Polycystic ovary syndrome (PCOS) is not a simple pathophysiologic process for which one treatment addresses all manifestations. It is a condition that occurs in approximately 5 to 10 percent of women of childbearing age.1 It can affect women in many different ways; therefore, physicians must individualize treatment goals and target treatment to specific manifestations. Comorbidities (e.g., cardiovascular risk factors, endocrinologic disease) and the patient's desire for pregnancy must be considered when choosing a treatment regimen.
|Clinical recommendation||Evidence rating||References||Comments|
|First-line agents for the treatment of hirsutism in patients with PCOS include spironolactone (Aldactone) and metformin (Glucophage), as well as eflornithine (Vaniqa) for facial hirsutism.||A||9, 13, 16, 20, 22, 23, 28–33||Eflornithine is the only one of these agents that is approved by the U.S. Food and Drug Administration for facial hirsutism; however, it has not been studied Specifically in women with PCOS.|
|First-line agents for ovulation induction and treatment of infertility in patients with PCOS include metformin and clomiphene (Clomid), alone or in combination, as well as rosiglitazone (Avandia).||A||6–8, 11, 15, 19, 20, 32, 35, 36||—|
|Metformin improves insulin resistance (diagnosed by elevated fasting glucose or fasting glucose/insulin ratios) in patients with PCOS; other useful agents include rosiglitazone and pioglitazone (Actos).||C||10–21, 33, 37, 46, 47||There are ample studies supporting the effectiveness of metformin for improving insulin resistance; however, physicians should be aware that there are few patient-oriented outcomes regarding the importance of improving insulin resistance.|
|Metformin is probably the first-line agent for obesity or weight reduction in patients with PCOS.||B||10, 46, 49||—|
|Metformin can improve menstrual irregularities (e.g., oligomenorrhea) in patients with PCOS.||A||10, 11, 47, 51||—|
Diagnosis of PCOS may be difficult because the signs and symptoms can be subtle and varied. The most common manifestations include hirsutism, infertility, insulin resistance, and menstrual irregularities.2 Physicians can diagnose PCOS when other causes of the symptoms or laboratory abnormalities are excluded; when oligo-ovulation or anovulation, usually manifested as oligomenorrhea or amenorrhea, is present; and when there is clinically confirmed hyperandrogenism (e.g., hirsutism, acne). Although the ovaries may be polycystic, this is usually not necessary for diagnosis. There is debate over which criteria should be used (e.g., 1990 National Institutes of Health criteria,3 2003 Rotterdam consensus workshop criteria4). Guidelines suggest screening women with PCOS for other disorders, such as hyperlipidemia, and treating accordingly.5
Limitations of Data on Drug Treatment for PCOS
There have been many studies on PCOS in the past several years; however, most are fairly small. Also, many studies examine medication effects on surrogate markers (e.g., androgen levels) rather than clinical outcomes (e.g., hirsutism). The study results are often conflicting, and in a recent systematic review, only 33 of 115 possible studies met basic inclusion criteria (e.g., randomized controlled trials), suggesting that many of the data in the literature may have methodologic flaws.1
One of the biggest challenges in reviewing the evidence for PCOS treatment is that many manifestations of the condition may be components of other disease processes. For example, there may be a study of medications that are useful for hirsutism, but the patient population in the study did not explicitly have PCOS. Thus, recommendations specific for treating symptoms of PCOS may be lacking. When reviewing a study of the treatment of insulin resistance in a general population, it cannot be assumed that the outcomes would mirror those in women with PCOS.
