Low TSH with Low T3: Central Hypothyroidism
This pattern of low TSH with low T3 (and presumably low T4) indicates central hypothyroidism—a pituitary or hypothalamic disorder requiring immediate evaluation for other pituitary hormone deficiencies and urgent levothyroxine replacement, but only after ruling out adrenal insufficiency to prevent life-threatening adrenal crisis. 1, 2
Diagnostic Confirmation
Measure both TSH and free T4 simultaneously, as low TSH can indicate either hyperthyroidism or central hypothyroidism—only a concomitant low free T4 confirms central hypothyroidism 1. In hypophysitis, TSH can remain within the normal range despite hypothyroidism, making free T4 measurement essential 1.
Check morning cortisol and ACTH levels immediately before starting any thyroid hormone replacement 1. Low ACTH with low cortisol indicates secondary adrenal insufficiency, the second most common hormonal loss with hypophysitis 1. If thyroid hormone is replaced first when cortisol is low, the increase in cortisol metabolism can trigger an adrenal crisis 1.
Evaluate for hypophysitis or pituitary disease by checking LH, FSH, testosterone (males) or estradiol (premenopausal females), and consider MRI of the brain with pituitary cuts if multiple endocrine abnormalities are present or if new severe headaches or visual field changes occur 1.
Critical Safety Consideration: Rule Out Adrenal Insufficiency First
Always start hydrocortisone several days before initiating levothyroxine when multiple pituitary hormones are deficient 1. Use hydrocortisone 10-20 mg orally in the morning and 5-10 mg in early afternoon as maintenance, with initial stress-dose therapy (20-30 mg in morning, 10-20 mg in afternoon) if symptomatic 1.
For severe symptoms or suspected adrenal crisis, administer IV hydrocortisone 100 mg (or dexamethasone 4 mg if diagnosis unclear and stimulation testing needed) with at least 2 liters normal saline 1. Taper stress-dose corticosteroids down to maintenance over 7-14 days after stabilization 1.
Levothyroxine Replacement for Central Hypothyroidism
Start levothyroxine only after corticosteroid replacement is established 1, 3. Dose levothyroxine by weight (approximately 1.6 mcg/kg/day for patients under 70 without cardiac disease, or 25-50 mcg/day for elderly or those with cardiac disease) 1, 3.
Monitor free T4 levels, not TSH, for dose titration in central hypothyroidism 1. TSH is not accurate for monitoring central hypothyroidism because the pituitary dysfunction prevents appropriate TSH response 1, 2, 4. Target free T4 in the upper half of the normal reference range 4, 5.
Recheck free T4 (and free T3 if available) in 6-8 weeks after dose adjustments 1, 3. Once adequately treated, repeat testing every 6-12 months or with symptom changes 1.
Common Causes to Investigate
Immune checkpoint inhibitor therapy causes hypophysitis most commonly with ipilimumab, presenting with central adrenal insufficiency and central hypothyroidism 1. The median time to onset is 14.5 weeks (range 1.5-130 weeks) 1.
Pituitary tumors, craniopharyngiomas, pituitary surgery, or cranial irradiation are common causes in adults and children 5. Traumatic brain injury, subarachnoid hemorrhage, Sheehan syndrome, and lymphocytic hypophysitis are additional etiologies 4.
Genetic causes include mutations in TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3, LHX4, and TSHB genes 4.
Critical Pitfalls to Avoid
Never start thyroid hormone before ruling out adrenal insufficiency, as this precipitates adrenal crisis 1, 3. The increased cortisol metabolism from thyroid hormone replacement can be fatal in untreated adrenal insufficiency 1.
Do not rely on TSH for diagnosis or monitoring in central hypothyroidism—TSH levels can be low, normal, or even slightly elevated despite severe hypothyroidism 2, 4, 5. Only free T4 (and free T3) accurately reflect thyroid status 1, 2.
Do not use TSH-reflex strategies (measuring TSH alone without free T4) as this misses central hypothyroidism entirely 2.
Recognize that clinical manifestations are usually milder than primary hypothyroidism, potentially delaying diagnosis 2. Fatigue and peripheral edema are the most specific clinical features 5.
Long-Term Management Considerations
All patients need education on stress dosing and a medical alert bracelet for adrenal insufficiency 1. Endocrine consultation is required prior to surgery or any procedure for stress-dose planning 1.
Consider combination T4/T3 therapy if symptoms persist despite adequate free T4 levels, as treated central hypothyroidism patients have lower free T3 to free T4 ratios than euthyroid controls 6, 7. The free T3 to free T4 ratio is lower in treated central hypothyroidism compared to euthyroidism, with similar free T3 but higher free T4 concentrations 6.
Monitor for other autoimmune conditions if autoimmune hypophysitis is the cause, though this is less common than tumor-related or iatrogenic central hypothyroidism 4.