How to manage resistant hypertension in patients with Cushing's syndrome?

Management of Resistant Hypertension in Cushing's Syndrome

Mineralocorticoid receptor antagonists (spironolactone or eplerenone) should be the cornerstone of antihypertensive therapy for resistant hypertension in patients with Cushing's syndrome, combined with definitive treatment of the underlying hypercortisolism. 1, 2

Pathophysiology of Hypertension in Cushing's Syndrome

Hypertension is extremely common in Cushing's syndrome, affecting approximately 80% of adult patients 3. The mechanisms responsible include:

• Mineralocorticoid receptor activation by excess cortisol 1, 3
• Activation of the renin-angiotensin system 3
• Enhanced sensitivity to vasoconstrictors 3
• Suppression of vasodilatory systems 3
• Increased peripheral vascular resistance 4
• Vascular remodeling 4

Diagnostic Confirmation

Before initiating treatment for resistant hypertension in Cushing's syndrome:

1. Confirm the diagnosis of true resistant hypertension:

   • Exclude pseudoresistance (white coat hypertension, medication non-adherence)
   • Use ambulatory blood pressure monitoring (ABPM) or home BP monitoring 1

2. Verify the diagnosis of Cushing's syndrome:

   • Exclude exogenous glucocorticoid use
   • Perform at least two positive screening tests:
     • 24-hour urinary free cortisol
     • Late-night salivary cortisol
     • 1 mg dexamethasone suppression test 2

Treatment Algorithm

Step 1: Definitive Treatment of Cushing's Syndrome

• Surgical approach (first-line):

  • Transsphenoidal adenomectomy for Cushing's disease
  • Unilateral adrenalectomy for adrenal Cushing's syndrome
  • Resection of primary tumor for ectopic ACTH-producing tumors 2

• Medical therapy (when surgery is delayed, contraindicated, or unsuccessful):

  • Steroidogenesis inhibitors: ketoconazole (400-1200 mg/day) or metyrapone (500-6000 mg/day) 2, 5
  • Glucocorticoid receptor antagonist: mifepristone (particularly useful in patients with diabetes) 2, 3

Step 2: Antihypertensive Therapy

1. First-line agents:

   • Mineralocorticoid receptor antagonists: spironolactone or eplerenone 1, 2
     • Directly addresses the mineralocorticoid activity of excess cortisol
     • Shown to be most effective in Cushing's syndrome hypertension

2. Second-line agents (add if BP remains uncontrolled):

   • ACE inhibitors or Angiotensin II receptor blockers 1, 3
     • Target the activated renin-angiotensin system

3. Additional agents (if needed):

   • PPAR-γ agonists may help address insulin resistance components 3
   • Calcium channel blockers (though often less effective as monotherapy) 1, 5

Step 3: Avoid Ineffective Agents

• Thiazides and furosemide should be avoided 3
• Adrenergic blockers are usually ineffective 3

Monitoring and Follow-up

• Regular BP monitoring to assess treatment efficacy
• Monitor for electrolyte abnormalities, particularly with mineralocorticoid receptor antagonists
• Assess for improvement in other Cushing's-related comorbidities (glucose intolerance, dyslipidemia)
• Long-term follow-up is essential, as hypertension may persist in approximately 30% of patients even after successful treatment of Cushing's syndrome 4

Clinical Pearls and Pitfalls

• Key pitfall: Relying solely on conventional antihypertensive therapy without addressing the underlying hypercortisolism. A study showed that conventional antihypertensive therapy alone normalized BP in only 4 of 28 patients with Cushing's syndrome 5.

• Important consideration: Blood pressure normalization is most effectively achieved after restoration of normal cortisol levels, highlighting the need for specific treatment targeting the underlying cause 5.

• Treatment challenge: Even after successful treatment of Cushing's syndrome, hypertension may persist in approximately 30% of patients, requiring ongoing antihypertensive therapy 4.