How to manage hypocortisolism (low cortisol levels)?

Management of Hypocortisolism (Low Cortisol Levels)

Initiate hydrocortisone replacement therapy at 15-20 mg daily in divided doses (two-thirds in the morning, one-third in the afternoon), with weight-adjusted dosing preferred to minimize interpatient variability and optimize cortisol exposure. 1

Diagnostic Workup

Before initiating treatment, obtain the following to establish the diagnosis and etiology:

• Morning ACTH and cortisol levels to differentiate primary (low cortisol with high ACTH) from secondary adrenal insufficiency (low cortisol with low ACTH) 1
• Basic metabolic panel to identify electrolyte abnormalities, particularly hyponatremia and hyperkalemia in primary adrenal insufficiency 1
• MRI of the brain with pituitary/sellar cuts if multiple endocrine abnormalities are present or new severe headaches suggest a pituitary/hypothalamic cause 1

Initial Treatment Algorithm

Mild to Moderate Symptoms (Outpatient Setting)

Start with hydrocortisone 15-20 mg daily in divided doses, administered as follows 1:

• Two-thirds of the total dose in the morning (upon waking, ideally 6-8 AM)
• One-third in the early afternoon (12-2 PM)
• Administer before meals to optimize absorption 2

Weight-adjusted dosing is superior to fixed dosing, reducing interpatient variability in cortisol exposure from 50% to 22% and decreasing overexposure to less than 5% 2. Body weight is the most important predictor of hydrocortisone clearance 2.

Consider thrice-daily dosing (e.g., morning-midday-afternoon) rather than twice daily, as twice-daily regimens result in very low cortisol levels by mid-afternoon (16:00-18:00 hours), and patients often report improved well-being with thrice-daily administration 3.

Primary Adrenal Insufficiency (Addison's Disease)

Add fludrocortisone 0.05-0.1 mg daily to replace mineralocorticoid function, as primary adrenal insufficiency affects both glucocorticoid and mineralocorticoid production 1.

• Monitor blood pressure and serum electrolytes regularly 4
• Adjust fludrocortisone dose based on blood pressure, potassium, and renin levels 4

Moderate Symptoms Requiring Higher Initial Dosing

For more symptomatic patients, initiate hydrocortisone 30-50 mg total daily dose or prednisone 20 mg daily 1. Remember that hydrocortisone 20 mg is equivalent to prednisone 5 mg 1.

Critical Illness or Adrenal Crisis

Administer hydrocortisone 100 mg IV bolus immediately, followed by either 5, 6:

• Continuous infusion of 200 mg over 24 hours, OR
• 50 mg IV/IM every 6 hours (total 200 mg/24 hours)

Continue stress-dose therapy until the patient is clinically stable, typically 48-72 hours, then taper to double the maintenance dose for 48 hours to one week before resuming standard replacement 5.

Medication Selection and Equivalency

Hydrocortisone is preferred over long-acting steroids like prednisone because it better recreates the diurnal rhythm of cortisol, with its shorter half-life of approximately 1.5 hours 1, 7.

Glucocorticoid equivalency 1:

• Hydrocortisone 20 mg = Prednisone 5 mg
• Use this conversion when switching between formulations

Critical Safety Considerations

When Both Glucocorticoid and Thyroid Replacement Are Needed

Always start glucocorticoids first before initiating thyroid hormone replacement to prevent precipitating adrenal crisis, as thyroid hormone increases cortisol metabolism 1.

Monitoring for Overreplacement

Reduce maintenance dosing if signs of iatrogenic Cushing's syndrome develop, including 1:

• Easy bruising
• Thin skin
• Edema
• Weight gain
• Hypertension
• Hyperglycemia

A single serum cortisol measurement 4 hours after hydrocortisone administration predicts cortisol AUC (r² = 0.78) and can be used to monitor adequacy of replacement 2.

Stress Dosing Education (Critical for All Patients)

All patients must understand stress dosing principles and double or triple their oral doses during illness, injury, or physiologic stress 1, 8. This is non-negotiable patient education.

Provide emergency injectable hydrocortisone (100 mg IM) with instructions for use in situations where oral intake is not possible (vomiting, severe illness, trauma) 1.

Recommend a medical alert bracelet indicating adrenal insufficiency to ensure appropriate treatment in emergencies 1.

Specific Stress Dosing Protocols

• Minor illness (cold, mild infection): Double the usual dose 1
• Moderate illness (fever, gastroenteritis): Triple the usual dose 1
• Severe illness, vomiting, or inability to take oral medication: Administer 100 mg hydrocortisone IM and seek immediate medical attention 1

Perioperative Management

For surgery under general anesthesia, administer hydrocortisone 100 mg IV at induction, followed by 5:

• 200 mg/24 hours as continuous infusion OR
• 50 mg IV/IM every 6 hours

After uncomplicated surgery, double the regular oral replacement dose for 48 hours, extending up to one week for major surgery before resuming maintenance dosing 5.

Special Populations

Pediatric Patients

Administer 2 mg/kg IV hydrocortisone at induction for surgery, followed by 2 mg/kg every 4 hours postoperatively or continuous infusion for major procedures 5. No child with adrenal insufficiency should be fasted for more than 6 hours 5.

Patients with Multiple Hormone Deficiencies

After establishing adequate cortisol replacement, consider testosterone or estrogen replacement in patients with multiple pituitary hormone deficiencies 1.

DHEA replacement (25-50 mg daily) may be considered in women with low libido and/or persistent fatigue despite adequate cortisol replacement 1.

Common Pitfalls to Avoid

• Never abruptly discontinue glucocorticoid therapy after long-term use; taper gradually to avoid drug-induced secondary adrenal insufficiency, which may persist for months 8
• Do not use fixed dosing for all patients; weight-adjusted dosing significantly reduces variability in cortisol exposure 2
• Avoid twice-daily dosing if patients report afternoon fatigue; thrice-daily dosing maintains more stable cortisol levels throughout the day 3
• Do not forget mineralocorticoid replacement in primary adrenal insufficiency; fludrocortisone is essential and not provided by hydrocortisone alone at physiologic doses 1
• Remember that stress dosing is required for up to one year after discontinuing chronic glucocorticoid therapy, even if the underlying adrenal insufficiency has resolved 8