice daily) is an effective primary therapy for hirsutism. Because of the potential teratogenic
effects of spironolactone, patients require an effective form of contraception (eg, an oral
contraceptive). Adverse effects of spironolactone include gastrointestinal discomfort and
irregular menstrual bleeding, which can be managed by adding an oral contraceptive.

Ovulation induction with clomiphene citrate, metformin, or both does not alter hirsutism in
infertile hirsute women with PCOS. [80]

Diet and Activity

Patients with polycystic ovarian syndrome (PCOS) who have impaired glucose tolerance should
start a comprehensive program of diet and exercise to reduce their risk of developing diabetes
mellitus. Encourage moderate physical activity, provided the patient has no contraindications.
Discourage smoking because of the increased risk of cardiovascular disease. In addition, obese
women with PCOS can benefit from a low-calorie diet for weight reduction.

A diet patterned after the type 2 diabetes diet has been recommended for PCOS patients. [81] This
diet emphasizes increased fiber; decreased refined carbohydrates, trans fats, and saturated fats;
and increased omega-3 and omega-9 fatty acids. However, in some obese patients with PCOS,
weight loss has improved menstrual regularity. [82] Omega-3 fatty acid supplementation has been
shown to reduce liver fat content and other cardiovascular risk factors in women with PCOS,
including those with hepatic steatosis, although these effects have not yet been proven to
translate into a reduction in cardiometabolic events. [83]

A study by Jamilian et al found that soy isoflavone administration for 12 weeks in women with
PCOS significantly improved markers of insulin resistance, hormonal status, triglycerides, and
biomarkers of oxidative stress. [84, 85]

Women with an abnormal lipid profile should be counseled on ways to manage the dyslipidemia.
Such measures include eating a diet low in cholesterol and saturated fats and increasing physical
activity. Guidelines from the Third Report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III, or ATP III) (2001) serve as a guide for the treatment of
women with PCOS and dyslipidemia. The NCEP is currently updating the ATP III guidelines;
Readers are encouraged to check the National Health Lung and Blood Institute Web site for the
most recent guidelines:

Accumulating evidence suggests an association of vitamin D deficiency with metabolic

syndrome. One study found insufficient levels of 25-hydroxyvitamin D (< 30 ng/mL) in almost
75% of PCOS patients, with lower levels in those with metabolic syndrome (17.3 ng/mL) than in
those without metabolic syndrome (25.8 ng/mL). [86]