Central Hypothyroidism (Secondary/Tertiary Hypothyroidism)
This pattern of low TSH, low T3, low T4 with normal thyroid antibodies indicates central hypothyroidism—a pituitary or hypothalamic disorder, not a thyroid gland problem. This requires immediate evaluation for other pituitary hormone deficiencies and treatment with levothyroxine guided by free T4 levels, not TSH.
Diagnostic Confirmation
The combination of low thyroid hormones (T3 and T4) with inappropriately low or normal TSH definitively indicates central hypothyroidism 1, 2, 3. In primary hypothyroidism, TSH would be markedly elevated; the absence of TSH elevation despite low thyroid hormones proves the pituitary/hypothalamus is failing to respond appropriately 1, 3.
Key Distinguishing Features:
- Normal thyroid antibodies (thyroglobulin antibodies and TPO antibodies) exclude autoimmune thyroid disease 4, 5
- The thyroid gland itself is structurally and functionally normal—it simply lacks adequate TSH stimulation 1, 3
- TSH may be low, normal, or even slightly elevated (but inappropriately so given the low T4) 2, 3
Critical Pitfall to Avoid:
Many laboratories use TSH-reflex strategies that only measure free T4 if TSH is abnormal—this approach will miss central hypothyroidism entirely 3. Central hypothyroidism requires simultaneous measurement of both TSH and free T4 for diagnosis 3.
Immediate Evaluation Required
Rule Out Adrenal Insufficiency FIRST:
Before initiating any thyroid hormone replacement, you must evaluate the hypothalamic-pituitary-adrenal axis and rule out hypocortisolism 4, 6. Starting levothyroxine before correcting adrenal insufficiency can precipitate life-threatening adrenal crisis 6, 7.
- Measure morning (9 AM) cortisol levels 6
- If adrenal insufficiency is present or suspected, start corticosteroids several days before initiating levothyroxine 4, 7
- This is non-negotiable in central hypothyroidism 4
Evaluate for Other Pituitary Hormone Deficiencies:
Central hypothyroidism is rarely isolated 3. Assess:
- Growth hormone deficiency 4, 3
- Gonadotropin deficiency (FSH/LH) 6, 3
- Prolactin levels 6
- ACTH/cortisol axis (as above) 4
Identify the Underlying Cause:
- Pituitary MRI to evaluate for pituitary adenoma, hypophysitis, or structural lesions 6, 3
- Review medication history for drugs causing central hypothyroidism 3
- Assess for history of head trauma, radiation therapy, or pituitary surgery 3, 5
- In patients on immunotherapy, consider immune checkpoint inhibitor-induced hypophysitis 6
Treatment Protocol
Levothyroxine Dosing:
Standard levothyroxine (L-T4) monotherapy is the treatment of choice for central hypothyroidism 4, 1, 2.
- Starting dose for most adults: 1.6 mcg/kg/day 4
- For elderly patients (>70 years) or those with cardiac disease: start with 25-50 mcg/day and titrate gradually 4, 8
- For patients with long-standing severe hypothyroidism: start low and increase slowly 4
Monitoring and Dose Adjustment:
In central hypothyroidism, TSH cannot be used to monitor treatment adequacy—you must use free T4 levels 4, 1, 2, 3.
- Target: Maintain free T4 in the upper half of the normal reference range 4, 1, 2
- Recheck free T4 (not TSH) 6-8 weeks after starting therapy or dose changes 4
- TSH levels will remain low or normal even with adequate replacement—this is expected and appropriate 1, 2, 3
- Once stable, monitor free T4 every 6-12 months 4
Critical Treatment Pitfalls:
- Never use TSH to guide levothyroxine dosing in central hypothyroidism—TSH will not normalize and attempting to "correct" it will lead to dangerous overtreatment 1, 2, 3
- Overtreatment increases risk for atrial fibrillation, osteoporosis, and cardiovascular complications 4
- Always ensure corticosteroid replacement is adequate before starting or increasing levothyroxine 4, 7
Special Considerations
Drug Interactions Affecting Levothyroxine:
- Proton pump inhibitors, antacids, and sucralfate reduce levothyroxine absorption—administer levothyroxine at least 4 hours before these medications 8
- Iron supplements, calcium carbonate, and bile acid sequestrants decrease absorption—separate by at least 4 hours 8
- Phenobarbital, rifampin, and carbamazepine increase levothyroxine metabolism—may require higher doses 8
- Estrogen-containing oral contraceptives increase thyroxine-binding globulin—may increase levothyroxine requirements 8, 7
Monitoring for Complications:
- Patients with coronary artery disease require careful monitoring—levothyroxine increases metabolic demands and may precipitate angina 7, 4
- Diabetic patients may require increased insulin or oral hypoglycemic doses when starting levothyroxine 8, 7
- Patients on anticoagulants may need dose reduction as levothyroxine increases anticoagulant response 8, 7
Prognosis and Long-Term Management
With appropriate levothyroxine replacement guided by free T4 levels (not TSH), patients with central hypothyroidism can achieve normal thyroid hormone status 1, 2. However: