Secondary and Tertiary Hypothyroidism
Secondary hypothyroidism is caused by pituitary dysfunction while tertiary hypothyroidism results from hypothalamic dysfunction, both characterized by low thyroid hormone levels with inappropriately normal or low TSH levels. 1, 2
Pathophysiology and Definitions
Secondary Hypothyroidism
- Results from failure of the pituitary gland to produce adequate thyroid-stimulating hormone (TSH)
- Characterized by low free T4 (FT4) with inappropriately normal or low TSH levels 3
- Often occurs as part of broader hypopituitarism affecting multiple pituitary hormones 2
Tertiary Hypothyroidism
- Results from inadequate thyrotropin-releasing hormone (TRH) secretion from the hypothalamus
- Also presents with low FT4 and inappropriately normal or low TSH 3
- Can be differentiated from secondary hypothyroidism using the TRH stimulation test 1, 3
Diagnostic Approach
Laboratory Findings
- Key diagnostic feature: Low free T4 with normal or low TSH levels (unlike primary hypothyroidism where TSH is elevated) 4, 2
- TRH stimulation test can help differentiate between secondary and tertiary hypothyroidism:
- Secondary (pituitary): Minimal or no TSH response (<2 μU/mL increase) to TRH in approximately 60% of cases
- Tertiary (hypothalamic): TSH response to TRH (>2 μU/mL increase) in approximately 95% of cases 1
Additional Evaluation
- Assessment of other pituitary hormones is essential, especially the hypothalamic-pituitary-adrenal axis 4
- Imaging of the pituitary and hypothalamus (MRI) to identify potential structural causes
- Evaluation for other manifestations of hypopituitarism 2
Common Causes
Secondary (Pituitary) Hypothyroidism
- Pituitary tumors (adenomas)
- Pituitary surgery or radiation
- Pituitary apoplexy (hemorrhage or infarction)
- Infiltrative diseases (sarcoidosis, hemochromatosis)
- Immune checkpoint inhibitor therapy 5, 6
Tertiary (Hypothalamic) Hypothyroidism
- Hypothalamic tumors or infiltrative diseases
- Cranial radiation
- Traumatic brain injury
- Congenital disorders
- Severe, prolonged illness 3, 2
Clinical Presentation
- Often less severe than primary hypothyroidism due to partial preservation of thyroid function
- May present with fatigue, cold intolerance, weight gain, constipation, dry skin
- Symptoms of other pituitary hormone deficiencies may predominate
- May have signs of the underlying condition (visual field defects, headaches with pituitary tumors) 7, 8
Treatment Considerations
Critical First Step
- Always evaluate and treat adrenal insufficiency before initiating thyroid hormone replacement to prevent precipitating an adrenal crisis 6, 4
Medication
- Levothyroxine (LT4) is the standard treatment 4, 8
- Unlike primary hypothyroidism, TSH cannot be used to monitor treatment
- Target free T4 levels in the upper half of the normal reference range 6, 4
- Starting dose depends on age, weight, and comorbidities:
- Young, healthy adults: 1.6 mcg/kg/day
- Elderly or those with cardiac disease: 25-50 mcg daily 6
Monitoring
- Monitor free T4 (not TSH) every 6-8 weeks during dose adjustment
- Once stable, monitor free T4 annually
- Adjust dose to maintain free T4 in the upper half of the reference range 6, 4
Common Pitfalls
- Misdiagnosis: Mistaking central hypothyroidism for subclinical hyperthyroidism (both can present with low TSH)
- Inadequate evaluation: Failing to assess other pituitary hormones, particularly cortisol
- Treatment error: Initiating thyroid hormone replacement before addressing adrenal insufficiency, which can precipitate adrenal crisis
- Monitoring error: Using TSH (rather than free T4) to monitor treatment effectiveness
- Overtreatment: Excessive thyroid hormone replacement leading to iatrogenic hyperthyroidism 6, 4
By understanding the distinct pathophysiology and management approach for central hypothyroidism, clinicians can provide appropriate care for this less common but important form of thyroid dysfunction.