What are the causes of central hypothyroidism?

Causes of Central Hypothyroidism

Central hypothyroidism is caused by insufficient stimulation of a normal thyroid gland due to dysfunction of the pituitary gland, hypothalamus, or both, resulting in low free T4 with low or inappropriately normal TSH levels. 1, 2

Primary Causes

Pituitary Causes (Secondary Hypothyroidism)

• Pituitary tumors/masses
  • Pituitary adenomas
  • Craniopharyngiomas
  • Metastatic tumors
• Pituitary surgery or radiation
• Pituitary apoplexy (hemorrhage or infarction)
• Pituitary infiltrative diseases
  • Sarcoidosis
  • Hemochromatosis
• Immune-related hypophysitis
  • Immune checkpoint inhibitor therapy (incidence ~10% of treated patients) 3
• Sheehan's syndrome (postpartum pituitary necrosis)
• Traumatic brain injury

Hypothalamic Causes (Tertiary Hypothyroidism)

• Hypothalamic tumors
• Cranial radiation
• Infiltrative diseases
• Traumatic brain injury
• Congenital disorders

Genetic Causes

• Mutations in genes regulating pituitary development
• Isolated TSH deficiency (rare)
• Combined pituitary hormone deficiencies 2, 4

Other Causes

• Drugs
  • Dopamine and dopamine agonists
  • High-dose glucocorticoids
  • Dobutamine 3
• Critical illness (euthyroid sick syndrome)
• Anorexia nervosa

Diagnostic Considerations

Central hypothyroidism is characterized by:

• Low free T4 with low or inappropriately normal TSH levels 1
• Often occurs with other pituitary hormone deficiencies 1, 5

Key diagnostic points:

• Morning laboratory testing (8 AM) is recommended 1
• Both TSH and Free T4 must be measured simultaneously 3, 1
• Additional pituitary hormone testing is essential, particularly for adrenal function (ACTH, cortisol) 1
• Subclinical central hypothyroidism may exist in patients with hypothalamic-pituitary disease even with normal free T4 levels 6

Clinical Manifestations

Symptoms are generally milder than primary hypothyroidism 2 and include:

• Fatigue
• Muscle cramps
• Constipation
• Cold intolerance
• Hair loss
• Voice changes
• Weight gain
• Intellectual slowness
• Insomnia 3, 1
• Low metabolic rate 1

Treatment Considerations

• Evaluate for other pituitary hormone deficiencies, particularly adrenal insufficiency, before starting thyroid replacement 1
• Treat adrenal insufficiency before thyroid hormone replacement to prevent precipitating an adrenal crisis 1
• Liothyronine (T3) or levothyroxine (T4) are indicated for replacement therapy in central hypothyroidism 7
• Unlike primary hypothyroidism, TSH levels cannot be used to monitor treatment adequacy; free T4 levels must be used instead 4

Clinical Pitfalls

• Central hypothyroidism is often overlooked due to:

  • Difficulty in achieving correct diagnosis
  • Sparse symptomatology
  • Risk of misinterpretation of biochemical changes 5
  • Sole TSH-reflex testing strategy (measuring only TSH) 2

• Undertreating central hypothyroidism may have serious metabolic consequences with potentially increased cardiovascular morbidity 5

• Central hypothyroidism is rarely isolated and typically occurs with other pituitary hormone deficiencies 8