Polycystic ovarian syndrome, PCOS, PCO

1. What every clinician should know

Polycystic ovarian syndrome is a medical condition associated with ovulatory dysfunction, hyperandrogenism, and polycystic ovaries. The diagnosis is made by considering a spectrum of signs and symptoms, rather than by a single test result. Although there is no universally accepted definition of PCOS, there are features to be considered in making the diagnosis, including anovulation/oligo-ovulation. Most women with PCOS have infrequent menses (e.g., eight or fewer menses per year) or amenorrhea. Women with PCOS may ovulate on occasion, but not typically on a regular monthly basis.

Another feature is hyperandrogenism. Although not all experts agree, women with PCOS commonly have biochemical or clinical features of hyperandrogenism. Polycystic ovaries may be ruled by ultrasound diagnosis. Most but not all women with PCOS will have PCO-appearing ovaries. However, “PCO-appearing” ovaries may also commonly be found in young women who have no other features of PCOS.

Other specific causes of ovulatory dysfunction must be excluded. Insulin resistance and obesity are commonly associated with PCOS, but are not required for diagnosis.

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Three expert groups have proposed diagnostic criteria for PCOS:

  • National Institutes of Health Criteria 1990: Requires hyperandrogenism and oligomenorrhea or amenorrhea

  • Rotterdam Consensus Criteria 2003: Requires 2 of 3 of the following: hyperandrogenism, olgiomenorrhea, polycystic-appearing ovaries by ultrasound

  • Androgen Excess Society 2006: Requires hyperandrogensism PLUS either oligomenorrhea/amenorrhea OR polycystic-appearing ovaries by ultrasound

Hyperandrogenism may be defined biochemically (by blood test) or clinically. The best way to measure circulating androgens is not certain as there is no standardized testosterone assay and the assay may not be reliable in the female ranges. Free testosterone should be measured either by equilibrium dialysis or by calculating the free testosterone index (using total testosterone and sex hormone binding globulin). You of course must confirm that the patient is not taking exogenous androgens. A rule of thumb is to consider a total testosterone over 50 to be elevated, but this will vary depending on the assay.

PCOS is commonly associated with acne, hirsutism, and less commonly with balding (androgenic alopecia). Clitormegaly is not a feature of PCOS and if present, should warrant investigation for an androgen-secreting tumor. It is important to ask a patient whether or not she is using treatment of acne or hair removal, and such treatments may mask clinical signs of androgen excess. Clinical signs of androgen excess may be less common in some ethnic groups with less body hair.

Polycystic-appearing ovaries are defined as:

  • 12 more follicles measuring 2-9 mm in diameter OR ovarian volume greater than 10cm3.

  • If there is a follicle greater than 10 mm in diameter, the scan should be repeated

  • One ovary with PCO appearance is sufficient for diagnosis using the Rotterdam criteria

Other specific diagnoses must be excluded, including hyperprolactinemia. Although mild elevations of prolactin may occur with PCOS, high levels of prolactin suggest the presence of a pituitary adenoma as a potential cause of menstrual irregularity. Thyroid dysfunction (as assessed by screening TSH level) should also be eliminated. Mild abnormalities are unlikely to explain menstrual dysfunction, but more significant abnormalities should be treated to see if menstrual function is restored before making the diagnosis of PCOS

Congenital adrenal hyperplasia should also be ruled out. Women with non-classical (late-onset) congenital adrenal hyperplasia may have a clinical picture including an ovulation and hirsutism that closely mimics PCOS. This condition is nearly always due to genetic defects in the enzyme 21-hydroxylase. In Europe and the United States, congenital adrenal hyperplasia occurs most commonly in Ashkenazi Jews, Hispanics, Yugoslavs, Native American Inuits in Alaska, and Italians. Women at risk for congenital adrenal hyperplasia should be screened by obtaining a fasting morning level of 17-hydroxyprogesterone in the follicular phase. A value of less than 2 ng/ml is typically considered normal. If the level is elevated, an adrenocorticotropic hormone (ACTH) stimulation test should be performed.

Primary ovarian insufficiency (also known as premature ovarian failure) should also be excluded. Women with POI will typically have elevated gonadotropin levels and be clinically hypoestrogenic. Although Anti-Mullerian Hormone levels are not yet routinely included in the diagnosis of POI, AMH levels will typically be low in women with POI, and high in women with PCOS. Women with PCOS are typically clinically euestrogenic.

