Polycystic Ovarian Syndrome - PCOS

Polycystic ovarian syndrome (PCOS) is a common endocrinopathy caused by androgen excess and is the leading cause of anovulatory infertility. Because it is associated with increased cardiovascular risk as well as other adverse effects, diagnosis is essential for both treatment and monitoring reasons.

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Diagnosis

Indications for Testing

Irregular menses, infertility, hirsutism, acne

Criteria for Diagnosis

Two of 3 of the following criteria in the absence of other etiology (American Association of Clinical Endocrinologists [AACE]/American College of Endocrinology [ACE]/Androgen Excess and Polycystic Ovarian Syndrome Society, 2015).

  • Menstrual irregularities
  • Hyperandrogenism (clinical or biological)
  • Polycystic ovaries
Criteria for Defining Polycystic Ovarian Syndrome (PCOS)

Androgen Excess and PCOS Society Guidelines (developed in 2006, reaffirmed in 2015 [Goodwin, 2015])

Amsterdam European Society of Human Reproduction and Embryology (ESHRE)/American Society for Reproductive Medicine (ASRM) Consensus (3rd PCOS Consensus 2012) – reaffirmed use of Rotterdam 2003 criteria

PCOS is a disorder of androgen excess or hyperandrogenism

Diagnosis requires all 3 of the following elements

  • Hyperandrogenisma
    • Clinical (hirsutism) and/or biochemical signs (elevated levels of total or free testosterone)
  • Ovarian dysfunction and/or polycystic ovaries (prominent but not universal feature of PCOS)
    • Polycystic ovarian morphology defined as per guidelines (Dewailey, 2014)
      •  ≥25 follicles/ovary – recommended criterion over ovarian volume
      •  ≥10 mL ovarian volume
  • Exclusion of other androgen excess disorders

Adult female

  • PCOS is a disorder of androgen excess or hyperandrogenism
  • Presence of 2 of the following 3 elements confirms PCOS
    • Hyperandrogenisma
      • Clinical (hirsutism) or biochemical signs
    • Oligo-ovulation and/or anovulation
    • Polycystic ovaries on ultrasound
      • Presence of ≥12 follicles in each ovary measuring 2-9 mm in diameter and/or increased ovarian volume >10 cm3
  • Exclusion of other androgen excess disorders

Adolescent female

  • Risk of overdiagnosis of PCOS in this population
  • All 3 of the following elements must be present to confirm diagnosis
    • Oligomenorrhea or amenorrhea for ≥2 years after menarche (or primary amenorrhea at 16 years)
    • Polycystic ovaries on ultrasound (size >10 cm3)
    • Hyperandrogenemia
aHyperandrogenism
  • Usually defined as >2.5 standard deviations above mean for assay
  • Measure between day 4 and 10 of menstrual cycle
  • Lab testing to confirm
    • Testosterone is the hormone usually measured
      • May have poor validity in some labs
      • Assay should measure testosterone levels for female and children
    • Androstenedione and dehydroepiandrosterone sulfate (DHEA-S) are informative markers but not necessary in most cases

Laboratory Testing

  • Initial testing
    • Serum free testosterone
      • Mass spectrometry – gold standard
      • Mass spectrometry with liquid chromatography (LC-MS/MS) – acceptable
      • Radioimmunoassay (RIA) that includes purification – acceptable
      • Assay that measures levels for females and children should be used
      • Sample should be collected between day 4 and 10 of menstrual cycle
      • Testosterone is elevated if >2.5 standard deviations above the mean
        • Value >200 ng/dL should prompt evaluation for androgen-secreting tumor
      • Testing should be performed by laboratories that use appropriate methods
  • Additional testing
    • Serum 17-hydroxyprogesterone
      • Test for nonclassic 21-hydroxylase deficiency – patients with this deficiency will present with same clinical signs and symptoms as those with PCOS
    • Anti-Mullerian hormone (AMH)
      AMH Reference Intervals for Females
      Age Reference Interval (ng/mL)

      6 mos-14 yrs

      0.256-6.345

      15-17 yrs

      0.861-10.451

      18-29 yrs

      0.401-16.015

      30-39 yrs

      0.176-11.705

      40-45 yrs

      ≤6.282

      46-50 yrs

      ≤0.064

      Postmenopausal

      ≤0.003

      • AMH testing can be used in place of ovarian morphology assessment
    • Progesterone
      • Test midcycle to confirm anovulation
      • Not required for diagnosis
  • Other hormone testing not indicated
    • Dehydroepiandrosterone (DHEA) – measurement does not add significantly to diagnosis
    • 11β-hydroxyandrostenedione and androstenedione – generally not needed to assist with diagnosis
    • Luteinizing hormone (LH)/follicle-stimulating hormone (FSH) – not indicated

Imaging Studies

  • Transvaginal ultrasound
    • Presence of polycystic ovaries alone is not sufficient to establish diagnosis
  • Magnetic resonance imaging (MRI)/computed tomography (CT) – most useful to rule out adrenal/ovarian tumors if testosterone level is moderately elevated

Differential Diagnosis

  • Pregnancy
    • Measure beta human chorionic gonadotropin (β-hCG) level 
  • Adrenal hyperfunction (Cushing syndrome)        
  • Late onset congenital adrenal hyperplasia (CAH) 
    • Present in <5% of hyperandrogenic women
    • Measure 17-hydroxyprogesterone
      • Morning testing preferred
      • If result is >200 ng/mL, further assessment is necessary to rule out CAH
  • Androgen-secreting tumors (ovarian, adrenal) 
    • Present in 0.2% of hyperandrogenic women
    • Testosterone >200 ng/dL combined with dehydroepiandrosterone sulfate (DHEA-S) >700 µg/dL suggests ovarian or adrenal tumor
  • Metabolic syndrome
  • Prolactinoma
    • Measure prolactin
  • Idiopathic hirsutism
  • Acromegaly
  • Thyroid dysfunction/hypothyroidism
    • Measure thyroid-stimulating hormone (TSH)
  • Drug related
    • Testosterone
    • Danazol
    • Androgenic progestins
    • Valproic acid
    • Acetazolamide
    • Minoxidil
    • High-dose glucocorticosteroids

Monitoring

  • Monitoring is recommended for long-term health consequences associated with polycystic ovarian syndrome (PCOS)
  • Laboratory testing (after diagnosis) to evaluate for metabolic complications of PCOS

Background

Epidemiology

Prevalence – 10-15% of adult females worldwide (Azziz, Androgen Excess and Polycystic Ovarian Syndrome Society, 2009).

