What are the causes, diagnostic criteria, and management of secondary (central) hypothyroidism?

Secondary (Central) Hypothyroidism

Causes and Pathophysiology

Secondary hypothyroidism results from insufficient TSH stimulation of an otherwise normal thyroid gland due to pituitary or hypothalamic dysfunction. 1, 2

Acquired Causes (Most Common in Adults)

• Pituitary macroadenomas are the leading cause of central hypothyroidism in adults 2
• Pituitary surgery or irradiation for tumors or hematological malignancies frequently results in TSH deficiency 2, 3
• Hypophysitis from immune checkpoint inhibitors (ipilimumab, nivolumab) occurs in ≤10% with anti-CTLA-4 monotherapy and ≤13% with combination therapy, with central hypothyroidism present in >90% of hypophysitis cases 4
• Traumatic brain injury and Sheehan syndrome (postpartum pituitary necrosis) are additional acquired causes 1

Congenital/Genetic Causes

• Genetic mutations affecting pituitary development or TSH synthesis can cause isolated or combined pituitary hormone deficiencies 1, 3
• Craniopharyngiomas are the most common cause in children 2
• Recent genetic discoveries have expanded the list of candidate genes, suggesting central hypothyroidism may be underdiagnosed in pediatric and adult patients without apparent pituitary lesions 3

Combined Pituitary Hormone Deficiencies

• Central hypothyroidism rarely occurs in isolation—approximately 50% of patients with hypophysitis present with panhypopituitarism (adrenal insufficiency plus hypothyroidism plus hypogonadism) 4
• Both central hypothyroidism and adrenal insufficiency occur in >75% of patients with hypophysitis 4

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Diagnostic Criteria

The biochemical hallmark of central hypothyroidism is low free T4 with low or inappropriately normal TSH levels. 1, 2, 3

Laboratory Findings

• Low free T4 (or low total T4) is the defining feature 1, 5
• TSH levels are low to normal (not elevated as in primary hypothyroidism), which is "inappropriate" given the low thyroid hormone levels 1, 2, 3
• TSH may appear normal on routine screening, making central hypothyroidism easy to miss with TSH-reflex strategies that only measure free T4 if TSH is abnormal 1, 3

Clinical Presentation

• Fatigue (66%) and headache (85%) are the most common symptoms in hypophysitis-induced central hypothyroidism 4
• Peripheral edema and fatigue are the most specific clinical features of central hypothyroidism in general 2
• Clinical manifestations are usually milder than those observed in primary hypothyroidism 1
• Visual changes are uncommon in hypophysitis despite pituitary enlargement 4

Confirmatory Testing

• Morning (8 AM) comprehensive pituitary hormone assessment should include TSH, free T4, ACTH, cortisol (or 1 mcg cosyntropin stimulation test), and gonadal hormones (testosterone in men, estradiol in women, FSH, LH) 4
• TRH stimulation test can confirm the diagnosis by demonstrating impaired TSH response 2
• MRI of the sella with pituitary cuts should be obtained to identify structural lesions; findings may include pituitary enlargement, stalk thickening, suprasellar convexity, and heterogeneous enhancement 4

Diagnostic Pitfalls to Avoid

• Do not rely on TSH alone for screening—the "reflex TSH strategy" will miss central hypothyroidism because TSH is not elevated 1, 3
• Methodological interference in free T4 or TSH assays can lead to misdiagnosis 1
• Concurrent systemic illness (non-thyroidal illness syndrome) can cause low free T4 with normal TSH, mimicking central hypothyroidism 1
• In neonatal screening programs, diagnosis based solely on TSH analysis without concomitant T4 measurement will miss congenital central hypothyroidism 1

Proposed Confirmation Criteria for Hypophysitis

• ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, OR 4
• ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) in the presence of headache and other symptoms 4

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Management

Levothyroxine monotherapy is the standard treatment for central hypothyroidism, but management differs critically from primary hypothyroidism in several ways. 5, 6

Critical Safety Consideration: Rule Out Adrenal Insufficiency First

• Always assess for concurrent adrenal insufficiency before starting levothyroxine—this is the most important safety principle in central hypothyroidism management 4, 6
• In the presence of both adrenal insufficiency and hypothyroidism, steroids must always be started prior to thyroid hormone to avoid precipitating adrenal crisis 4
• Physiologic doses of hydrocortisone (typically 20 mg morning, 10 mg afternoon) should be initiated at least one week before levothyroxine 6
• All patients with adrenal insufficiency should obtain and carry a medical alert bracelet 4

Levothyroxine Dosing Strategy

• Start with standard replacement doses of levothyroxine (approximately 1.6 mcg/kg/day for most adults) 6
• For elderly patients or those with cardiac disease, initiate at lower doses (25-50 mcg/day) and titrate gradually 6
• For patients with long-standing severe hypothyroidism, start low and increase slowly to avoid cardiac complications 6

Monitoring and Treatment Targets

• Monitor free T4 levels, NOT TSH—this is the fundamental difference from primary hypothyroidism management 3, 5, 6
• Target free T4 in the upper half of the normal reference range (or upper limit of normal) 2, 5, 6
• TSH will be suppressed or low-normal during adequate treatment—this is expected and appropriate in central hypothyroidism 3
• Finding of normal TSH levels may actually indicate thyroxine under-replacement in central hypothyroidism patients, contrary to general assumption 3

Management of Hypophysitis-Induced Central Hypothyroidism

• Replacement of deficient hormones with physiologic doses (steroids and thyroid hormone) is the cornerstone of management 4
• High-dose steroids are necessary only in the setting of severe headaches, vision changes, or adrenal crisis 4
• Both adrenal insufficiency and hypothyroidism appear to represent long-term sequelae—lifelong hormonal replacement is needed in most cases 4
• Pituitary enlargement on MRI commonly resolves within two months, but hormone deficiencies typically persist 4

Special Considerations for Combined Pituitary Deficiencies

• Introduction of sex steroids or growth hormone replacement may unmask latent central hypothyroidism or increase levothyroxine requirements 3
• Evaluate all pituitary axes in patients with central hypothyroidism, as isolated deficiency is uncommon 2, 6
• Reassess thyroid hormone requirements when initiating other hormone replacements 3

Common Pitfalls in Management

• Never use TSH to monitor treatment adequacy—TSH is unreliable in central hypothyroidism and will remain low/suppressed even with adequate replacement 3, 5, 6
• Avoid under-replacement—free T4 should be maintained in the upper normal range, not mid-range as sometimes targeted in primary hypothyroidism 2, 5, 6
• Do not overlook adrenal insufficiency—failure to replace cortisol before thyroid hormone can be fatal 4, 6
• Recognize that central hypothyroidism often represents a clinical challenge because physicians cannot rely on the 'reflex TSH strategy' for screening or therapy monitoring 3

Prognosis and Long-Term Management

• Central hypothyroidism is usually permanent after pituitary surgery, irradiation, or hypophysitis, requiring lifelong replacement 4, 2
• Regular monitoring of free T4 levels is essential to maintain euthyroidism 5
• Periodic reassessment of other pituitary hormones is warranted, as additional deficiencies may develop over time 2, 6