Hypothalamic amernorrhea should also be ruled out. Women with hypothalamic amenorrhea will typically by hypoestrogenic, low or normal gonadotropins, and often have a low body mass index. These women may have a deficit of energy consumption relative to energy expenditure due to excessive exercise or an eating disorder. Clitormegaly or a history of rapidly progressive symptoms associated with androgen excess should warrant consideration for an androgen-secreting tumor of the adrenal gland or ovary. Such tumors are extremely rare. Levels of androgens are typically high, but no specific cut-off has been determined.

Cushing syndrome is extremely rare, but should be ruled out. Although routine screening (e.g. using 24-hour urinary free-cortisol) is not indicated for all women with hyperandrogenic chronic anovulation, the diagnosis is so serious that it must be considered in the differential diagnosis of PCOS. Signs of Cushing syndrome include moon faces, buffalo hump, abdominal striae, centripetal fat distribution, hypertension, proximal myompathy, and easy bruising. Testing to rule out Cushing syndrome is indicated if there is clinical suspicion. Acrogmegaly and genetic defects in insulin action should also be considered in the differential diagnosis.

The clinical manifestations of PCOS may vary for an individual over time. For example, if a woman with PCOS loses weight, she may notice spontaneous resumption of menses and decreased hirsutism as well as improvements in glucose and lipid levels. Aging has been associated with increased menstrual regularity and potentially increased fecundity. Further androgen levels normalize and ovarian volume shrinks in women with PCOS, though perhaps at a slower rate than women without PCOS. Metabolic abnormalities may plateau with age or worsen. There are few data to suggest they lessen.

2. Diagnosis and differential diagnosis

Long-term health risks of PCOS

Women with PCOS are at increased risk of insulin resistance, nonalcoholic fatty liver disease, and obesity-related disorders such as sleep apnea. These conditions are risk factors for long-term sequalae including type 2 diabetes and cardiovascular disease. The increased risk for cardiovascular disease in women with PCOS is strongly suspected but less well-documented than the risk of diabetes. Women with PCOS are at risk of endometrial cancer due to chronic anovulation, obesity, and diabetes. More recently it has been suggested that mood disturbances, including anxiety and depression may be associated with PCOS.

The phenotype used to diagnose PCOS has been associated with varying degrees of metabolic dysfunction. Certainly the phenotype that contains all three diagnostic criteria tends to be the most insulin resistant with highest prevalence of the metabolic syndrome. Subphenotypes that contain polycystic ovaries but lack either hyperandrogenism or oligomenorrea tend to be more metabolically normal. Finally, the presence of polycystic ovaries alone is rarely associated with insulin resistance. There is ongoing debate about the relative association of either oligomenorrhea or hyperandrogensim to metabolic dysfunction.

Evaluation for metabolic syndrome
Physical examination
  • Blood pressure

  • Body mass index (weight in kg divided by height in m2)

    Overweight 25-30

    Obese >30

  • Waist circumference as an aid in determining body fat distribution

    Abnormal >35 inches

In addition, Acanthosis nigricans is characterized by thickened, velvety, verrucous, hyperpigmented skin on the back of the neck, axillae, underneath the breasts, or on the vulva. Although commonly associated with insulin resistance, it can be more rarely a sign of insulinoma or adenocarcinoma of the stomach.

Laboratory evaluation
  • 2-hour 75 gram oral glucose load test. Fasting blood sugar alone may miss impaired glucose tolerance in women with PCOS

    Fasting glucose: normal <110 mg/dL, impaired fasting glucose (IFG) 100-125 mg/dL, type 2 diabetes > 125 mg/dL

    2 hour glucose: normal <140 mg/dL, impaired glucose tolerance (IGT) 140-199, type 2 diabetes 200 or greater mg/dL

    Insulin levels may be considered, but their utility is not clear.

  • Fasting lipid and lipoprotein profile (total cholesterol, high density lipoprotein, triglycerides, low density lipoprotein)

3. Management

Treating infertility in women with PCOS

Infertility associated with PCOS is principally due to chronic oligoovulation or anovulation. Thus the mainstay of treatment is ovulation induction. Before ovulation induction is initiated, preconception counseling should include the recommendation for weight reduction and exercise in overweight and obese women. Routine pre-conception counseling should also include recommendations for use of prenatal vitamins, smoking cessation, and reduction of alcohol consumption.

