What is central hypothyroidism?

What is Central Hypothyroidism

Central hypothyroidism is a thyroid disorder caused by insufficient stimulation of an otherwise normal thyroid gland due to inadequate TSH production from the pituitary gland or inadequate TRH production from the hypothalamus. 1, 2

Pathophysiology and Etiology

Central hypothyroidism results from abnormal function of the pituitary gland, the hypothalamus, or both, leading to defective thyroid hormone secretion despite a structurally normal thyroid gland. 2 The condition can be:

• Acquired (most common): Results from pituitary or hypothalamic lesions, tumors, surgery, radiation, or immune checkpoint inhibitor-induced hypophysitis 1, 3
• Congenital (rare): Caused by genetic mutations affecting TSH or TRH production 2, 4
• Isolated or combined: Can occur alone or with other pituitary hormone deficiencies, with approximately 50% presenting as panhypopituitarism 1

Biochemical Hallmark

The defining laboratory pattern distinguishes central hypothyroidism from primary hypothyroidism:

• Low or low-normal free T4 with low or inappropriately normal TSH 1, 2, 4
• In primary hypothyroidism, TSH would be elevated in response to low thyroid hormone
• TSH levels in central hypothyroidism are typically in the normal range or only mildly elevated, making diagnosis challenging 5, 3

Clinical Presentation

Symptoms are generally milder than primary hypothyroidism and include:

• Fatigue (66% of patients) 1
• Headache (85% of patients) 1
• Classic hypothyroid symptoms: cold intolerance, weight gain, constipation, cognitive slowing 2
• Visual changes are uncommon unless there is mass effect from a pituitary lesion 1

Critical Diagnostic Pitfalls

Central hypothyroidism is frequently missed or delayed in diagnosis due to:

• The "TSH-reflex strategy": Screening with TSH alone misses central hypothyroidism since TSH is not elevated 2, 4
• Normal TSH levels: Most patients have TSH in the normal reference range, falsely reassuring clinicians 5, 3
• Concurrent illness: Nonthyroidal illness can produce similar biochemical patterns (low T4, normal TSH) 2
• Methodological interference: Laboratory assays for free T4 or TSH may be affected by various factors 2

Diagnostic Approach

When central hypothyroidism is suspected based on low free T4 with low/normal TSH, comprehensive evaluation is required:

• Thyroid function: TSH and free T4, preferably measured around 8 AM 1
• Adrenal function: Morning cortisol and ACTH, or 1 mcg cosyntropin stimulation test 1
• Gonadal function: Testosterone (men), estradiol (women), FSH, and LH 1
• Pituitary imaging: MRI with thin cuts through the pituitary 1
• TRH stimulation test: Can confirm diagnosis by demonstrating inadequate TSH response 5

Frequency and Epidemiology

Central hypothyroidism is approximately 1000-fold rarer than primary hypothyroidism, though the true frequency may be underestimated due to diagnostic challenges. 3 Recent genetic discoveries suggest that isolated central hypothyroidism may be more common than previously recognized, particularly in pediatric and adult patients without apparent pituitary lesions. 4

Critical Management Principle

When both adrenal insufficiency and central hypothyroidism coexist, steroids must always be initiated before thyroid hormone replacement to prevent life-threatening adrenal crisis. 6, 1 Thyroid hormone increases cortisol metabolism, which can trigger adrenal crisis if cortisol is already deficient. 6

Treatment Monitoring

Unlike primary hypothyroidism where TSH guides therapy:

• Free T4 levels guide treatment, targeting the upper half of the normal range for age 1
• TSH is not a reliable marker for monitoring therapy adequacy 1, 4
• Adequate thyroid hormone replacement typically suppresses residual TSH secretion 4, 3
• Check TSH and free T4 every 6-8 weeks during dose titration, then every 6-12 months once stabilized 1

Subclinical Central Hypothyroidism

Emerging evidence suggests that patients with hypothalamic-pituitary disease may have tissue hypothyroidism despite free T4 levels in the mid-normal range, analogous to subclinical primary hypothyroidism. 7 Prolonged isovolumic contraction time on Doppler echocardiography has been proposed as a biomarker for this condition, which may be more frequent than previously recognized. 7

Long-Term Considerations

• Central hypothyroidism from hypophysitis typically requires lifelong hormonal replacement 1
• Approximately 25% of patients on levothyroxine are inadvertently overtreated with suppressed TSH, increasing risks for atrial fibrillation and osteoporosis 1
• Introduction of sex steroid or growth hormone replacement may unmask latent central hypothyroidism or increase thyroxine requirements 4