Clinical meaning
Thyroid-stimulating hormone (TSH) is a glycoprotein produced by the anterior pituitary gland and is the single most sensitive and specific test for evaluating thyroid function. The hypothalamic-pituitary-thyroid (HPT) axis operates through a negative feedback loop: the hypothalamus secretes thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary to release TSH, which then acts on the thyroid gland to produce thyroxine (T4) and triiodothyronine (T3). T4 is the predominant circulating hormone (>80% of thyroid output) and is converted to the active form T3 by deiodinase enzymes in peripheral tissues. Free T4 and T3 exert negative feedback on both the hypothalamus and pituitary, suppressing TRH and TSH secretion. The TSH-free T4 relationship follows a log-linear pattern: small changes in free T4 produce exponential changes in TSH. This means TSH is abnormal long before free T4 falls outside the normal range, making TSH the earliest and most sensitive marker of thyroid dysfunction. Normal TSH reference range is typically 0.4-4.0 mIU/L, though upper limits vary by laboratory, age (increases with age), and pregnancy (lower in first trimester due to hCG cross-stimulation of TSH receptor). Interpretation requires correlation with clinical presentation and additional testing. Primary hypothyroidism: TSH elevated, free T4 low (thyroid gland failure). Subclinical hypothyroidism: TSH elevated, free T4 normal. Primary hyperthyroidism: TSH suppressed (<0.1), free T4 and/or free T3 elevated. Subclinical hyperthyroidism: TSH suppressed, free T4/T3 normal. Central (secondary) hypothyroidism: TSH low or inappropriately normal, free T4 low (pituitary or hypothalamic failure — TSH is unreliable for diagnosis in this rare scenario). TSH-secreting pituitary adenoma: TSH elevated with elevated free T4 (rare, loss of negative feedback).