What conditions should be ruled out in a reproductive‑age woman being evaluated for polycystic ovary syndrome?

What Needs to be Ruled Out When Considering a Diagnosis of PCOS

Before diagnosing PCOS, you must exclude thyroid disease, hyperprolactinemia, Cushing's syndrome, non-classical congenital adrenal hyperplasia, androgen-secreting tumors, primary ovarian failure, and hypothalamic amenorrhea. 1

Mandatory Exclusions Before PCOS Diagnosis

Thyroid Disease

• Measure thyroid-stimulating hormone (TSH) to rule out thyroid dysfunction as a cause of menstrual irregularity, since both hypothyroidism and hyperthyroidism can mimic PCOS with oligomenorrhea and anovulation. 1
• Primary hypothyroidism should be treated first, as normalizing thyroid function alone may restore regular menses and resolve apparent PCOS features. 2

Hyperprolactinemia

• Obtain morning resting serum prolactin levels to exclude hyperprolactinemia, with values >20 μg/L considered abnormal. 1
• Confirm any elevation with 2-3 samples at 20-60 minute intervals via indwelling cannula to exclude stress-related spurious elevation. 2
• Hyperprolactinemia suppresses GnRH pulsatility and causes anovulation, menstrual irregularity, and infertility that directly mimics PCOS presentation. 2
• Functional hyperprolactinemia may be increased in women with epilepsy and can cause oligomenorrhea, amenorrhea, subfertility, galactorrhea, and hirsutism. 3

Cushing's Syndrome

• Screen for Cushing's syndrome if the patient presents with buffalo hump, moon facies, hypertension, abdominal striae, central fat distribution, easy bruising, or proximal myopathies. 1
• This is critical because untreated Cushing's carries significant morbidity and mortality risks that far exceed those of PCOS.

Non-Classical Congenital Adrenal Hyperplasia (NCCAH)

• Measure DHEAS (dehydroepiandrosterone sulfate) levels, with age-adjusted thresholds (≥3800 ng/mL for ages 20-29, ≥2700 ng/mL for ages 30-39) prompting evaluation for NCCAH. 1
• Elevated DHEAS levels specifically suggest adrenal androgen excess rather than ovarian source. 3

Androgen-Secreting Tumors

• Consider androgen-secreting tumors if there is rapid onset of symptoms, severe hirsutism, or very high testosterone levels. 1
• Measure androstenedione if testosterone is normal but clinical suspicion remains high; levels >10.0 nmol/L indicate possible adrenal or ovarian tumor. 1
• This is a critical exclusion because these tumors require urgent surgical intervention and missing this diagnosis can be life-threatening.

Primary Ovarian Failure

• Check FSH levels to rule out primary ovarian failure, particularly in women presenting in their third decade with amenorrhea. 3
• FSH values above 50 mIU/mL indicate primary gonadal failure, which occurs in approximately 1% of the general population but may be more common in certain populations. 3

Hypothalamic Amenorrhea (Hypogonadotropic Hypogonadism)

• Evaluate for hypothalamic amenorrhea, which presents with disturbed pituitary gonadotropin secretion and low luteinizing hormone levels. 3
• This condition causes amenorrhea or oligomenorrhea and infertility in the absence of signs of hyperandrogenemia, distinguishing it from PCOS. 3
• Hypothalamic amenorrhea affects approximately 1.5% of the general population but may be found in up to 12% of women with temporal lobe epilepsy. 3

Acromegaly

• Assess for acromegaly if coarse facial features or enlarged hands/feet are present, as growth hormone excess can cause menstrual irregularities and metabolic dysfunction. 1

Key Diagnostic Pitfalls to Avoid

• Do not diagnose PCOS based solely on polycystic ovarian morphology on ultrasound, as isolated polycystic ovaries occur in 17-22% of normal women without any symptoms or hormonal abnormality. 3
• Do not use ultrasound for PCOS diagnosis within 8 years of menarche due to high incidence of multifollicular ovaries during this life stage, which creates unacceptable false-positive rates. 1
• Do not rely on LH/FSH ratio >2 as a diagnostic requirement, as this is abnormal in only 35-44% of women with confirmed PCOS, making it a poor standalone marker. 1
• Remember that PCOS is a diagnosis of exclusion—the Rotterdam criteria require two of three features (oligo/anovulation, clinical/biochemical hyperandrogenism, polycystic ovarian morphology), but only after excluding the conditions listed above. 3, 4