Is fludrocortisone and hydrocortisone (cortisol) therapy preferred over hydrocortisone (cortisol) alone in patients with adrenal insufficiency?

Combination Therapy of Fludrocortisone and Hydrocortisone for Adrenal Insufficiency

In patients with primary adrenal insufficiency, combination therapy with fludrocortisone and hydrocortisone is strongly preferred over hydrocortisone alone to ensure optimal management of both glucocorticoid and mineralocorticoid deficiencies. 1, 2

Rationale for Combination Therapy

• Primary adrenal insufficiency (PAI) requires replacement of both glucocorticoids and mineralocorticoids, as the adrenal cortex normally produces both hormone types 1
• Fludrocortisone is specifically designed to replace the mineralocorticoid component, which is vital for maintaining blood pressure, water and electrolyte homeostasis 1
• The FDA label for fludrocortisone explicitly states that in Addison's disease, "the combination of fludrocortisone acetate tablets with a glucocorticoid such as hydrocortisone or cortisone provides substitution therapy approximating normal adrenal activity with minimal risks of unwanted effects" 2
• Under-replacement of mineralocorticoids is common and possibly predisposes patients to recurrent adrenal crises 1

Standard Dosing Regimens

Glucocorticoid Replacement

• Hydrocortisone: 15-25 mg/day in divided doses (typically three doses at 07:00,12:00, and 16:00) 1
• Common regimens include:
  • 10 mg + 5 mg + 2.5 mg
  • 15 mg + 5 mg + 5 mg
  • 10 mg + 5 mg + 5 mg 1

Mineralocorticoid Replacement

• Fludrocortisone: 50-200 μg (0.05-0.2 mg) daily, usually taken as a single dose upon awakening 1, 2
• The FDA-recommended starting dose is 0.1 mg daily 2
• Higher doses (up to 500 μg daily) may be needed in children, younger adults, or during pregnancy 1

Clinical Monitoring and Dose Adjustment

• Mineralocorticoid replacement should be evaluated by:

  • Asking about salt cravings or lightheadedness
  • Measuring blood pressure in supine and standing positions (to detect postural hypotension)
  • Checking for peripheral edema
  • Monitoring serum sodium and potassium levels
  • Measuring plasma renin activity (aim for upper normal range) 1, 3, 4

• Signs of inadequate mineralocorticoid replacement:

  • Postural hypotension
  • Salt craving
  • Hyperkalemia
  • Hyponatremia
  • Elevated plasma renin activity 3, 4

• Signs of excessive mineralocorticoid replacement:

  • Hypertension
  • Edema
  • Hypokalemia
  • Suppressed plasma renin activity 1

Common Pitfalls and Considerations

• Overreplacement with glucocorticoids: Often occurs as compensation for inadequate mineralocorticoid replacement 1, 4
• Underreplacement with fludrocortisone: Studies suggest many PAI patients may be underreplaced with mineralocorticoids, as symptoms like salt craving and postural dizziness persist 4
• Drug interactions: Several medications can interact with both hydrocortisone and fludrocortisone:
  • Medications requiring increased hydrocortisone: Anti-epileptics, barbiturates, antituberculosis drugs, etomidate, topiramate 1
  • Medications to avoid with fludrocortisone: Diuretics, acetazolamide, carbenoxolone, NSAIDs 1
  • Phenytoin can dramatically increase fludrocortisone requirements 5
• Dietary considerations: Patients should eat sodium salt and salty foods without restriction and avoid potassium-containing salts 1
• Essential hypertension: Should be treated with vasodilators rather than by stopping mineralocorticoid replacement, although dose reduction may be considered 1

Long-term Management

• Regular monitoring is essential to evaluate replacement therapy adequacy and quality of life 1
• Annual follow-up should include assessment of:
  • Blood pressure (supine and standing)
  • Electrolytes (sodium, potassium)
  • Plasma renin activity when mineralocorticoid deficiency is suspected 1, 3
• Fludrocortisone dose may need to be reduced in long-term follow-up (>60 months) 3
• Inadequate mineralocorticoid replacement may contribute to poor cardiometabolic outcomes in PAI patients 4

Special Situations

• Adrenal crisis: Requires immediate high-dose hydrocortisone (100 mg bolus followed by 100-300 mg/day) and fluid replacement; mineralocorticoid replacement should be restarted when hydrocortisone dose falls below 50 mg/day 1
• Pregnancy: May require higher fludrocortisone doses (up to 500 μg daily) in the third trimester due to progesterone's antimineralocorticoid effects 1
• Stress situations: Require increased glucocorticoid doses but generally not increased fludrocortisone 1