What is the differential diagnosis and recommended workup for a 28-year-old female with hirsutism, hair thinning, facial swelling, constipation, and elevated cortisol and androstenedione levels, despite normal testosterone levels?

Differential Diagnosis and Workup

Primary Differential Diagnosis

This patient most likely has nonclassical congenital adrenal hyperplasia (NCCAH), specifically 3β-hydroxysteroid dehydrogenase deficiency, given her elevated androstenedione and cortisol with normal testosterone, combined with hirsutism, hair thinning, and severe constipation requiring disimpaction. 1

Key Differential Diagnoses to Consider:

1. Nonclassical Congenital Adrenal Hyperplasia (NCCAH)

• 3β-hydroxysteroid dehydrogenase deficiency is characterized by markedly elevated androstenedione and DHEA with disproportionately normal or mildly elevated testosterone 1
• Presents with hirsutism, acne, androgenic alopecia in peri- and postpubertal women 1
• The elevated cortisol suggests adrenal involvement 1
• Her thin body habitus argues against PCOS-related insulin resistance 2

2. 21-hydroxylase Deficiency (Less Likely)

• Would typically show markedly elevated 17-hydroxyprogesterone after ACTH stimulation 3
• Can present with hirsutism and menstrual irregularities 2
• However, the pattern of elevated androstenedione with normal testosterone is more consistent with 3β-HSD deficiency 1

3. Polycystic Ovary Syndrome (PCOS) - Lower on Differential

• Typically presents with elevated testosterone, not just androstenedione 2
• Usually associated with obesity and insulin resistance, which this patient lacks 2
• Her normal testosterone makes classic PCOS less likely 4

4. Cushing's Syndrome

• Elevated cortisol warrants consideration 2
• However, she is very thin rather than having central obesity, moon facies, or violaceous striae 2
• Constipation and facial swelling could fit, but the overall presentation is atypical 2

5. Hypothyroidism

• Can cause constipation, hair thinning, and facial swelling (myxedema) 2
• Should be ruled out as a contributing factor 2

Recommended Workup

Essential Initial Testing:

Hormonal Evaluation:

• ACTH stimulation test - This is the single most important test to diagnose NCCAH and differentiate between enzyme deficiencies 3

  • Measure: 17-hydroxypregnenolone (Δ5-17P), DHEA, 17-hydroxyprogesterone (17-OHP), androstenedione, cortisol, progesterone, and 11-deoxycortisol 3
  • Calculate ratios: Δ5-17P to 17-OHP ratio >11 suggests 3β-HSD deficiency 1
  • Calculate DHEA to androstenedione ratio >7.5 supports 3β-HSD deficiency 1
  • Basal steroid levels alone are NOT predictive and can be misleading 3

• Morning cortisol and dexamethasone suppression test - To evaluate for Cushing's syndrome given her elevated cortisol 2, 5

  • Overnight 1-mg dexamethasone suppression test 2, 5
  • 24-hour urinary free cortisol if Cushing's suspected 2, 5

• Thyroid function tests - TSH and free T4 to rule out hypothyroidism as cause of constipation, hair loss, and facial swelling 2, 5

• Complete androgen panel with high-quality assays:

  • Free and total testosterone using radioimmunoassay with extraction/chromatography or mass spectrometry 4
  • DHEA-sulfate 2
  • Repeat androstenedione 2

Ovarian Assessment:

• LH, FSH, and progesterone - Measured on days 3-6 of cycle to assess for PCOS 2

  • LH/FSH ratio >2 suggests PCOS 2
  • Mid-luteal progesterone <6 nmol/L indicates anovulation 2

• Pelvic ultrasound (transvaginal preferred) - To evaluate for polycystic ovaries 2

  • Perform on days 3-9 of cycle 2

  • 10 peripheral cysts (2-8mm) suggests PCOS 2

Metabolic Evaluation:

• Fasting glucose and insulin - To assess insulin resistance despite thin habitus 2
• Prolactin - Morning resting level to rule out hyperprolactinemia 2
  • Must not be measured post-ictally 2

  • 20 μg/L is abnormal 2

Important Clinical Caveats:

Critical Pitfalls to Avoid:

• Do NOT rely on basal DHEA-sulfate levels alone - 61% of women with hirsutism have subtle adrenal enzyme defects that require ACTH stimulation to detect, and basal levels correlate poorly with ACTH response 3
• Do NOT use standard testosterone assays - Require high-quality assays (mass spectrometry or RIA with extraction) for accurate measurement in women 4
• Do NOT assume PCOS based on hirsutism alone - Her normal testosterone and thin body habitus make NCCAH more likely 1, 3
• Oral contraceptives can worsen constipation - As she experienced, and may mask underlying hormonal abnormalities 2

Regarding Her Severe Constipation:

• The need for ER disimpaction is concerning and warrants gastroenterology evaluation if not already done
• Hypothyroidism must be ruled out 2
• Consider evaluation for other causes of severe constipation if endocrine workup is unrevealing

Facial Swelling Considerations:

• Could represent myxedema from hypothyroidism 2
• Could represent Cushingoid features, though other stigmata are absent 2
• Warrants careful thyroid and cortisol evaluation 2, 5