What are the other causes of hyperandrogenism in a female patient of reproductive age with a history of Polycystic Ovary Syndrome (PCOS)?

Other Causes of Hyperandrogenism in Reproductive-Age Women

In a woman with known PCOS presenting with hyperandrogenism, you must systematically exclude non-classical congenital adrenal hyperplasia (NCCAH), Cushing's syndrome, androgen-secreting tumors, hyperprolactinemia, thyroid disease, exogenous androgen use, and acromegaly before attributing symptoms solely to PCOS. 1

Primary Differential Diagnoses to Exclude

Non-Classical Congenital Adrenal Hyperplasia (NCCAH)

• NCCAH presents with oligomenorrhea and hyperandrogenism that can be clinically indistinguishable from PCOS 2
• Diagnose by measuring basal or ACTH-stimulated 17-hydroxyprogesterone (17-OHP) levels—elevated values confirm NCCAH 2
• Alternative diagnostic approach: perform a 2-day dexamethasone suppression test showing significant decreases in testosterone and DHEA-S 2
• This is one of the most common mimickers of PCOS and must be ruled out in every case 1, 2

Cushing's Syndrome

• Consider Cushing's in any woman with recent onset hyperandrogenism accompanied by buffalo hump, moon facies, hypertension, abdominal striae, centripetal fat distribution, easy bruising, or proximal myopathy 1
• Screen with overnight dexamethasone suppression test or 24-hour urinary free cortisol measurement 1, 2
• While rare, Cushing's disease (ACTH-producing pituitary adenoma) must always be considered when coexisting signs of hypercortisolism are present 1, 2

Androgen-Secreting Tumors (Ovarian or Adrenal)

• Severe, rapidly progressive hyperandrogenism with virilization (clitoromegaly, balding, deepening voice) demands immediate evaluation for androgen-secreting tumors 1, 2
• These tumors are rare but present with very high serum androgen levels and recent onset of severe symptoms 2
• Pelvic examination may reveal ovarian enlargement; imaging studies are essential 1
• Total testosterone levels >150-200 ng/dL should raise strong suspicion 2

Hyperprolactinemia

• Mild hyperandrogenism with recent-onset oligomenorrhea should prompt prolactin level measurement 2
• Prolactin disorders can present with similar menstrual irregularities and must be excluded 1

Thyroid Disease

• Measure thyroid-stimulating hormone (TSH) in all women with suspected hyperandrogenism 1
• Thyroid dysfunction can contribute to menstrual irregularities and metabolic disturbances 1

Additional Causes to Consider

Exogenous Androgen Exposure

• Obtain detailed medication history including supplements, performance-enhancing substances, and anabolic steroids 1
• Certain medications like valproate (antiepileptic) can trigger or exacerbate PCOS-like symptoms 3

Acromegaly

• Rare cause but should be considered in the differential diagnosis of androgen excess 1
• Look for characteristic features including acral enlargement and coarse facial features 1

Primary Ovarian or Hypothalamic Disorders

• Primary hypothalamic amenorrhea and primary ovarian failure can present with hormonal abnormalities mimicking PCOS 1
• Genetic defects in insulin action may present similarly to PCOS 1

Critical Clinical Pitfalls

Timing and Onset Matter

• Recent, rapid onset of severe hyperandrogenism suggests tumor or Cushing's syndrome rather than PCOS 2
• PCOS typically begins after menarche with gradual progression 2

Associated Malignancy Risk

• In women with acanthosis nigricans, consider associated insulinoma or malignancy, particularly gastric adenocarcinoma 1
• Obesity, chronic anovulation, and hyperinsulinemia increase endometrial cancer risk 1

Physical Examination Red Flags

• Clitoromegaly strongly suggests virilizing tumor 1
• Rapid progression of hirsutism, severe acne, or male-pattern baldness warrant aggressive workup 1
• Palpable ovarian enlargement on pelvic exam suggests possible tumor 1

Recommended Laboratory Workup Algorithm

Initial screening should include: 1

• TSH (thyroid disease)
• Prolactin level (hyperprolactinemia)
• Total testosterone or free/bioavailable testosterone (degree of hyperandrogenism)
• 17-hydroxyprogesterone (NCCAH screening)
• DHEA-S (adrenal androgen excess)

If clinical suspicion for Cushing's: 1, 2

• Overnight dexamethasone suppression test or 24-hour urinary free cortisol

If severe hyperandrogenism or virilization: 2

• Imaging studies (pelvic ultrasound, adrenal CT/MRI)
• Consider tumor markers