secondary hypothyroidism

**Definition & classification** - Primary: thyroid gland failure (low T4, high TSH). This is the most common type (Hashimoto thyroiditis in iodine-sufficient areas, iodine deficiency worldwide). - Secondary (central): pituitary failure, with decreased TSH from thyrotropes. - Tertiary: hypothalamic failure, with decreased TRH. Secondary and tertiary are often grouped together as "central hypothyroidism."

**Pathophysiology** - Normal axis: hypothalamus (TRH) → anterior pituitary (TSH) → thyroid (T4 > T3) → negative feedback on both TRH and TSH. - In secondary hypothyroidism, loss of TSH stimulation causes thyroid atrophy and decreased T4/T3 synthesis and release. The thyroid itself is normal. - Some patients have a TSH that is biologically inactive (abnormal glycosylation) but immunoreactive. This explains a "normal" or mildly elevated TSH with low T4.

**Etiologies** - Pituitary macroadenoma (most common acquired cause) compressing normal tissue - Pituitary surgery or radiation - Sheehan syndrome (postpartum pituitary infarction after hemorrhage) - Pituitary apoplexy - Infiltrative or inflammatory disease: hemochromatosis, sarcoidosis, lymphocytic hypophysitis (including immune checkpoint inhibitors, e.g., ipilimumab), histiocytosis - Craniopharyngioma (hypothalamic/pituitary stalk lesions, more tertiary) - Traumatic brain injury, empty sella - Congenital: PROP1, POU1F1 (Pit-1), and TSHβ mutations - Drugs: bexarotene (suppresses TSH), high-dose glucocorticoids, dopamine, and octreotide (transient suppression)

**Clinical features** - Same as primary hypothyroidism: fatigue, cold intolerance, weight gain, constipation, dry skin, bradycardia, delayed relaxation of deep tendon reflexes, depression, and menstrual irregularities. - Typically milder, and **no goiter** (the gland is atrophic). - Look for other pituitary deficits and mass effect: headache, bitemporal hemianopsia (optic chiasm compression), hypogonadism, hypoprolactinemia (failure to lactate in Sheehan), and ACTH/cortisol deficiency.

**Diagnosis** - Low free T4 with low or inappropriately normal TSH. A normal TSH does NOT exclude central hypothyroidism if free T4 is low. - Do not use TSH alone to screen when pituitary disease is suspected. Measure free T4. - Evaluate other pituitary hormones (ACTH/cortisol, LH/FSH, prolactin, IGF-1) and obtain pituitary MRI. - TRH stimulation test (historical): a blunted TSH response suggests a pituitary cause. A delayed or exaggerated response suggests a hypothalamic cause.

**Management** - Levothyroxine, **titrated to free T4** (target the mid-to-upper normal range). TSH cannot be used to monitor therapy because it is unreliable in this condition. - **Always evaluate and replace glucocorticoids first** if concomitant adrenal insufficiency is present. Starting levothyroxine first increases cortisol clearance and can precipitate adrenal crisis. - Treat the underlying cause (e.g., adenoma resection or dopamine agonist for a prolactinoma).

**High-yield board pearls** - Low T4 with low/normal TSH = central. Low T4 with high TSH = primary. - Sheehan syndrome presents as postpartum failure to lactate, fatigue, and amenorrhea. - Replace cortisol before thyroid hormone. - Secondary hypothyroidism has no goiter. Hashimoto (primary) can have a goiter. - Monitor treatment with free T4, not TSH. - Compare with TSH-secreting adenoma (secondary hyperthyroidism): high T4 with inappropriately normal or high TSH.