Polycystic Ovarian Syndrome - PCOS

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

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 testing can be used in place of ovarian morphology assessment
    • AMH reference intervals for females (age dependent)

      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
  • 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)
  • Metabolic syndrome
  • Cardiovascular disease
  • Impaired glucose tolerance and diabetes
  • Increased endometrial cancer risk
• Laboratory testing (after diagnosis) to evaluate for metabolic complications of PCOS
  • Fasting 2-hour glucose tolerance test or hemoglobin A1c
  • Fasting lipid profile (see Atherosclerotic Cardiovascular Disease [ASCVD] Risk Markers)
  • Liver function testing (alanine aminotransferase, aspartate aminotransferase)

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

• Late-onset congenital adrenal hyperplasia (CAH)
• Androgen secreting tumors (ovarian, adrenal)
• Thyroid dysfunction
• Prolactinoma
• Pregnancy