When to initiate levothyroxine (thyroid hormone replacement) treatment in a patient with primary adrenal insufficiency and coexisting hypothyroidism?

When to Initiate Levothyroxine in Primary Adrenal Insufficiency with Hypothyroidism

Always start glucocorticoid replacement several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 1

Critical Sequencing Rule

The fundamental principle is that corticosteroids must be started first and stabilized before any thyroid hormone is given. 1, 2 This is because thyroid hormone increases metabolic rate and cortisol clearance, which can unmask or worsen adrenal insufficiency and trigger life-threatening adrenal crisis in patients with inadequate glucocorticoid coverage. 1, 2

Step-by-Step Treatment Algorithm

Step 1: Initiate Glucocorticoid Replacement First

• Start hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, and 2.5-5 mg at 4 PM) immediately upon diagnosis of primary adrenal insufficiency. 2, 3
• Add fludrocortisone 50-200 mcg daily as a single morning dose for mineralocorticoid replacement in primary adrenal insufficiency. 2, 3
• Wait a minimum of several days (typically 3-7 days) to ensure the patient is stable on glucocorticoid replacement before introducing levothyroxine. 1

Step 2: Assess Clinical Stability Before Adding Levothyroxine

Before initiating thyroid hormone, confirm the patient has:

• Stable blood pressure without orthostatic hypotension (indicating adequate mineralocorticoid replacement). 1
• Resolution of acute symptoms like severe weakness, nausea, or salt craving. 2
• Normal or near-normal serum sodium and potassium levels. 1
• No signs of impending adrenal crisis. 1, 2

Step 3: Initiate Levothyroxine at Appropriate Dose

• Start levothyroxine at weight-based dosing (typically 1.6 mcg/kg/day for younger patients, lower doses for elderly or those with cardiac disease). 1
• In patients with coexisting adrenal insufficiency, some clinicians prefer starting at a lower dose (25-50 mcg daily) and titrating up gradually to minimize metabolic stress, though this is not explicitly mandated by guidelines. 4

Step 4: Monitor Free T4, Not TSH

• Use free T4 (FT4) levels to guide thyroid hormone replacement titration, not TSH. 1
• In patients with central hypothyroidism (which can coexist with adrenal insufficiency in hypopituitarism), TSH is unreliable and will remain low or inappropriately normal. 1, 2
• Even in primary hypothyroidism with primary adrenal insufficiency, initial monitoring should focus on FT4 to ensure adequate replacement. 1

Common Clinical Scenarios

Scenario 1: Newly Diagnosed Primary Adrenal Insufficiency + Primary Hypothyroidism

• Start hydrocortisone and fludrocortisone immediately. 2, 3
• Wait 3-7 days until glucocorticoid replacement is stable. 1
• Then initiate levothyroxine, monitoring FT4 every 4-6 weeks until stable. 1
• Screen thyroid function annually thereafter, as hypothyroidism frequently develops or worsens in autoimmune adrenal insufficiency. 1

Scenario 2: Known Adrenal Insufficiency on Stable Replacement + New Hypothyroidism Diagnosis

• Verify the patient is on adequate glucocorticoid replacement (no symptoms of under-replacement like fatigue, weight loss, nausea). 1
• If glucocorticoid dosing is adequate and stable, levothyroxine can be initiated without delay. 1
• However, educate the patient to increase their hydrocortisone dose by 25-50% during the first 2-4 weeks of levothyroxine initiation to account for increased cortisol metabolism. 2

Scenario 3: Hypopituitarism with Central Hypothyroidism + Secondary Adrenal Insufficiency

• Start hydrocortisone first (fludrocortisone is not needed in secondary adrenal insufficiency). 1, 2
• Wait several days for stabilization. 1
• Initiate levothyroxine, using FT4 (not TSH) for monitoring. 1

Critical Pitfalls to Avoid

• Never start levothyroxine before or simultaneously with glucocorticoid replacement in untreated adrenal insufficiency—this can precipitate acute adrenal crisis with potentially fatal consequences. 1, 2
• Do not rely on TSH alone in patients with known or suspected pituitary disease, as central hypothyroidism presents with low FT4 and low or inappropriately normal TSH. 1, 2
• Do not assume adequate adrenal replacement based solely on normal electrolytes—hyperkalemia is present in only 50% of primary adrenal insufficiency cases. 2
• Ensure patients understand stress-dosing protocols (doubling or tripling glucocorticoid dose during illness) and carry emergency injectable hydrocortisone. 2, 3

Annual Monitoring Requirements

Once both conditions are treated and stable:

• Monitor thyroid function (TSH, FT4) every 12 months in primary adrenal insufficiency patients, as autoimmune hypothyroidism frequently develops or progresses. 1
• Assess adequacy of glucocorticoid replacement by evaluating symptoms, weight stability, blood pressure, and electrolytes. 1
• Check for signs of glucocorticoid over-replacement (weight gain, insomnia, edema) or under-replacement (fatigue, nausea, weight loss, hyperpigmentation). 1, 3
• Evaluate mineralocorticoid adequacy by assessing for salt craving, orthostatic hypotension, and plasma renin activity. 1, 5