Differential Diagnosis

Why exclude other conditions?

The Rotterdam criteria stipulate that PCOS can only be diagnosed after excluding conditions that can cause irregular cycles and/or hyperandrogenism. These conditions can mimic PCOS and require very different specific treatments.

1. Non-classic congenital adrenal hyperplasia (NC-CAH)

Symptoms mimicking PCOS: hirsutism, irregular cycles, acne, elevated androgens (mainly DHEA-S and androstenedione).

Distinguishing test: fasting 17-OH-progesterone measured in the early follicular phase. A level > 6 nmol/L suggests NC-CAH, confirmed by ACTH stimulation test. The cause is a mutation in the CYP21A2 gene (21-hydroxylase deficiency).

2. Cushing's syndrome

Symptoms mimicking PCOS: abdominal weight gain, irregular cycles, hyperandrogenism, hirsutism, acne, insulin resistance. Cushing's is rare but can simulate severe PCOS.

Distinguishing test: 24-hour urinary free cortisol and/or 1 mg overnight dexamethasone suppression test (cortisol > 50 nmol/L next morning is suspicious). If abnormal, pituitary MRI and adrenal imaging are indicated.

3. Hyperprolactinaemia

Symptoms mimicking PCOS: amenorrhoea or irregular cycles, sometimes galactorrhoea (milk discharge), infertility.

Distinguishing test: serum prolactin. A prolactin > 200 mIU/L (laboratory-dependent) is significant. If markedly elevated, a pituitary MRI is performed to look for a pituitary adenoma (prolactinoma).

4. Androgen-secreting tumours

Warning signs: rapid-onset hirsutism, virilisation (clitoral enlargement, voice deepening), very high androgen levels.

Warning thresholds: total testosterone > 5 nmol/L or DHEA-S > 800 µg/dL (21.6 µmol/L). These values should trigger urgent imaging (ultrasound, MRI) of the ovaries and adrenal glands to rule out a tumour.

5. Thyroid dysfunction

Symptoms mimicking PCOS: hypothyroidism can cause irregular cycles, weight gain, fatigue, and secondary hyperprolactinaemia. Thyroid dysfunction can mask or worsen PCOS.

Distinguishing test: TSH (thyroid-stimulating hormone). If abnormal, free T4 and anti-TPO antibodies (autoimmune thyroid disease) should be measured.

6. Premature ovarian insufficiency (POI)

Symptoms mimicking PCOS: amenorrhoea, infertility, sometimes hot flushes. Must be distinguished from PCOS as treatment is the opposite.

Distinguishing test: FSH > 40 IU/L on two occasions 4 weeks apart, associated with very low or undetectable AMH (the opposite of PCOS, where AMH is elevated).

Key takeaways

• NC-CAH: elevated 17-OH-progesterone in follicular phase
• Cushing's: urinary free cortisol / dexamethasone suppression test
• Hyperprolactinaemia: serum prolactin + MRI if elevated
• Androgen tumour: testosterone > 5 nmol/L or DHEA-S > 800 µg/dL → urgent imaging
• Thyroid dysfunction: TSH systematic in any irregular cycle workup
• POI: FSH > 40 + very low AMH (opposite of PCOS)