What diseases and diagnostic tests should be considered to rule out in the diagnosis of Polycystic Ovary Syndrome (PCOS) as a condition of exclusion?

Differential Diagnosis and Diagnostic Testing for PCOS

Before diagnosing PCOS, you must systematically exclude thyroid disease, hyperprolactinemia, non-classical congenital adrenal hyperplasia (NCCAH), Cushing's syndrome, and androgen-secreting tumors through targeted laboratory testing and clinical assessment. 1, 2

Conditions That Must Be Ruled Out

Primary Endocrine Disorders to Exclude

• Thyroid disease must be excluded by measuring TSH, as thyroid dysfunction commonly presents with menstrual irregularity mimicking PCOS 1, 3

• Hyperprolactinemia requires measurement of morning resting serum prolactin levels (>20 μg/L is abnormal), as this condition causes oligomenorrhea and can mimic PCOS 1, 3, 4

• Non-classical congenital adrenal hyperplasia (NCCAH) is distinguished by measuring basal 17-hydroxyprogesterone (17-OHP) in the early follicular phase, with ACTH stimulation testing if basal levels are equivocal 1, 4, 5, 6

• Cushing's syndrome should be screened when patients exhibit buffalo hump, moon facies, hypertension, abdominal striae, centripetal fat distribution, easy bruising, or proximal myopathies using overnight dexamethasone suppression test or 24-hour urinary free cortisol 1, 3, 4

Neoplastic Conditions Requiring Urgent Exclusion

• Androgen-secreting tumors (ovarian or adrenal) must be considered with rapid onset of severe hyperandrogenism, virilization (clitoromegaly, voice deepening), or very high testosterone levels (typically >150-200 ng/dL) 1, 3, 4, 5

• Acromegaly should be assessed if coarse facial features or enlarged hands/feet are present 1

• Insulinoma or gastric adenocarcinoma must be considered in women with acanthosis nigricans, particularly if severe or rapidly progressive 1

Other Reproductive Disorders

• Primary ovarian failure requires FSH measurement, with levels >35 IU/L indicating ovarian failure rather than PCOS 1

• Primary hypothalamic amenorrhea related to stress, excessive exercise, or eating disorders should be distinguished by history and absence of hyperandrogenism 1

Essential Diagnostic Tests

First-Line Hormonal Assessment

• Total testosterone or free testosterone using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the primary androgen test, with LC-MS/MS showing superior specificity (92%) compared to direct immunoassays (78%) 2, 3

• TSH measurement to exclude thyroid disease as a cause of menstrual irregularity 1, 2, 3

• Prolactin level using morning resting serum sample (not post-ictal) to exclude hyperprolactinemia 1, 3

• 17-hydroxyprogesterone (17-OHP) measured in early follicular phase to exclude NCCAH; if basal levels are borderline elevated, proceed with ACTH stimulation test 1, 4, 5, 6

Metabolic Screening (Mandatory for All Suspected PCOS)

• Two-hour oral glucose tolerance test with 75g glucose load to detect type 2 diabetes and glucose intolerance, regardless of BMI, as insulin resistance occurs independently of body weight 1, 2, 3

• Fasting lipid profile including total cholesterol, LDL, HDL, and triglycerides, as women with PCOS have elevated cardiovascular risk 1, 3

• BMI calculation and waist-to-hip ratio measurement, with WHR >0.9 indicating truncal obesity and increased metabolic risk 1, 2, 3

Additional Hormonal Tests When Indicated

• LH and FSH measured between cycle days 3-6 (average of three samples 20 minutes apart), with LH/FSH ratio >2 suggesting PCOS, though this is abnormal in only 35-44% of PCOS cases 1, 3

• Mid-luteal progesterone (<6 nmol/L indicates anovulation) to confirm ovulatory dysfunction 1, 3

• DHEA-S (dehydroepiandrosterone sulfate) to rule out adrenal sources of hyperandrogenism, with age-specific thresholds (age 20-29: >3800 ng/mL; age 30-39: >2700 ng/mL) 1, 3

• Androstenedione if testosterone is normal but clinical suspicion remains high, with levels >10.0 nmol/L suggesting adrenal/ovarian tumor 1, 3

Imaging Studies

• Pelvic transvaginal ultrasound (if sexually active and acceptable to patient) using ≥8 MHz transducer to assess for polycystic ovarian morphology (≥20 follicles per ovary and/or ovarian volume ≥10 mL) and to exclude ovarian masses 2, 3

• Pituitary MRI if prolactin is elevated or clinical features suggest pituitary pathology (galactorrhea, visual field defects, headaches) 1

Critical Physical Examination Findings

• Acanthosis nigricans on neck, axillae, under breasts, or vulva indicates insulin resistance and warrants consideration of insulinoma or malignancy if severe 1, 2

• Clitoromegaly, severe hirsutism with rapid onset, or virilization (voice deepening, male-pattern baldness) mandates urgent evaluation for androgen-secreting tumor 1, 4

• Signs of Cushing's syndrome including buffalo hump, moon facies, purple striae, proximal muscle weakness require dexamethasone suppression testing 1, 3

Common Pitfalls to Avoid

• Do not rely solely on testosterone levels: 30% of women with confirmed PCOS have normal total testosterone, so clinical hyperandrogenism (hirsutism, acne, alopecia) plus menstrual irregularity can establish the diagnosis without biochemical confirmation 3

• Avoid using LH/FSH ratio as a primary diagnostic tool: This ratio is elevated in only 35-44% of PCOS cases and has poor sensitivity 3

• Do not use ultrasound in adolescents with gynecological age <8 years: Multifollicular ovaries are physiologically common in this age group, leading to false-positive diagnoses 2, 3

• Measure prolactin only when patient is not post-ictal: Seizures transiently elevate prolactin and can cause false-positive results 1

• Consider timing of 17-OHP measurement: Must be drawn in early follicular phase (days 3-6) for accurate interpretation, as luteal phase levels are physiologically elevated 4, 5, 6