Diagnosis
Diagnosis in Adults
- 1.1. The Endocrine Society (ES) suggests that the diagnosis of polycystic ovary syndrome (PCOS) be made if two of the three following criteria are met: androgen excess, ovulatory dysfunction, or polycystic ovaries (PCO) (Table 1), whereas disorders that mimic the clinical features of PCOS are excluded. These include, in all women: thyroid disease, hyperprolactinemia, and nonclassic congenital adrenal hyperplasia (primarily 21-hydroxylase deficiency by serum 17-hydroxyprogesterone [17-OHP]) (Table 2). In select women with amenorrhea and more severe phenotypes ES suggests more extensive evaluation excluding other causes. (Table 3) (2|⊕⊕⊕◯)
Diagnosis in Adolescents
- 1.2. ES suggests that the diagnosis of PCOS in an adolescent girl be made based on the presence of clinical and/or biochemical evidence of hyperandrogenism (after exclusion of other pathologies) in the presence of persistent oligomenorrhea. Anovulatory symptoms and PCO morphology are not sufficient to make a diagnosis in adolescents, since they may be evident in normal stages in reproductive maturation. (2|⊕⊕◯◯)
Diagnosis in Perimenopause and Menopause
- 1.3. Although there are currently no diagnostic criteria for PCOS in perimenopausal and menopausal women, ES suggests that a presumptive diagnosis of PCOS can be based upon a well-documented long-term history of oligomenorrhea and hyperandrogenism during the reproductive years. The presence of PCO morphology on ultrasound would provide additional supportive evidence, although this is less likely in a menopausal woman. (2|⊕⊕◯◯)
Associated Morbidity and Evaluation
Cutaneous Manifestations
- 2.1. ES recommends that a physical examination should document cutaneous manifestations of PCOS: terminal hair growth, acne, alopecia, acanthosis nigricans, and skin tags. (1|⊕⊕⊕◯)
Infertility
- 2.2. Women with PCOS are at increased risk of anovulation and infertility. In the absence of anovulation, the risk of infertility is uncertain. ES recommends screening ovulatory status using menstrual history in all women with PCOS seeking fertility. Some women with PCOS and a eumenorrheic menstrual history may still experience anovulation, and a midluteal serum progesterone may be helpful as an additional screening test. (1|⊕⊕◯◯)
- 2.3. ES recommends excluding causes of infertility other than anovulation in couples where a woman has PCOS. (1|⊕⊕◯◯)
Pregnancy Complications
- 2.4. Because women with PCOS are at increased risk of pregnancy complications (gestational diabetes, preterm delivery, and pre-eclampsia) exacerbated by obesity, ES recommends preconception assessment of body mass index (BMI), blood pressure, and oral glucose tolerance. (1|⊕⊕⊕◯)
Fetal Origins
- 2.5. The evidence for intrauterine effects on development of PCOS is inconclusive. ES suggests no specific interventions for prevention of PCOS in offspring of women with PCOS. (2|⊕◯◯◯)
Endometrial Cancer
- 2.6. Women with PCOS share many of the risk factors associated with the development of endometrial cancer including obesity, hyperinsulinism, diabetes, and abnormal uterine bleeding. However, ES suggests against routine ultrasound screening for endometrial thickness in women with PCOS. (2|⊕⊕⊕◯)
Table 1. Summary of Proposed Diagnostic Criteria for PCOS in Adults
| Category | Specific Abnormality | Comment | NIHa | Rotterdamb (2 of 3 met)a | Androgen Excess PCOS Society Hyperandrogenism With 1 of 2 Remaining Criteriaa |
|---|---|---|---|---|---|
| Androgen status | Clinical hyperandrogenismc | Clinical hyperandrogenism may include hirsutism (defined as excessive terminal hair that appears in a male pattern), acne, or androgenic alopecia. | XX or | X or | XX or |
| Androgen status | Biochemical hyperandrogenismc | Biochemical hyperandrogenism refers to an elevated serum androgen level and typically includes an elevated total, bioavailable, or free serum T level. Given variability in T levels and the poor standardization of assays, it is difficult to define an absolute level that is diagnostic of PCOS or other causes of hyperandrogenism, and the Task Force recommends familiarity with local assays. | XX | X | XX |
| Menstrual history | Oligo- or anovulation | Anovulation may manifest as frequent bleeding at intervals <21 d or infrequent bleeding at intervals >35 d. Occasionally, bleeding may be anovulatory despite falling within a normal interval (25-35 d). A mid-luteal progesterone documenting anovulation may help with the diagnosis if bleeding intervals appear to suggest regular ovulation. | XX | X | X |
| Ovarian appearance | Ovarian size/ morphology on ultrasound | PCO morphology has been defined as the presence of ≥12 follicles 2-9 mm in diameter and/or an increased ovarian volume >10 mL (without a cyst or dominant follicle) in either ovary. | X | X |
The Endocrine Society Task Force suggests using the Rotterdam criteria for the diagnosis of PCOS, acknowledging the limitations of each of the three criteria. All criteria require exclusion of other diagnoses (listed in Table 2) that cause the same symptoms and/or signs.
a X, may be present for diagnosis; XX, must be present for diagnosis.
b Hum Reprod. 2004;19:41–47.
c Clinical or biochemical hyperandrogenism is included as one criterion in all classification systems. If clinical hyperandrogenism is present with the absence of virilization, then serum androgen levels are not necessary for the diagnosis. Similarly, when a patient has signs of hyperandrogenism and ovulatory dysfunction, an ovarian ultrasound is not necessary.