Insulin-sensitizing agents are indicated for most women with PCOS because they have positive effects on insulin resistance, menstrual irregularities, anovulation, hirsutism, and obesity. Of all the drugs used to treat manifestations of PCOS, metformin (Glucophage) has the most data supporting its effectiveness. Table 1 details the most common medications used to treat manifestations of PCOS.6–27
|Medication||Description||Manifestations treated||FDA pregnancy category||Main adverse effects||Typical dosage||Approximate monthly cost*|
|Clomiphene (Clomid)†||Ovulation induction agent||Infertility||X||Multiple pregnancy/ovarian hyperstimulation, thromboembolism, visual disturbances||50 to 100 mg per day6–8||$52 (generic) and $128 (brand) for 100 mg per day for 5 days|
|Eflornithine (Vaniqa)‡||Inhibits hair growth||Hirsutism||C||Mild skin irritation||13.9% cream applied to face twice per day9||$46 (brand) for one 30-g tube|
|Metformin (Glucophage)§||Insulin-sensitizing agent||Hirsutism; infertility; insulin resistance; menstrual irregularities||B||GI upset, lactic acidosis, increase in homocysteine levels||1,500 to 2,250 mg per day10–16||$73 (generic) and $107 (brand) for 850 mg twice per day|
|Oral contraceptives§||||—||Hirsutism; menstrual irregularities||X||Nausea, headache, spotting, thrombophlebitis, deep venous thrombosis||Varies||Varies|
|Pioglitazone (Actos)§||Insulin-sensitizing agent||Hirsutism; infertility; insulin resistance||C||CHF, may cause weight gain||30 mg per day14,17,18||$199 (brand)|
|Rosiglitazone (Avandia)§||Insulin-sensitizing agent||Hirsutism; infertility; insulin resistance; menstrual irregularities||C||CHF, hepatotoxicity, edema, increase in homocysteine levels||2 to 8 mg per day (beneficial effects are dose related)19–21||$113 (brand) for 4 mg per day|
|Spironolactone (Aldactone)§||Antiandrogenic antimineralocorticoid||Hirsutism; menstrual irregularities||C||Hyperkalemia, nausea, breast tenderness||50 mg per day to 100 to 200 mg per day22,23||$61 (generic) and $97 (brand) for 50 mg twice per day|
|Acarbose (Precose)§||Insulin-sensitizing agent||Hirsutism; menstrual irregularities||B||GI upset||150 mg per day24 (for menses regulation)||$94 (brand)|
|Desogestrel/ethinyl estradiol (Apri)§¶||Oral contraceptive||Hirsutism||X||Increased total cholesterol and low-density lipoprotein cholesterol; thromboembolism, stroke, MI||0.15 mg desogestrel plus 30 mcg ethinyl estradiol per day||$31 (brand)|
|Finasteride (Propecia)§||5-alpha-reductase inhibitor||Hirsutism||X||Hypersensitivity reaction, decreased libido||5 mg per day25||$148 (generic) and $100 to $343 (brand)|
|Flutamide (formerly Eulexin)§||Nonsteroidal antiandrogen used mostly in prostate cancer||Hirsutism||D||Thrombocytopenia, leukopenia, liver toxicity, hot flashes||250 mg once or twice per day25||$140 (generic) for 250 mg per day|
|Letrozole (Femara)§||Nonsteroidal competitive inhibitor of aromatase; inhibits conversion of adrenal androgens||Infertility||C||Osteoporosis, thromboembolism, MI, hot flashes, arthralgias||2.5 mg per day6||$340 (brand)|
|Sibutramine (Meridia)§||Centrally acting appetite suppressant||Hirsutism||C||Tachycardia, hypertension, headache, dry mouth||10 mg per day26||$116 (brand)|
Medications for Manifestations of PCOS
Treatments for hirsutism in women with PCOS are similar to those in women without PCOS, such as patients with idiopathic hirsutism. There are many nonpharmacologic treatment options, including electrolysis, waxing, bleaching, plucking, depilatory creams (a form of hair removal that dissolves the hair), thermolysis (use of heat), and laser therapy. Several medications have been studied for the treatment of hirsutism in women with PCOS. First-line agents include spironolactone (Aldactone)22,23,28–30 and metformin,13,16,20,22,31–33 as well as eflornithine (Vaniqa) for facial hirsutism.9
Combination oral contraceptives, especially those with progestins of norgestimate, desogestrel, or drospirenone (because of their low androgenic effects), are among the most commonly used medications for hirsutism in women with PCOS.2 However, they are not approved by the U.S. Food and Drug Administration (FDA) for this use. One study found that women taking desogestrel/ethinyl estradiol (Apri) had lower hirsutism scores on a standardized scale (i.e., the Ferriman-Gallwey hirsutism score).34 Finasteride (Propecia) and flutamide (formerly Eulexin) are effective, but are FDA pregnancy categories X and D, respectively; the use of these agents for hirsutism is strictly off-label.2
Because of its antiandrogenic effects, spironolactone is effective, but not FDA-approved, for this indication.22,23 A Cochrane review suggested that spironolactone is superior to finasteride.28 Combining spironolactone with oral contraceptives may be synergistic, but caution should be used in women taking drospirenone because each agent can cause hyperkalemia.2 Spironolactone is FDA pregnancy category C.