Genetics

  • Family incidence nearly 40%
  • Appears to be autosomal dominant

Pathophysiology

  • Etiology is unknown
  • Excess androgen production (hyperandrogenism) and insulin resistance play a role in disease pathogenesis

Clinical Presentation

  • Irregular menses or amenorrhea
  • Infertility
  • Signs of hyperandrogenism, including
    • Acne
    • Hirsutism
      • Increased number of terminal hairs
      • Hatch modification of the Ferriman-Gallwey scale should be used to evaluate
    • Alopecia – similar to male pattern baldness
  • High rate of type 2 diabetes mellitus (T2DM), metabolic syndrome, sleep apnea, and obesity

Pediatrics

Epidemiology

  • Prevalence – affects 5-10% of adolescent females
  • 40% develop type 2 diabetes mellitus (T2DM) or impaired glucose tolerance by age 40

Clinical Presentation

  • Hirsutism
    • Increased number of terminal hairs
    • Hatch modification of the Ferriman-Gallwey scale should be used to evaluate
    • Ethnic differences affect hirsutism
  • Alopecia – similar to male pattern baldness
  • Acne – consider diagnosis of polycystic ovarian syndrome (PCOS) if acne is severe or does not respond to standard therapies
  • Irregular menses of >2 years duration
  • Obesity (central or refractory)

Indications for Testing

Irregular menses, hirsutism, acne, infertility

Laboratory Testing

  • Initial testing
    • Diagnosis may be more difficult in adolescents, but PCOS is important to be aware of and address early due to the risks associated with nontreatment
    • Symptoms in patients <18 years may represent transient adolescent hormonal changes
    • Serum or urine human chorionic gonadotropin (hCG) should be measured to rule out pregnancy
  • Refer to main Laboratory Testing subsection within Diagnosis
  • Refer to Secondary Amenorrhea Testing Algorithm

Imaging Studies

  • Transvaginal ultrasound to evaluate ovaries
    • Complicated by increased number of cysts normally occurring in adolescents
    • Required by Amsterdam criteria, but not by Androgen Excess and Polycystic Ovarian Syndrome Society criteria

Differential Diagnosis

ARUP Laboratory Tests

Recommended initial test in the evaluation of suspected hyperandrogenemia in women and children

Acceptable test for evaluating androgen deficiency in men

Indicator of adrenal androgen production

Aid in the investigation of virilizing endocrinopathies in conjunction with other sex steroids

Not recommended for initial evaluation of polycystic ovarian syndrome (PCOS)

Not generally recommended

Adjunct tool for the evaluation of hirsutism

Aid in the investigation of virilizing endocrinopathies and in managing congenital adrenal hyperplasia (CAH) in conjunction with other sex steroids

Not recommended for initial evaluation of PCOS

Detect enzyme deficiencies causing CAH

Screening for anterior pituitary tumor

Rule out Cushing syndrome

Assess thyroid function

Reflex pattern: if the thyroid stimulating hormone is outside the reference interval, then free thyroxine (free T4) testing will be added

Diagnose and manage diabetes mellitus (DM) and other carbohydrate metabolism disorders

Assess cardiovascular disease risk and guide therapy

Panel includes cholesterol, serum or plasma; triglycerides, serum or plasma; HDL cholesterol; LDL cholesterol, direct; VLDL, calculated; non-HDL cholesterol; appearance chemistry

Monitor liver function

Related Tests

Generally not used to contribute to polycystic ovarian syndrome (PCOS) diagnosis

Preferred test for screening and monitoring of thyroid function

Aid in detection and subclassification of hyperandrogenism

Most useful in women and children with moderate/severe hirsutism or hirsutism of any degree when it is sudden in onset or rapidly progressive

Hirsutism evaluation panel is generally preferred

Panel includes androstenedione; dehydroepiandrosterone, serum or plasma; and free testosterone, females or children

Aid in detection of nonclassical congenital adrenal hyperplasia (CAH) in individuals presenting with hyperandrogenism

Panel includes androstenedione; 17-hydroxyprogesterone quantitative by HPLC-MS/MS, serum or plasma; testosterone, females or children; and dehydroepiandrosterone, serum or plasma

Suitable for measurement of estradiol in adult premenopausal women

In all other groups, preferred test is estrogens, fractionated by tandem mass spectrometry (HPLC)

Aid in detection and subclassification of hyperandrogenism

Most useful in women and children with moderate/severe hirsutism or hirsutism of any degree when it is sudden in onset or rapidly progressive

Panel includes androstenedione; dehydroepiandrosterone sulfate (DHEA-S), serum; testosterone, free, females or children; testosterone, females or children; and sex hormone binding globulin

Adjunct test for the investigation of hyperandrogenic and adrenal disorders

Not recommended for initial evaluation of PCOS

Aid in the detection of insulinoma

Do not use to diagnose diabetes mellitus

Medical Experts

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References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®