Table 2. Other Diagnoses to Exclude in All Women Before Making a Diagnosis of PCOS
| Disorder | Test | Abnormal Values |
|---|---|---|
| Thyroid disease | Serum TSH |
|
| Prolactin excess | Serum prolactin | >Upper limit of normal for the assay |
| Nonclassical congenital adrenal hyperplasia | Early morning (before 8 am) serum 17-OHP | 200-400 ng/dL depending on the assay (applicable to the early follicular phase of a normal menstrual cycle as levels rise with ovulation), but a cosyntropin stimulation test (250 µg) is needed if levels fall near the lower limit and should stimulate 17-OHP >1000 ng/dL |
Table 3. Diagnoses to Consider Excluding in Select Women, Depending on Presentation
| Other Diagnosesa | Suggestive Features in the Presentation | Tests to Assist in the Diagnosis |
|---|---|---|
| Pregnancy | Amenorrhea (as opposed to oligomenorrhea), other signs and symptoms of pregnancy including breast fullness, uterine cramping, etc. | Serum or urine hCG (positive) |
| Hypothalamic amenorrhea (HA) including functional HA | Amenorrhea, clinical history of low body weight/BMI, excessive exercise, and a physical exam in which signs of androgen excess are lacking. Multifollicular ovaries are sometimes present |
|
| Primary ovarian insufficiency | Amenorrhea combined with symptoms of estrogen deficiency including hot flashes and urogenital symptoms |
|
| Androgen secreting tumor | Virilization including change in voice, male pattern androgenic alopecia, and clitoromegaly. Rapid onset of symptoms | Serum T and DHEAS levels (markedly elevated), ultrasound imaging of ovaries, MRI of adrenal glands (mass or tumor present) |
| Cushing’s syndrome | Many of the signs and symptoms of PCOS can overlap with Cushing’s—eg, striae, obesity, dorsocervical fat (buffalo hump), glucose intolerance. However, Cushing’s is more likely to be present when a large number of signs and symptoms, especially those with high discriminatory index—eg, myopathy, plethora, violaceous striae, easy bruising—are present. This presentation should lead to screening. | 24-h urinary collection for urinary free cortisol (elevated), late-night salivary cortisol (elevated), overnight dexamethasone suppression test (failure to suppress morning serum cortisol level) |
| Acromegaly | Oligomenorrhea and skin changes (thickening, tags, hirsutism, hyperhidrosis) may overlap with PCOS. However, headaches, peripheral vision loss, enlarged jaw (macrognathia), frontal bossing, macroglossia, increased shoe and glove size, etc., are indications for screening. | Serum free IGF-1 level (elevated), MRI of pituitary (mass or tumor present) |
a Additionally there are very rare causes of hyperandrogenic chronic anovulation that are not included in this table because they are so rare, but they must be considered in patients with an appropriate history. These include other forms of congenital adrenal hyperplasia (eg, 11β-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase), related congenital disorders of adrenal steroid metabolism or action (eg, apparent cortisone reductase deficiency, apparent DHEA sulfotransferase deficiency, glucocorticoid resistance), virilizing congenital adrenal hyperplasia (adrenal rests, poor control, fetal programming), syndromes of extreme insulin resistance, drugs, portohepatic shunting, and disorders of sex development.
