What is the recommended investigation and management approach for a female patient suspected of having polycystic ovary syndrome (PCOS) with symptoms such as oligomenorrhea, acne, and excess hair growth?

Investigation of Polycystic Ovary Syndrome (PCOS)

For a patient with oligomenorrhea, acne, and excess hair growth, diagnose PCOS using the Rotterdam criteria requiring at least two of three features: hyperandrogenism (clinical or biochemical), ovulatory dysfunction, and polycystic ovarian morphology on ultrasound—after excluding other causes of androgen excess. 1

Initial Clinical Assessment

History and Physical Examination

• Document onset and duration of hyperandrogenic symptoms (hirsutism, acne, hair loss), menstrual pattern (cycle length >35 days suggests chronic anovulation), medication use including exogenous androgens, family history of cardiovascular disease and diabetes, and lifestyle factors (diet, exercise, smoking, alcohol). 2

• Examine for signs of hyperandrogenism: acne distribution, hirsutism pattern, androgenic alopecia (vertex, crown, or diffuse pattern), clitoromegaly (suggests virilizing tumor if present), and acanthosis nigricans (neck, axillae, under breasts, vulva—indicates insulin resistance). 2, 1

• Measure anthropometric parameters: Calculate BMI and waist-to-hip ratio (>0.9 indicates central obesity and increased metabolic risk). 1, 3

Red Flags Requiring Immediate Investigation

• Rapid onset of virilization with clitoromegaly suggests androgen-secreting tumor rather than PCOS and requires urgent evaluation. 4
• Cushing's syndrome features (buffalo hump, moon facies, hypertension, abdominal striae, easy bruising, proximal myopathy) warrant dexamethasone suppression testing. 2, 3

Essential Laboratory Investigations

First-Line Hormonal Tests

• Measure total testosterone or free testosterone using liquid chromatography-tandem mass spectrometry (LC-MS/MS), which shows superior specificity (92%) compared to direct immunoassays (78%). Total testosterone has 74% sensitivity and 86% specificity; free testosterone demonstrates 89% sensitivity and 83% specificity. 3

• Measure TSH to exclude thyroid disease as a cause of menstrual irregularity. 1, 3

• Measure prolactin using morning resting serum levels to exclude hyperprolactinemia (>20 μg/L is abnormal). 2, 3

• Measure LH and FSH between days 3-6 of menstrual cycle (average of three measurements 20 minutes apart). An LH/FSH ratio >2 suggests PCOS but is only abnormal in 35-44% of cases, making it a poor standalone marker. 2, 3

• Measure mid-luteal phase progesterone (day 21 of 28-day cycle) to confirm anovulation; levels <6 nmol/L indicate anovulation. 2, 3

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

• Measure androstenedione (sensitivity 75%, specificity 71%); levels >10.0 nmol/L suggest adrenal/ovarian tumor. 2, 3

• Measure DHEAS (sensitivity 75%, specificity 67%) to rule out non-classical congenital adrenal hyperplasia. Age-specific thresholds: age 20-29 >3800 ng/mL, age 30-39 >2700 ng/mL. 2, 3

Mandatory Metabolic Screening (All Patients Regardless of BMI)

• Perform 2-hour oral glucose tolerance test with 75g glucose load to detect type 2 diabetes and glucose intolerance. Fasting glucose >7.8 mmol/L suggests diabetes. 2, 1, 3

• Measure fasting glucose/insulin ratio; ratio >4 suggests reduced insulin sensitivity. 2

• Obtain fasting lipid panel including total cholesterol, LDL, HDL, and triglycerides to assess cardiovascular risk. 2, 3

Imaging Studies

Pelvic Ultrasound

• Perform transvaginal ultrasound (if sexually active and acceptable to patient) using ≥8 MHz transducer on days 3-9 of cycle. Diagnostic criteria: ≥20 follicles (2-9mm diameter) per ovary and/or ovarian volume ≥10 mL, with no corpus luteum, cyst, or dominant follicle present. 2, 1

• Use transabdominal approach for non-sexually active patients, focusing on ovarian volume ≥10 mL. 1

• Important caveat: Ultrasound is NOT necessary for diagnosis if patient has both irregular cycles AND hyperandrogenism—these two criteria alone are sufficient. 1

• Do NOT use ultrasound for diagnosis in adolescents <8 years post-menarche due to high false-positive rates from physiologically normal multifollicular ovaries. 1

Alternative Imaging

• Consider MRI without IV contrast in obese patients where ultrasound is technically limited. 1

Exclusion of Other Causes

Tests to Rule Out Differential Diagnoses

• Measure 17-hydroxyprogesterone to exclude non-classical congenital adrenal hyperplasia. 1

• Screen for Cushing's syndrome with dexamethasone suppression test if clinical features present. 2, 3

• Evaluate for androgen-secreting tumors if testosterone >2.5 nmol/L or rapid symptom onset. 2

Diagnostic Algorithm

Step 1: Confirm at least two of three Rotterdam criteria are present:

• Oligo/anovulation (cycle length >35 days or mid-luteal progesterone <6 nmol/L)
• Clinical hyperandrogenism (hirsutism, acne, alopecia) OR biochemical hyperandrogenism (elevated testosterone)
• Polycystic ovarian morphology on ultrasound (≥20 follicles per ovary and/or volume ≥10 mL)

Step 2: Exclude other causes of hyperandrogenism:

• Normal TSH rules out thyroid disease
• Normal prolactin rules out hyperprolactinemia
• Normal 17-hydroxyprogesterone rules out congenital adrenal hyperplasia
• Absence of Cushing's features or negative dexamethasone suppression test

Step 3: Assess metabolic complications (mandatory in all patients):

• 2-hour oral glucose tolerance test
• Fasting lipid panel
• BMI and waist-to-hip ratio

Critical Pitfalls to Avoid

• Do not rely solely on testosterone levels: 30% of women with confirmed PCOS have normal testosterone levels. Clinical hyperandrogenism (hirsutism, acne) plus irregular cycles is sufficient for diagnosis. 3

• Do not use LH/FSH ratio as primary diagnostic criterion: It is abnormal in only 35-44% of PCOS cases. 3

• Do not skip metabolic screening in lean patients: Insulin resistance occurs independently of BMI and affects both lean and overweight women with PCOS. 1

• Do not use Anti-Müllerian Hormone (AMH) as a diagnostic test: While AMH ≥35 pmol/L shows 92% sensitivity and 97% specificity, it should not replace ultrasound or serve as a standalone test due to lack of assay standardization. 3

• Do not overlook endometrial cancer risk: Chronic anovulation increases risk of endometrial hyperplasia and cancer; patients with prolonged amenorrhea require endometrial assessment. 4

Additional Screening Recommendations

• Screen for depression and anxiety, which occur more frequently in women with PCOS. 5, 6

• Screen for obstructive sleep apnea, particularly in obese patients with PCOS. 5

• Assess cardiovascular risk factors: Women with PCOS have increased coronary artery calcium scores and carotid intima-media thickness. 6