Insulin-sensitizing agents, including metformin,31 acarbose (Precose),24 and rosiglitazone (Avandia),20 may be used to treat hirsutism in women with PCOS. Spironolactone22 and rosiglitazone32 have been shown to be more effective than metformin, based on Ferriman-Gallwey hirsutism scores. A Cochrane review suggested that metformin is as effective as oral contraceptives for treating hirsutism in women with PCOS,33 but in contrast, a recent systematic review suggested that metformin is not effective.1 Topical eflornithine cream is FDA-approved for management of unwanted facial hair, but there are no published data regarding its use specifically in women with PCOS. Sibutramine (Meridia), which is approved for obesity management, can also improve hirsutism.26
Hormonal aberrations in women with PCOS (e.g., elevated androgen levels) can cause menstrual irregularities (e.g., oligomenorrhea, amenorrhea, anovulatory cycles) that can lead to dysfunctional uterine bleeding and infertility.2 First-line agents for ovulation induction and treatment of infertility in patients with PCOS include metformin8,11,15,32,35,36 and clomiphene (Clomid),6,7 alone or in combination, as well as rosiglitazone.19,20,32
Clomiphene is an ovulation induction agent that has been used and studied in patients with and without PCOS.6–8,15,35,36 Studies have found that letrozole (Femara) regulates ovulation and improves pregnancy rates in women with PCOS6,37,38; however, this use is controversial because the drug is FDA pregnancy category D. It is embryotoxic and fetotoxic in animal studies, and there are no studies in pregnant women.
Insulin-sensitizing agents, including metformin,11,32 rosiglitazone,19,20,32 and pioglitazone (Actos),17 have been effective in improving fertility and ovulation in women with PCOS. There are contradictions in the literature regarding whether metformin, clomiphene, or a combination of the two agents is superior for improving pregnancy rates in women with PCOS. A 2003 Cochrane review suggested that metformin should be a first-line treatment for infertility in women with PCOS.39 A more recent study confirmed that six months of metformin therapy was more effective than six months of clomiphene therapy for improving fertility in anovulatory, nonobese women with PCOS.8 However, a large randomized trial of more than 600 women found that clomiphene is superior to metformin in achieving live birth in infertile women with PCOS, with no statistical benefit to the addition of metformin to clomiphene.40 Another study also showed no benefit from adding metformin to clomiphene.35 However, two meta-analyses suggested that the combination is better than clomiphene alone.41,42 A more recent study found that, although ovulation rates were better with metformin than with clomiphene, pregnancy rates were similar.43 Finally, two systematic reviews found conflicting results; one suggests metformin does not affect ovulation or pregnancy rates,1 and the other suggests it does.44
The prevalence of insulin resistance in women with PCOS, as measured by impaired glucose tolerance, is substantially higher than expected compared with age-and weight-matched populations of women without PCOS.45 Although insulin resistance alone is a laboratory (not clinical) aberration, it can lead to diabetes, and it may be associated with the metabolic syndrome, thus leading to increased cardiovascular risk.2 As with diabetes, optimal treatment of PCOS requires lifestyle modifications (e.g., diet, exercise) in addition to appropriate medications.
Metformin improves insulin resistance, as diagnosed by elevated fasting glucose or fasting glucose/insulin ratios, in patients with PCOS,10–16,46,47 and is probably the best agent to use. Women with PCOS who are not obese may benefit more from metformin than women who are obese.13,48 Metformin is FDA pregnancy category B.
Other insulin-sensitizing agents are also effective for improving insulin resistance in women with PCOS, including rosiglitazone19–21 and pioglitazone.14,17,18 However, these agents may cause or worsen congestive heart failure, according to recent black box warnings,27 or cause unwanted weight gain.
If a woman's weight is excessive, the physician should be aggressive in championing a weight-loss program. Medications effective for weight loss (in addition to lifestyle modifications) that have been specifically studied in women with PCOS include metformin, acarbose, sibutramine, and orlistat (Xenical). Metformin is probably the first-line medication for obesity or weight reduction in patients with PCOS. Metformin results in a decrease in body mass index (BMI) of 1 to 2 kg per m2 or weight loss up to 6 lb, 10 oz to 8 lb, 13 oz (3 to 4 kg)10,46,49; acarbose results in an approximate 3 kg per m2 decrease in BMI24; sibutramine results in a decrease in BMI of 5.8 kg per m2 and weight loss of 31 lb, 11 oz (14.4 kg)26; and orlistat results in weight loss of approximately 11 lb (5 kg).50 However, a recent systematic review suggested that metformin is not effective for lowering BMI in patients with PCOS.1
Anecdotally, oral contraceptives are among the most common agents used to treat menstrual irregularities in women with PCOS. However, there are few studies examining their effect on menstrual cycles in women with PCOS. Cyproterone acetate plus ethinyl estradiol has been extensively studied, but it is not available in the United States. Studies suggest that the following agents may improve menstrual irregularities (e.g., oligomenorrhea): spironolactone (in an open-label study),22 acarbose,24 rosigli-tazone,32 and metformin.10,11,32,47,51 Metformin is probably the best choice because it may improve insulin resistance in addition to improving menstrual irregularities.