Clomiphene citrate remains first-line treatment for ovulation induction in women with PCOS. The usual starting dose of clomiphene is 50 mg for 5 days, with a dose increase to 100 mg daily for 5 days if ovulation fails to occur at 50 mg. Daily doses higher than 150-200 mg are not recommended. Alternative clomiphene regimens include the addition of metformin (typically 1500-2000 mg daily throughout the cycle), prolonging the period of clomiphene administration to 8 days, dexamethoasone, and pre-treatment with oral contraceptives. The biggest risk of clomiphene citrate is the 5-10% risk of twins. There is also a risk of triplets which is 1% or lower. Side effects can include hot flashes, mood changes, decreased cervical mucus, decreased thickness of the endometrial lining, and blurry vision.

It is important to determine whether or not ovulation has occurred at a given dose of clomiphene. Evidence of ovulation can include rise in basal body temperature, elevation of serum progesterone in the luteal phase of the cycle, development of a dominant follicle by ultrasound. A serum progesterone level of over 3 is evidence of ovulation. Although typically drawn on approximately day 21 of a menstrual cycle, it should be noted that a late ovulation may be missed with this strategy.

Metformin alone is not recommended as first-line treatment for ovulation induction. It is not FDA-approved for ovulation induction. It is unclear if the addition of metformin to clomiphene increases the pregnancy rate above clomiphene alone. Metformin is classified as Pregnancy Category B and it is not known to be a human teratogen. It is not known whether or not metformin use in early pregnancy prevents pregnancy loss.

If clomiphene citrate fails to lead to pregnancy, treatment with exogenous gonadotropins can be considered. Gonadotropins should be administered in low dose (starting dose of 75 international units or lower) with careful monitoring of follicle development by a clinician experienced in the use of these medications. The risks of ovarian hyper stimulation syndrome and multiple gestation are higher with exogenous gonadotropins compared with clomiphene, and may be as high as a 20-25% risk of twins and a 5% risk of triplets.

Aromatase inhibitors such as letrozole have been proposed as an option for inducing ovulation in women with PCOS. A recent large, randomized study demonstrated that ovulation, conception, pregnancy and live birth rates were higher after treatment with letrozole compared to treatment with clomiphene for women with PCOS. Further studies with larger numbers of infants are needed to verify the safety of teratogenic risks of letrozole as compared with other treatments for PCOS. Aromatase inhibitors are not FDA-approved for ovulation induction.

Laparoscopic ovarian drilling using laser or diathermy has also been considered as a second-line treatment to allow spontaneous restoration of ovulatory cycles in women with PCOS. In some cases, the fertility benefit of ovarian drilling may be temporary and ovulation induction with medications is still needed. The long-term effects of ovarian drilling on ovarian reserve (egg supply) are not clear. Ovarian drilling does not appear to improve the metabolic abnormalities in women with PCOS. Surgical risks (e.g., anesthesia, adhesion formation) should also be considered before proceeding with this option.

Consideration should be given to the possibility of endometrial abnormalities (e.g. endometrial polyps over 1 cm in size), particularly if women fail to conceive with successful ovulation induction. A semen analysis is obtained, preferably before beginning ovulation induction, but definitely if no pregnancy occurs after several cycles of treatment. If no conception occurs after 3-6 ovulatory cycles, it is reasonable to consider a test for tubal patency before further cycles of ovulation induction.

Treating adolescent girls with PCOS
Diagnostic considerations

Normal puberty can overlap with the diagnostic criteria for PCOS. Mutlifollicular ovaries are more common, there is a relative androgen excess with both elevations in adrenal and ovarian androgens and acne is common, and oligomenorrhea can be a normal stage in reproductive development for one to three years post menarche.

Therefore observation may be necessary to make the diagnosis, or as many experts feel, some measure either of biochemical hyperandrogenemia comparable to that found in adult women, or signs of midline hirsutism. This would further support the central role of hyperandrogenism in the ontogeny of the disorder. Girls with premature adrenarche have been found to be at increased risk for developing stigmata of PCOS including both reproductive and metabolic abnormalities as they pass through puberty, but this remains relatively rare and thus is unlikely to precede PCOS in most women.

Treatment considerations

There have been unfortunately fewer trials in adolescents with PCOS than adults. The two most common treatments for adolescents with PCOS are either hormonal contraception (either oral or parenteral, i.e., vaginal ring or skin patch) or metformin. The choice will depend on the presenting complaint of the adolescent and must also balance desire and need for contraception.

