Hydrocortisone Management in Hypothyroidism with Adrenal Insufficiency
In patients with both hypothyroidism and adrenal insufficiency, hydrocortisone (or another glucocorticoid) must ALWAYS be started several days before initiating or increasing levothyroxine to prevent precipitating a life-threatening adrenal crisis. 1
This is a non-negotiable safety principle: thyroid hormone replacement increases metabolic rate and cortisol clearance, which can unmask or worsen adrenal insufficiency if glucocorticoid replacement is not already established 1, 2.
Critical Diagnostic Sequence
Before starting levothyroxine in any patient with suspected central hypothyroidism or multiple pituitary hormone deficiencies:
- Measure morning (8 AM) cortisol and ACTH levels to assess for concurrent adrenal insufficiency 1
- If morning cortisol is <250 nmol/L (<9 μg/dL) with low or inappropriately normal ACTH, this indicates secondary adrenal insufficiency requiring immediate glucocorticoid replacement 1
- Perform cosyntropin stimulation test (0.25 mg IV or IM) if initial cortisol is indeterminate (250-400 nmol/L), with peak cortisol <500 nmol/L diagnostic of adrenal insufficiency 1
Never delay treatment of suspected adrenal crisis for diagnostic testing—if the patient is clinically unstable with hypotension, give hydrocortisone 100 mg IV immediately plus 0.9% saline infusion 1
Hydrocortisone Dosing Protocol
Step 1: Initiate Glucocorticoid Replacement FIRST
- Start hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM) to mimic physiological cortisol secretion 1
- Alternative regimens include cortisone acetate 25-37.5 mg daily or prednisolone 4-5 mg daily 1
- For primary adrenal insufficiency, add fludrocortisone 0.05-0.1 mg daily for mineralocorticoid replacement 1
Step 2: Wait at Least 1 Week Before Starting Levothyroxine
- This waiting period allows glucocorticoid levels to stabilize and prevents the increased cortisol metabolism that occurs when thyroid hormone is introduced 1, 2
- In cases of severe adrenal insufficiency or adrenal crisis, wait until the patient is clinically stable on hydrocortisone before introducing levothyroxine 1
Step 3: Initiate Levothyroxine at Appropriate Dose
- For patients <70 years without cardiac disease: start levothyroxine 1.6 mcg/kg/day (full replacement dose) 3
- For patients >70 years or with cardiac disease: start at 25-50 mcg/day and titrate gradually 3
- Monitor TSH and free T4 every 6-8 weeks during titration 3
Physiological Rationale
Why glucocorticoids must precede thyroid hormone:
- Glucocorticoid deficiency causes reversible elevation of TSH and can mimic primary hypothyroidism 4, 5
- In some patients with isolated adrenal insufficiency, TSH elevation resolves completely with hydrocortisone replacement alone, without requiring levothyroxine 5
- Thyroid hormone increases metabolic rate and accelerates cortisol clearance, which can precipitate adrenal crisis in patients with marginal adrenal reserve 2
- Adequate glucocorticoids are required for normal thyroid hormone metabolism and peripheral conversion of T4 to T3 6, 4
Monitoring During Combined Therapy
After initiating both medications:
- Recheck TSH and free T4 at 6-8 weeks after starting or adjusting levothyroxine 3
- Monitor for signs of glucocorticoid under-replacement: morning nausea, fatigue, hypotension, hyponatremia 1
- Monitor for signs of glucocorticoid over-replacement: weight gain, hyperglycemia, hypertension 1
- Assess mineralocorticoid adequacy (in primary adrenal insufficiency) by checking orthostatic blood pressure, sodium levels, and plasma renin activity 1
Target ranges:
- TSH: 0.5-4.5 mIU/L for primary hypothyroidism 3
- Free T4: within normal reference range 3
- Morning cortisol: not useful for monitoring replacement therapy once established 1
Special Clinical Scenarios
Adrenal Crisis Prevention
- All patients need education on stress dosing: double or triple hydrocortisone dose during illness, fever, or physical stress 1
- Prescribe hydrocortisone 100 mg IM injection kit with self-injection training 1
- Patients must wear medical alert bracelet indicating adrenal insufficiency 1
Perioperative Management
- Minor stress: double usual daily dose for 1-2 days 1
- Moderate stress: hydrocortisone 50-75 mg daily 1
- Major stress/surgery: hydrocortisone 100-150 mg daily 1
Drug Interactions Affecting Hydrocortisone Requirements
- Medications that increase hydrocortisone requirements: anti-epileptics, rifampin, antifungals, etomidate 1
- Medications that decrease hydrocortisone requirements: grapefruit juice, licorice 1
Critical Pitfalls to Avoid
- Never start or increase levothyroxine before establishing glucocorticoid replacement in patients with suspected central hypothyroidism or hypopituitarism 1, 2
- Do not assume hypothyroidism is permanent in patients with adrenal insufficiency—TSH elevation may resolve with hydrocortisone alone 5
- Do not rely on TSH alone in suspected central hypothyroidism—measure free T4 alongside TSH, as TSH may be low, normal, or even mildly elevated despite low thyroid hormone levels 1
- Avoid using dexamethasone for chronic replacement therapy—it lacks mineralocorticoid activity and is inadequate for primary adrenal insufficiency 1
- In primary adrenal insufficiency, do not forget mineralocorticoid replacement with fludrocortisone, as glucocorticoids alone are insufficient 1
Evidence Quality Considerations
The recommendation to start glucocorticoids before thyroid hormone is based on high-quality guideline evidence from multiple endocrine societies 1 and supported by case reports demonstrating reversible TSH elevation with glucocorticoid replacement alone 4, 5 and documented adrenal crises precipitated by thyroid hormone initiation in glucocorticoid-deficient patients 7, 6, 2. This represents a critical safety principle with potentially fatal consequences if violated.