What causes secondary hypothyroidism and how is it treated?

Secondary Hypothyroidism: Causes and Treatment

Secondary hypothyroidism is primarily caused by pituitary or hypothalamic dysfunction resulting in inadequate TSH secretion, and is treated with levothyroxine replacement therapy with dosing based on free T4 levels rather than TSH levels.

Causes of Secondary Hypothyroidism

Secondary (central) hypothyroidism occurs due to failure of adequate thyroid-stimulating hormone (TSH) secretion from the pituitary gland or thyrotropin-releasing hormone (TRH) from the hypothalamus, rather than from primary thyroid gland dysfunction 1.

Common causes include:

• Hypophysitis (pituitary inflammation) - often associated with immune checkpoint inhibitor therapy in cancer treatment 2
• Pituitary tumors or masses compressing the pituitary gland 2
• Pituitary surgery or radiation therapy 1, 3
• Infiltrative diseases affecting the pituitary 3
• Genetic disorders such as 22q11.2 deletion syndrome 2
• Severe head trauma affecting the hypothalamic-pituitary axis 3
• Congenital pituitary defects 1

Diagnosis of Secondary Hypothyroidism

Secondary hypothyroidism presents with different laboratory findings compared to primary hypothyroidism:

• Low free T4 (FT4) with normal or low TSH levels (unlike primary hypothyroidism where TSH is elevated) 1, 3
• Morning hormone testing is recommended for accurate assessment 2
• Additional pituitary hormone evaluation is necessary, including ACTH, cortisol, LH, FSH, and sex hormones 2
• MRI of the brain with pituitary cuts is recommended to evaluate for structural abnormalities 2

For patients with suspected hypophysitis, diagnostic criteria include:

• ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, or
• ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) with headache and other symptoms 2

Treatment Approach

Hormone Replacement Therapy

The cornerstone of treatment is thyroid hormone replacement:

• Levothyroxine (T4) is the first-line treatment 4, 5
• Critical safety note: In patients with both adrenal insufficiency and hypothyroidism, corticosteroids must always be started before thyroid hormone to prevent adrenal crisis 2
• Unlike primary hypothyroidism, TSH cannot be used to monitor therapy in secondary hypothyroidism 4
• Dosing should be titrated based on free T4 levels, aiming for the upper half of the normal range 4, 3

Dosing Considerations

• For adults with secondary hypothyroidism, the starting dose is typically lower than the full replacement dose of 1.6 mcg/kg/day 4
• Lower starting doses are particularly important for:
  • Elderly patients 4
  • Patients with cardiac disease or at risk for atrial fibrillation 4
  • Patients with long-standing severe hypothyroidism 3
• Titrate gradually by 12.5-25 mcg increments every 4-6 weeks until the patient is clinically euthyroid and free T4 is in the upper half of normal range 4, 3

Monitoring and Follow-up

• Monitor free T4 levels 6-8 weeks after initiating treatment or changing dose 5
• Once stabilized, monitor annually to avoid overtreatment or undertreatment 5
• Evaluate for other pituitary hormone deficiencies periodically 2
• For patients with adrenal insufficiency, provide education on stress dosing and emergency management 2
• Medical alert bracelet is recommended for patients with adrenal insufficiency 2

Special Considerations

• Liothyronine (T3) may be considered in specific cases but is not first-line therapy 6
• Combination T4/T3 therapy remains controversial and is not routinely recommended 3
• Patients with hypopituitarism may require lifelong hormonal replacement 2
• Pregnancy requires careful monitoring and dose adjustments 2
• Avoid treatment during recovery phase of subacute thyroiditis 4, 6

Complications of Untreated Secondary Hypothyroidism

• Fatigue, weight gain, cold intolerance, and cognitive issues 5, 7
• Cardiovascular complications including heart failure 5
• Reproductive issues including menstrual irregularities, infertility, and increased miscarriage risk 5
• In severe cases, progression to myxedema coma, a life-threatening emergency 2, 5

By understanding the causes and appropriate treatment approach for secondary hypothyroidism, clinicians can effectively manage this condition and prevent associated complications.