What is the treatment plan for a patient with central hypothyroidism (low Thyroid hormone (T4) with inappropriately low Thyroid-stimulating hormone (TSH))?

Treatment Plan for Central Hypothyroidism

Immediate Diagnostic Workup

Before initiating any thyroid hormone replacement, you must evaluate for concurrent pituitary hormone deficiencies, particularly adrenal insufficiency, as starting levothyroxine before corticosteroids can precipitate life-threatening adrenal crisis. 1, 2, 3

Required Morning Laboratory Tests

• ACTH and cortisol (drawn at 8 AM) to assess for central adrenal insufficiency, which occurs in >75% of patients with hypophysitis 1
• TSH and free T4 to confirm central hypothyroidism and establish baseline 1
• FSH, LH, and testosterone (males) or estradiol (premenopausal females) to evaluate for hypogonadotropic hypogonadism, present in approximately 50% of patients with panhypopituitarism 1
• Prolactin to assess for hyperprolactinemia or prolactin deficiency 1
• Consider standard-dose ACTH stimulation testing if morning cortisol is indeterminate (>3 mg/dL and <15 mg/dL) 1

Imaging Studies

• MRI brain with contrast and dedicated pituitary/sellar cuts is essential for all patients with new hormonal deficiencies, particularly those with multiple endocrine abnormalities 1
• MRI findings may show pituitary enlargement, stalk thickening, suprasellar convexity, or heterogeneous enhancement in hypophysitis 1

Treatment Algorithm

Step 1: Address Adrenal Insufficiency FIRST

If central adrenal insufficiency is confirmed (low morning cortisol with low/normal ACTH), initiate hydrocortisone 15-20 mg daily in divided doses BEFORE starting thyroid hormone replacement. 1, 2, 3

• Typical dosing: hydrocortisone 10 mg upon waking, 5 mg at noon, and 2.5-5 mg in early afternoon 1
• Alternative: prednisone 5 mg daily as maintenance after any initial pulse-dose therapy 1
• Critical safety point: Starting thyroid hormone before corticosteroids accelerates cortisol metabolism and can trigger adrenal crisis 1, 2

Step 2: Initiate Levothyroxine Replacement

Once adrenal insufficiency is addressed (or ruled out), start levothyroxine with dosing based on age and cardiac status. 4, 2

Dosing Guidelines:

• For patients <70 years without cardiac disease: Start with full replacement dose of approximately 1.6 mcg/kg/day 5, 4
• For patients >70 years or with cardiac disease/multiple comorbidities: Start with lower dose of 25-50 mcg/day and titrate gradually 5, 4
• Administer as single daily dose on empty stomach, 30-60 minutes before breakfast 4

Step 3: Monitoring and Titration

For central hypothyroidism, TSH is NOT a reliable marker—use free T4 to guide therapy. 4, 2, 6, 7

Monitoring Protocol:

• Target free T4 in the upper half of the normal reference range (TSH cannot be used for monitoring in central hypothyroidism) 1, 4, 2, 6, 7
• Recheck free T4 every 6-8 weeks during dose titration until target achieved 5, 4
• Titrate levothyroxine by 12.5-25 mcg increments based on free T4 levels and clinical response 5, 4
• Once stable, monitor free T4 every 6-12 months or if symptoms change 5

Management of Other Hormone Deficiencies

Hypogonadism Treatment (if confirmed):

• Testosterone replacement in males without contraindications (e.g., prostate cancer) 1
• Estrogen therapy in premenopausal females without contraindications (e.g., breast cancer, DVT history) 1
• Initiate only AFTER adrenal replacement is established 1

Patient Education Requirements:

All patients with adrenal insufficiency require comprehensive education on: 1

• Stress dosing protocols for sick days (typically double or triple maintenance dose)
• Use of emergency injectable hydrocortisone
• When to seek immediate medical attention for impending adrenal crisis
• Medical alert bracelet or necklace for adrenal insufficiency 1

Critical Pitfalls to Avoid

• Never start thyroid hormone before ruling out and treating adrenal insufficiency in patients with suspected central hypothyroidism—this is the most dangerous error 1, 2, 3
• Do not use TSH to monitor therapy in central hypothyroidism; TSH remains inappropriately low/normal despite adequate or inadequate replacement 1, 4, 2, 6, 7
• Do not overlook evaluation of other pituitary axes—approximately 50% have panhypopituitarism requiring multiple hormone replacements 1
• Avoid overtreatment—excessive levothyroxine increases risk for atrial fibrillation, osteoporosis, and cardiac complications 5, 2
• ACTH stimulation testing can give false-negative results early in hypophysitis as adrenal reserve declines slowly; when uncertain, opt for replacement and retest at 3 months 1

Special Considerations for Immune Checkpoint Inhibitor-Related Hypophysitis

If this patient's central hypothyroidism is related to immune checkpoint inhibitor therapy:

• Median time to onset is 8-9 weeks after starting ipilimumab (or after third dose) 1
• Consider oral pulse-dose corticosteroids (prednisone 1 mg/kg/day) if MRI shows significant pituitary swelling, optic chiasm compression, or severe headache, then taper over 1-2 weeks to physiologic maintenance 1
• Most hormonal deficiencies are permanent and require lifelong replacement 1
• Continue immune checkpoint inhibitor therapy once patient is stabilized on hormone replacement (for grades 1-2) 1