Obesity
- 2.7. Increased adiposity, particularly abdominal, is associated with hyperandrogenemia and increased metabolic risk. Therefore, ES recommends screening adolescents and women with PCOS for increased adiposity by BMI calculation and measurement of waist circumference. (1|⊕⊕⊕◯)
Depression
- 2.8. ES suggests screening women and adolescents with PCOS for depression and anxiety by history and, if identified, providing appropriate referral and/or treatment. (2|⊕⊕◯◯)
Sleep-disordered breathing/obstructive sleep apnea (OSA)
- 2.9. ES suggests screening overweight/obese adolescents and women with PCOS for symptoms suggestive of OSA and, when identified, obtaining a definitive diagnosis using polysomnography. If OSA is diagnosed, patients should be referred for institution of appropriate treatment. (2|⊕⊕◯◯)
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)
- 2.10. ES suggests awareness of the possibility of NAFLD and NASH but recommend against routine screening. (2|⊕⊕◯◯)
Type 2 Diabetes Mellitus (T2DM)
- 2.11. ES recommends the use of an oral glucose tolerance test (OGTT) (consisting of a fasting and 2-hour glucose level using a 75-g oral glucose load) to screen for impaired glucose tolerance (IGT) and T2DM in adolescents and adult women with PCOS because they are at high risk for such abnormalities. (1|⊕⊕⊕◯) A hemoglobin A1c (HgbA1c) test may be considered if a patient is unable or unwilling to complete an OGTT. (2|⊕⊕◯◯) Rescreening is suggested every 3-5 years, or more frequently if clinical factors such as central adiposity, substantial weight gain, and/or symptoms of diabetes develop. (2|⊕⊕◯◯)
Cardiovascular Risk
- 2.12. ES recommends that adolescents and women with PCOS be screened for the following cardiovascular disease risk factors (Table 4): family history of early cardiovascular disease, cigarette smoking, IGT/T2DM, hypertension, dyslipidemia, OSA, and obesity (especially increased abdominal adiposity). (1|⊕⊕◯◯)
Table 4. Cardiovascular Risk Stratification in Women with PCOS
| At risk—PCOS women with any of the following risk factors: |
|---|
| Obesity (especially increased abdominal adiposity) |
| Cigarette smoking |
| Hypertension |
| Dyslipidemia (increased LDL-cholesterol and/or non-HDL-cholesterol) |
| Subclinical vascular disease |
| Impaired glucose tolerance |
| Family history of premature cardiovascular disease (<55 y of age in male relative; <65 y of age in female relative) |
| At high risk—PCOS women with: |
| Metabolic syndrome |
| Type 2 Diabetes Mellitus |
| Overt vascular or renal disease, cardiovascular diseases |
| OSA |
The Androgen Excess and Polycystic Ovary Syndrome Society relied upon evidence-based studies and concluded that women with PCOS be stratified as being either at risk or at high risk for cardiovascular disease using the criteria shown.
Treatment
Hormonal Contraceptives (HCs): Indications and Screening
- 3.1. ES recommends HCs (ie, oral contraceptives, patch, or vaginal ring) as first-line management for the menstrual abnormalities and hirsutism/acne of PCOS since HCs treat these two problems concurrently. (1|⊕⊕◯◯)
- 3.2. ES recommends screening for contraindications to HC use via established criteria. (1|⊕⊕⊕◯) For women with PCOS, we do not suggest one HC formulation over another. (2|⊕⊕◯◯)
Role of Exercise in Lifestyle Therapy
- 3.3. ES suggests the use of exercise therapy in the management of overweight and obesity in PCOS. (2|⊕⊕◯◯) Although there are no large randomized trials of exercise in PCOS, exercise therapy, alone or in combination with dietary intervention, imcreases weight loss and reduces cardiovascular risk factors and diabetes risk in the general population.
Role of Weight Loss in Lifestyle Therapy
- 3.4. ES suggests that weight loss strategies begin with calorie-restricted diets (with no evidence that one type of diet is superior) for adolescents and women with PCOS who are overweight or obese. (2|⊕⊕◯◯) Weight loss is likely to improve both reproductive and metabolic dysfunction in this setting. Weight loss is likely insufficient as a treatment for PCOS in normal-weight women.
Use of Metformin
- 3.5. ES suggests against the use of metformin as a first-line treatment of cutaneous manifestations, for prevention of pregnancy complications, or for the treatment of obesity. (2|⊕⊕◯◯)
- 3.6. ES recommends metformin in women with PCOS who have T2DM or IGT who fail lifestyle modification. (1|⊕⊕⊕◯) For women with PCOS with menstrual irregularity who cannot take or do not tolerate HCs, ES suggests metformin as second-line therapy. (2|⊕⊕⊕◯)
Treatment of Infertility
- 3.7. ES recommends clomiphene citrate (or comparable estrogen modulators such as letrozole) as the first-line treatment of anovulatory infertility in women with PCOS. (1|⊕⊕⊕◯)
- 3.8. ES suggests the use of metformin as an adjuvant therapy for infertility to prevent ovarian hyperstimulation syndrome in women with PCOS undergoing in vitro fertilization (IVF). (2|⊕⊕◯◯)
Use of Other Drugs
- 3.9. ES recommends against the use of insulin sensitizers, such as inositols (due to lack of benefit) or thiazolidinediones (given safety concerns), for the treatment of PCOS. (1|⊕⊕⊕◯)
- 3.10. ES suggests against the use of statins for treatment of hyperandrogenism and anovulation in PCOS until additional studies demonstrate a favorable risk/benefit ratio. (2|⊕⊕◯◯) However, ES suggests statins in women with PCOS who meet current indications for statin therapy. (2|⊕⊕◯◯)
Treatment of Adolescents
- 3.11. ES suggests HCs as the first-line treatment in adolescents with suspected PCOS (if the therapeutic goal is to treat acne, hirsutism, or anovulatory symptoms, or to prevent pregnancy). (2|⊕⊕◯◯) ES suggests that lifestyle therapy (calorie-restricted diet and exercise) with the objective of weight loss should also be first-line treatment in the presence of overweight/obesity. (2|⊕⊕◯◯) ES suggests metformin as a possible treatment if the goal is to treat IGT/metabolic syndrome. (2|⊕⊕◯◯) The optimal duration of HC or metformin use has not yet been determined.
- 3.12. For premenarchal girls with clinical and biochemical evidence of hyperandrogenism in the presence of advanced pubertal development (ie, ≥Tanner stage IV breast development), ES suggests starting HCs. (2|⊕⊕◯◯)