The most common presenting complaints in adolescents include hirsutism/acne, menstrual infrequency, and obesity. For hirsutism/acne or for marked biochemical hyperandrogenemia, hormonal contraception will provide the best treatment benefit, and many formulations have an additional FDA indication for the treatment of acne. Obviously adolescents must be carefully screened for relative or absolute contraindication to oral contraceptive use including obesity, smoking, hypertension, and history of blood clots.

For obesity, metformin is likely to provide the best benefit, though it is not approved as a weight loss drug. However there is evidence that metformin either alone or in combination with lifestyle can augment weight loss and in some studies improve menstrual frequency. There is less evidence that metformin alone improves hirsutism or acne, though it is associated with lower androgen levels.

Both hormonal contraception and metformin can regulate menses. The best means of hormonal contraception, i.e., extended cycle vs. 21/7 day cycle has not been established, though there are theoretical reasons to favor continuous instead of episodic ovarian suppression with the oral contraceptive pill. The rationale for treating oligo/amenorrhea with an extended cycle hormonal contraceptive is often not intuitive to patient or parents, and requires careful and often repeated explanation. It is best is to focus on the concept of uncontrolled endometrial proliferation vs. constant endometrial suppression. Metformin does improve menstrual regularity, and improves ovulatory frequency; therefore the possibility of conception must be addressed in sexually active adolescents.

Clearly, underlying metabolic abnormalities, such as metabolic syndrome, impaired glucose tolerance, or type 2 diabetes may tip the scales in favor of metformin as first line treatment agent.

When to initiate treatment

This can sometimes be a conundrum especially in girls in the young teens. It is probably safe to initiate hormonal contraceptives when pubertal maturation is nearly complete, i.e., Tanner Stage IV development or beyond. There is a theoretical concern about inducing premature closure of the epiphyses with high dose estrogen in girls without advanced pubertal maturation and decreasing adult height potential.

What to avoid

Some studies recommend anti-androgens such as flutamide or finasteride. The risk benefit ratio of these is less favorable in adolescents and there must always be heightened vigilance about unexpected pregnancy.

Treating obesity in women with PCOS

This is one of the most difficult questions and one with the least reassuring answer. One of the most frequently quoted lines (to patients and to clinicians) is;”As little as 5% weight losses in women with PCOS can restore ovulation and lead to pregnancy”. This is likely only true for a small minority of women with PCOS.

One of the most common clinical presentations in adolescents and adults with PCOS is the co-existence of obesity. This often leads to the supposition that obesity is the prime cause of PCOS and further that weight loss would “cure” PCOS. Although there is no doubt that obesity is associated with more metabolic disturbance, and that weight loss improves these, there is controversy about whether weight loss cures PCOS.

Clearly many women, especially in other parts of the world, are normal weight with PCOS, and there are no studies that support weight loss or lifestyle to treat PCOS in this population. However there are case series of women with PCOS who have undergone bariatric surgery, having complete resolution of their symptoms and restoration of normal menses. These findings are still preliminary and need to be confirmed in larger studies, and the relative risk benefit ratio of bariatric surgery in morbidly obese women seeking pregnancy is still being studied.

Another common perception is that because women with PCOS are insulin resistant, they are less likely to lose weight with similar amounts of caloric restriction than women who are obese with PCOS and insulin resistance. This is more of an urban legend than medical fact. In fact studies in women with PCOS with careful oversight of caloric restriction have shown appropriate and expected weight loss similar to that in other populations instituting the same amount of caloric restriction. There is no clear PCOS diet above and beyond a hypocaloric diet (and generally a deficit beyond 500kCal/day may be excessive).

In other populations, high protein diets result in more rapid initial weight loss, but over time the degree of weight loss between hypocaloric diets of varying composition even out with no clear winner. Lifestyle therapy in women with PCOS is recommended by many expert panels as first line therapy if obesity is present. Potential benefits include an improved chance of response to drug, for instance obesity is negatively correlated with both ovulation and pregnancy rates in women with PCOS receiving clomiphene, gonadotropins, etc.

