Why is medical therapy with mineralocorticoid receptor antagonists (MRAs) the first line of treatment for patients with aldosterone-secreting tumors, but not for those with cortisol-secreting tumors?

Why Medical Therapy is First-Line for Aldosterone-Secreting Tumors but Not Cortisol-Secreting Tumors

Medical therapy with mineralocorticoid receptor antagonists (MRAs) is first-line for aldosterone-secreting tumors because it achieves equivalent long-term outcomes to surgery for blood pressure control, cardiovascular outcomes, and kidney function, whereas cortisol-secreting tumors cannot be effectively controlled medically and require surgical removal to prevent progressive metabolic complications and irreversible target organ damage. 1, 2

Fundamental Differences in Treatment Response

Aldosterone-Secreting Tumors: Medical Therapy is Highly Effective

• MRAs directly block the pathophysiological effects of excess aldosterone at the receptor level, preventing sodium retention, potassium wasting, and aldosterone-mediated cardiovascular damage regardless of whether aldosterone production continues. 3

• Medical therapy with spironolactone or eplerenone achieves blood pressure improvement in virtually 100% of patients with aldosterone-producing adenomas, with complete normalization occurring in approximately 50%—identical to surgical cure rates. 1, 2

• MRAs can reverse aldosterone-specific target organ damage, including left ventricular hypertrophy, albuminuria, and carotid intima-media thickness, making them disease-modifying rather than merely symptomatic treatment. 1

• Studies comparing surgery versus medical therapy for aldosterone-producing adenomas found no difference in blood pressure control, serum potassium levels, or cardiovascular and renal outcomes between the two approaches. 4

Cortisol-Secreting Tumors: Medical Therapy is Inadequate

• No medication can effectively block cortisol's diverse metabolic effects across multiple organ systems (glucose metabolism, protein catabolism, bone remodeling, immune function, psychiatric effects). Unlike aldosterone, which acts primarily through a single receptor in specific tissues, cortisol affects virtually every cell type through multiple mechanisms.

• Cortisol excess causes progressive and often irreversible complications including diabetes, osteoporosis, muscle wasting, cardiovascular disease, and increased mortality that cannot be prevented by receptor blockade. 5

• Delayed treatment of cortisol-secreting tumors leads to irreversible vascular remodeling and metabolic damage that persists even after the tumor is removed, making early surgical intervention critical. 6

• Hormone hypersecretion, particularly cortisol excess, portends an increased risk of recurrence after tumor removal, emphasizing the importance of definitive surgical treatment. 5

Clinical Decision Algorithm

For Aldosterone-Secreting Adenomas:

• Start with MRA therapy (spironolactone 50-100 mg daily or eplerenone 50-100 mg daily) as first-line treatment for all patients, regardless of whether disease is unilateral or bilateral. 1, 2

• Reserve surgery (laparoscopic unilateral adrenalectomy) for patients who: 2

  • Are young with desire to avoid lifelong medication
  • Develop intolerable side effects from MRAs (gynecomastia, sexual dysfunction, hyperkalemia)
  • Have confirmed unilateral disease and explicitly prefer surgical cure

• For elderly patients (>80 years) or those with multiple comorbidities, proceed directly to medical therapy regardless of disease laterality due to substantially elevated perioperative cardiovascular risk. 1

For Cortisol-Secreting Adenomas:

• Proceed directly to surgical removal as the only definitive treatment that prevents progressive metabolic complications. 5, 6

• Administer hydrocortisone perioperatively (150 mg/day during surgery and postoperatively) in all patients with glucocorticoid excess to prevent adrenal crisis. 5

• Medical therapy is reserved only for patients with metastatic or unresectable disease, where it serves as palliative rather than curative treatment. 5

Important Caveats

Co-Secreting Tumors

• Aldosterone- and cortisol-co-secreting tumors are more common than traditionally recognized and require surgical removal due to the cortisol component. 7, 8, 9

• Suspect co-secretion if the aldosterone-producing adenoma is larger than 2.5 cm, cortisol is non-suppressible with overnight low-dose dexamethasone, or serum 18-hydroxy-cortisol is grossly elevated. 9

• Failure to diagnose co-secretion preoperatively can result in postoperative adrenal crisis if glucocorticoid replacement is not provided. 7, 8

Monitoring Requirements for MRA Therapy

• Check potassium and creatinine at 3 days, 7 days, then monthly for the first 3 months, and subsequently every 3 months if stable. 1, 2

• Discontinue MRAs if potassium exceeds 6.0 mEq/L or creatinine rises above 2.5 mg/dL in men or 2.0 mg/dL in women. 1

• Avoid combining MRAs with potassium supplements, potassium-sparing diuretics, ACE inhibitors, ARBs, or NSAIDs without close monitoring due to severe hyperkalemia risk. 2, 3