What are the treatment options for primary bilateral macronodular adrenal hyperplasia?

Treatment Options for Primary Bilateral Macronodular Adrenal Hyperplasia

Medical treatment with mineralocorticoid receptor antagonists (MRAs) is the first-line therapy for primary bilateral macronodular adrenal hyperplasia (PBMAH), with unilateral adrenalectomy reserved for severe cases or marked adrenal asymmetry. 1

Primary Treatment Approach

Medical Management (First-Line)

Bilateral adrenal disease makes medical treatment the preferred initial approach because bilateral adrenalectomy requires lifelong glucocorticoid and mineralocorticoid replacement therapy, creating significant treatment burden 1.

Mineralocorticoid Receptor Antagonists

• Spironolactone: Start 25-50 mg daily, titrate up to maximum 400 mg/24h

  • Most widely available and effective MRA
  • Side effects: hyperkalemia, gynecomastia and impotence in males, menstrual irregularities in women, gastrointestinal symptoms 1

• Eplerenone: Start 50 mg twice daily, maximum 200-300 mg/24h

  • Requires 2-3 times higher doses than spironolactone for equivalent efficacy
  • Preferred in men due to lack of anti-androgenic side effects 1
  • Only side effect: hyperkalemia 1

Alternative Medical Agents

• Epithelial sodium channel blockers (amiloride 2.5-10 mg twice daily or triamterene 100 mg twice daily) can be used if MRAs are not tolerated 1

• Cortisol synthesis inhibitors (metyrapone) have demonstrated sustained biochemical control for over 5 years in ARMC5-mutated patients 2

• β-blockers (propranolol) may be effective as adjunctive or alternative therapy, particularly in ARMC5-mutated patients with aberrant β-adrenergic receptor expression 3, 2

Surgical Management (Selective Cases)

Unilateral adrenalectomy should be considered when:

• Severe clinical manifestations of cortisol excess are present
• Marked adrenal asymmetry exists on imaging (remove the larger/more nodular gland) 1
• Baseline 24-hour urinary free cortisol (UFC) is ≤2 times the upper limit of normal AND suppresses with low-dose dexamethasone suppression test (better predictor of remission) 4

Surgical Outcomes

Recent evidence shows variable long-term efficacy:

• Short-term remission rate: 48.89% at 6 months
• Long-term remission rate: only 32% at median 38-month follow-up
• Recurrence occurs in approximately 20% of initial responders 4
• Unilateral total or subtotal adrenalectomy of the more nodular side provides better outcomes than partial adrenalectomy 5, 3

Critical Surgical Decision Points

Adrenal venous sampling (AVS) can help identify functional lateralization in select patients to guide which adrenal to remove, though this is more established for primary aldosteronism than PBMAH 6. The larger adrenal gland typically correlates with greater cortisol secretion 6.

Special Considerations

Coexisting Primary Aldosteronism

Screen for concurrent primary aldosteronism, which occurs in 37-44% of PBMAH patients 5. This significantly impacts treatment selection and monitoring requirements.

Genetic Forms

• ARMC5 mutations (most common genetic cause): Respond to standard medical therapy; consider genetic screening of family members 7, 8
• KDM1A mutations (GIP-dependent PBMAH): May respond to specific GPCR blockers 7
• Glucocorticoid-remediable aldosteronism/Familial hyperaldosteronism type 1: Requires dexamethasone or prednisone at night (lowest effective dose), with MRA added if targets not achieved 1

Treatment Algorithm

1. Confirm bilateral disease and assess cortisol excess severity
2. Screen for coexisting primary aldosteronism (present in ~40% of cases)
3. Initiate MRA therapy (spironolactone or eplerenone based on sex and side effect profile)
4. Monitor potassium and creatinine closely, especially if combining with ACE inhibitors or ARBs
5. Consider unilateral adrenalectomy only if:
   • Severe symptoms persist despite medical therapy
   • Marked asymmetry on imaging (>2:1 size ratio)
   • Baseline 24h UFC ≤2× ULN with suppression on LDDST
   • Patient accepts 68% risk of persistent hypercortisolism long-term
6. If surgery performed: Remove the larger/more nodular gland; total or subtotal adrenalectomy superior to partial

Critical Monitoring

• Hyperkalemia risk requires regular electrolyte monitoring, particularly when MRAs are combined with renin-angiotensin system blockers
• Post-surgical surveillance is mandatory due to high recurrence rates (up to 20%)
• Hypertension and osteoporosis improve with cortisol control but worsen with persistent hypercortisolism 4

Common Pitfalls

Avoid bilateral adrenalectomy except in truly severe, refractory cases, as it mandates lifelong dual hormone replacement 1, 9. The historical approach of bilateral surgery has been largely abandoned in favor of medical management or selective unilateral surgery 5.