Additionally, they may be at lower risk through weight loss for pregnancy complications and long term cardiovascular and cancer morbidity. Randomized trials examining these lifestyle interventions have found modest improvements in weight, and many reproductive and metabolic factors associated with PCOS, and there have been reports of spontaneous pregnancies. However it should also be noted that these trials have very high screen out rates (i.e., subjects unwilling to even try the intervention) and also very high dropout rates (subjects unable to comply or are disappointed with the return).

Metformin is often utilized for it potential to augment weight loss in women with PCOS. Studies have suggested that metformin in combination with lifestyle does not add much to weight loss above and beyond lifestyle alone. However there is also evidence that metformin alone is probably better than nothing at all and generally there is a modest weight loss in the range of five to seven pounds after six months of metformin therapy. Thus metformin should be considered as a treatment agent in the presence of obesity and metabolic dysfunction.

Further study and more effective interventions are needed for obesity in all populations including women with PCOS.

Long term treatments

The long term treatments of PCOS revolve around amelioration of obesity (see question above), prevention of endometrial hyperplasia and cancer, prevention of diabetes, and amelioration of cardiovascular risk factors. Thus the most common long term treatments are hormonal contraception, metformin, and lifestyle therapy. Weight loss can lead to improvements in glucose and lipid levels as noted above. Lifestyle modification including an increase in exercise and caloric restriction are recommended. Low glycemic load diets have been recommended by some experts, but reducing calorie consumption to avoid or treat obesity appears to be the most critical lifestyle modification rather than adherence to a particular diet.

Exercise per se may have benefits on cardiovascular prevention and diabetes prevention, but it is unlikely to result in significant weight loss or significant change in reproductive aspects of PCOS such as menstrual irregularity or hirsutism. Long-term use of metformin has not been specifically studied in women with PCOS. However, diabetes prevention trials have suggested that both lifestyle interventions and antidiabetic drugs such as metformin reduce the risk of developing diabetes in women with impaired glucose tolerance. The effects of long term use of metformin on endometrial hyperplasia or cancer risk are unknown.

Oral contraceptives or cyclic use of progestin can be prescribed to prevent endometrial hyperplasia, and there is good epidemiologic evidence that oral contraceptive use is associated with a dose duration reduction in endometrial cancer and ovarian cancer. This benefit persists after discontinuation of the oral contraceptive pill. Additional cardiovascular risk factors such as dyslipidemia or hypertension should be recognized and appropriate referral for treatment or treatment should be initiated.

There are studies suggesting that menstrual regularity improves, and hyperandrogenism ameliorates in women with PCOS as they age into their forties. Thus it may be reasonable at some point to discontinue hormonal contraception if it is being used for non-contraceptive benefits. Additionally since age is associated with development of obesity and hypertension, as well as an increased rate of serious adverse events on hormonal contraception, their use must be carefully monitored in women with PCOS and risk factors.

4. What is the evidence for specific management and treatment recommendations

“American College of Obstetricians and Gynecologists. Polycystic Ovary Syndrome”. Obstetrics and Gynecology. vol. 114. 2009. pp. 936-50. (This practice bulletin summarizes ACOG recommendations for clinicians treating women with PCOS. The reference list covers a broad range of practical and important topics related to PCOS.)

Azziz, R, Carmina, E, Dewailly, D, Diamanti-Kandarakis, E, Escobar-Morreale, HF. “Position statement: criteria for defining polycystic ovary syndrome: an androgen excess society guideline”. J Clin Endocrinol Metab. vol. 91. 2006. pp. 4237-45. (This paper presents the views of the Androgen Excess Society with respect to diagnosis of PCOS.)

Legro, RS, Brzyski, RG, Diamond, MP, Coutifaris, C, Schlaff, WD. “Letrozole versus clomiphene citrate for infertility in polycystic ovarian syndrome”. NEJM.

“Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.Revised 2003 consensus on diagnostic criteria and long-term health risk related to polcystic ovary syndrome”. Fertil Steril. vol. 81. 2004. pp. 19-25. (This manuscript details the Rotterdam criteria for diagnosis of PCOS.)

“Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus of infertility treatment related to polycystic ovary syndrome”. Fertil Steril. vol. 89. 2008. pp. 505-22. (The authors review current treatments for women with PCOS who wish to achieve pregnancy.)

Fauser, BC, Tarlatzis, BC, Rebar, RW, Legro, RS, Balen, AH. “Consensus on women's health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM-sponsored third PCOS Consensus Workshop”. Fertil Steril. vol. 97. 2012. pp. 28-38.e25.