What are the diagnostic tests and treatment options for a female patient of reproductive age with symptoms of irregular menstrual cycles, weight gain, and infertility suspected to have polycystic ovary syndrome (PCOS)?

PCOS Testing: Diagnostic Approach

For a reproductive-age woman with irregular cycles, weight gain, and infertility, begin with clinical assessment for hyperandrogenism (hirsutism, acne, male-pattern hair loss) and measure total testosterone or free testosterone using LC-MS/MS, TSH, prolactin, and perform transvaginal ultrasound to count follicles and measure ovarian volume—diagnosis requires two of three Rotterdam criteria: oligo/anovulation, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology (≥20 follicles per ovary or ovarian volume ≥10 mL). 1, 2

Initial Clinical Assessment

Document menstrual pattern precisely:

• Track cycles for at least 6 months to identify oligomenorrhea (>35 days), polymenorrhea (<23 days), or amenorrhea (>6 months without bleeding) 2
• Calculate body mass index (BMI >25 indicates obesity) and waist-hip ratio (>0.9 indicates truncal obesity, which exacerbates PCOS features) 2, 1

Physical examination for hyperandrogenism:

• Assess for hirsutism using Ferriman-Gallwey score or inspect for male escutcheon pattern 2
• Document acne, male-pattern alopecia, and acanthosis nigricans 3, 4

First-Line Laboratory Tests

Androgen assessment (mandatory):

• Measure total testosterone AND free testosterone using liquid chromatography-tandem mass spectrometry (LC-MS/MS)—this is the gold standard with 92% specificity compared to 78% for direct immunoassays 1
• Total testosterone shows 74% sensitivity and 86% specificity for PCOS diagnosis 1
• Free testosterone demonstrates superior sensitivity of 89% with 83% specificity 1
• Critical caveat: 30% of women with confirmed PCOS have normal testosterone levels, so normal results do not exclude the diagnosis 1

Exclude other endocrine disorders:

• TSH to rule out thyroid disease causing menstrual irregularity 2, 1
• Prolactin using morning resting serum levels (not post-ictal), with levels >20 μg/L considered abnormal 2, 1
• If prolactin is elevated, confirm with 2-3 samples at 20-60 minute intervals via indwelling cannula to exclude stress-related spurious elevation 1

Assess ovulatory function:

• Mid-luteal phase progesterone (levels <6 nmol/L indicate anovulation) 2, 1
• LH and FSH measured between cycle days 3-6 (average of three estimations taken 20 minutes apart); LH/FSH ratio >2 suggests PCOS, though this is abnormal in only 35-44% of PCOS cases, making it a poor standalone marker 2, 1

Imaging: Transvaginal Ultrasound

Perform transvaginal ultrasound with ≥8 MHz transducer to assess polycystic ovarian morphology: 2

• Count follicles 2-9 mm in diameter: ≥20 follicles in at least one ovary meets diagnostic criteria (87.64% sensitivity, 93.74% specificity) 2, 1
• Measure ovarian volume: >10 mL in at least one ovary is diagnostic (81.48% sensitivity, 81.04% specificity) 2, 1
• Document increased echogenicity of ovarian stroma (most sensitive and specific sign, though subjective) 2

Important exception: If the patient has both irregular cycles AND clinical/biochemical hyperandrogenism, ultrasound is not necessary for diagnosis, though it identifies the complete phenotype 1

Avoid ultrasound in adolescents with <8 years since menarche due to high false-positive rates from physiologic multifollicular ovaries 1

Second-Line Tests (If First-Line Normal but Suspicion High)

Additional androgen markers:

• Androstenedione (sensitivity 75%, specificity 71%) 1
• DHEAS (sensitivity 75%, specificity 67%) to rule out non-classical congenital adrenal hyperplasia 2, 1
• These have poorer specificity than testosterone and should only be used as adjunctive tests 1

Mandatory Metabolic Screening

All women with PCOS require metabolic assessment due to increased cardiovascular and diabetes risk: 1, 3

• Two-hour oral glucose tolerance test with 75g glucose load 1
• Fasting lipid panel (total cholesterol, LDL <100 mg/dL, HDL >35 mg/dL, triglycerides <150 mg/dL) 1
• Fasting glucose and insulin with glucose/insulin ratio (ratio >4 suggests reduced insulin sensitivity) 2, 1

Exclude Serious Conditions

Screen for Cushing's syndrome if: buffalo hump, moon facies, hypertension, abdominal striae, central fat distribution, easy bruising, or proximal myopathies are present 1

Consider androgen-secreting tumor if: rapid symptom onset, severe hirsutism, or very high testosterone levels (>2.5 nmol/L) 2, 1

Check FSH >35 IU/L to exclude primary ovarian failure 2, 1

Diagnostic Algorithm

1. If irregular cycles + clinical/biochemical hyperandrogenism are present → PCOS diagnosis confirmed without ultrasound 1
2. If irregular cycles + polycystic ovaries on ultrasound (without hyperandrogenism) → PCOS diagnosis confirmed 1
3. If hyperandrogenism + polycystic ovaries (with regular cycles) → PCOS diagnosis confirmed 1

The Rotterdam criteria require only 2 of 3 features (77-89% sensitivity, 83% specificity), making it more sensitive but less specific than older NIH criteria 1

Critical Pitfalls to Avoid

• Do not use Anti-Müllerian Hormone (AMH) as a standalone diagnostic test or as an alternative to ultrasound—despite 92% sensitivity and 97% specificity at ≥35 pmol/L, it lacks assay standardization and validated cut-offs 1
• Do not dismiss normal testosterone levels as excluding PCOS—30% of confirmed cases have normal values 1
• Do not use color Doppler ultrasound routinely—limited evidence supports its diagnostic value 2
• Do not delay metabolic screening—metabolic syndrome is twice as common in PCOS, and type 2 diabetes risk is four times higher than the general population 4

Treatment Considerations for This Patient

For infertility in PCOS:

• Letrozole (aromatase inhibitor) is first-line treatment for PCOS-related anovulation 5, 4
• Clomiphene citrate is FDA-approved for ovulatory dysfunction in PCOS, starting at 50 mg daily for 5 days, with most patients ovulating after the first course 6
• Weight loss of 5-10% significantly decreases PCOS symptoms and improves fertility 5, 4

Monitor for ovarian hyperstimulation syndrome (OHSS) if using ovulation induction—patients with PCOS are unusually sensitive to gonadotropins and should start with the lowest dose 6