What is the appropriate workup and treatment for a female patient presenting with hirsutism, intermittent nausea, and headache, suspected of having polycystic ovary syndrome (PCOS) or other hormonal imbalances?

Workup for Hirsutism with Intermittent Nausea and Headache

Initial Diagnostic Approach

Begin with morning (8 AM) blood draw to assess for PCOS, adrenal hyperplasia, and Cushing's disease, as these conditions commonly present with hirsutism and can cause nausea and headache as part of their clinical spectrum. 1

Essential Laboratory Testing

Hormonal Assessment (Morning Collection Required):

• Total testosterone and free testosterone - elevated in 70-80% of hirsute patients with androgen excess 2
• DHEAS (dehydroepiandrosterone sulfate) - to rule out adrenal tumors or non-classical congenital adrenal hyperplasia 3
  • Age 20-29: abnormal if >3800 ng/ml
  • Age 30-39: abnormal if >2700 ng/ml
• Androstenedione - levels >10.0 nmol/L warrant evaluation for adrenal/ovarian tumor 3
• 17-hydroxyprogesterone - to screen for non-classical adrenal hyperplasia 3
• LH and FSH - LH:FSH ratio >2 suggests PCOS 1
• Prolactin - elevated levels may indicate prolactinoma, which can cause headaches 1
• TSH and free T4 - thyroid dysfunction commonly coexists with PCOS 1

Metabolic Assessment:

• Fasting glucose and insulin - glucose:insulin ratio >4 suggests reduced insulin sensitivity associated with PCOS 3
• Fasting glucose >7.8 mmol/L is suggestive of diabetes 3

Cortisol Assessment (Critical for Nausea/Headache Evaluation):

• Morning cortisol and ACTH - to evaluate for Cushing's disease, which presents with hirsutism, nausea, and headache 3, 1
• 24-hour urinary free cortisol (UFC) - if Cushing's suspected 3
• Late-night salivary cortisol - to assess circadian rhythm if Cushing's suspected 4

Imaging Studies

Transvaginal or transabdominal pelvic ultrasound (perform on days 3-9 of menstrual cycle):

• Look for >10 peripheral cysts (2-8 mm diameter) in one plane with thickened ovarian stroma, diagnostic of polycystic ovaries 3
• PCOS prevalence is 4-6% in general population but accounts for 62-70% of hirsutism cases 3, 5

Interpretation Algorithm

If Testosterone Elevated with Normal Cortisol:

• DHEAS >3800 ng/ml (age 20-29) or >2700 ng/ml (age 30-39): Consider non-classical congenital adrenal hyperplasia or adrenal tumor 3
• Androstenedione >10.0 nmol/L: Rule out adrenal/ovarian tumor with CT imaging 3
• LH:FSH ratio >2 with polycystic ovaries on ultrasound: Diagnose PCOS 1
• Normal androgens with hirsutism: Idiopathic hirsutism (5-15% of cases) 2

If Cortisol Elevated with Hirsutism:

• Elevated UFC with hirsutism, nausea, and headache: Cushing's disease is likely - nausea and headache occur in 8-11% of Cushing's patients 3
• Proceed with dexamethasone suppression testing 6
• Consider pituitary MRI if biochemical Cushing's confirmed 3

If Prolactin Elevated:

• Prolactinoma can cause headaches, hirsutism, and nausea 1
• Obtain pituitary MRI 1

Critical Timing Considerations

Morning collection (8 AM) is mandatory for accurate interpretation of ACTH, cortisol, testosterone, LH, and FSH 1. Testing must be performed before any steroid administration, as corticosteroids suppress the hypothalamic-pituitary axis and confound results 1.

For menstruating women, FSH and LH should be collected during early follicular phase (days 2-5) for baseline assessment 1.

Common Pitfalls to Avoid

• Do not assume eumenorrhea rules out PCOS - 40% of PCOS patients with hirsutism have regular menses 5
• Do not measure cortisol in patients on hormonal contraceptives without adjusting for elevated cortisol-binding globulin - measure free cortisol index (total cortisol ÷ CBG) instead, or discontinue contraceptives for 2 months before testing 4
• Do not initiate thyroid hormone replacement before addressing potential adrenal insufficiency, as this can precipitate adrenal crisis 4
• Do not rely on single time-point measurements - androgen levels are pulsatile and may require frequent sampling to detect subtle hyperandrogenic states 6

Additional Evaluation for Nausea and Headache

While hirsutism points toward endocrine etiology, the combination of nausea and headache warrants specific consideration of Cushing's disease, where these symptoms occur as adverse effects of hypercortisolism 3. If Cushing's is confirmed, medical therapies like osilodrostat cause nausea and headache in 8-11% of patients, but these are typically manageable 3.

If initial endocrine workup is negative, consider neuroimaging (MRI brain) to evaluate for other causes of headache, particularly if headaches are severe, progressive, or associated with visual changes.