TSH

**Structure and synthesis** - TSH is a glycoprotein with an α subunit and a β subunit. The α subunit is shared with FSH, LH, and hCG. The β subunit confers specificity. - It is secreted by thyrotroph cells (basophils) of the anterior pituitary.

**Regulation (hypothalamic-pituitary-thyroid axis)** - Hypothalamic TRH stimulates TSH release through the Gq receptor (PLC, IP3/DAG, increased Ca2+). - Free T3/T4 exert negative feedback on the pituitary and hypothalamus. Pituitary T4 is converted to T3 by type 2 deiodinase, which is the main feedback signal. - Somatostatin, dopamine, and glucocorticoids inhibit TSH release. - TRH also stimulates prolactin. This explains why primary hypothyroidism can cause hyperprolactinemia, galactorrhea, and amenorrhea.

**Action on the thyroid** - TSH binds the TSH receptor, a Gs-coupled receptor that increases cAMP and activates PKA. - Effects include: - Increased iodide uptake via the Na+/I− symporter (NIS) - Increased thyroglobulin synthesis - Increased thyroid peroxidase (TPO) activity, which drives oxidation, organification, and coupling - Increased colloid endocytosis and hormone release - Follicular cell growth (goiter if chronically elevated)

**Interpretation** - Primary hypothyroidism (Hashimoto, iodine deficiency, post-ablation): TSH is high and free T4 is low. - Primary hyperthyroidism (Graves, toxic adenoma, toxic multinodular goiter): TSH is low and free T4/T3 are high. - Central (secondary or tertiary) hypothyroidism: TSH is low or inappropriately normal, and free T4 is low. - TSH-secreting pituitary adenoma (rare): TSH is high or inappropriately normal, and T4 is high. - Subclinical hypothyroidism: TSH is high and free T4 is normal. - Subclinical hyperthyroidism: TSH is low and free T4/T3 are normal. - Thyroid hormone resistance: TSH and T4 are both high. - Exogenous thyroid hormone (factitious thyrotoxicosis) and thyroiditis (early phase): TSH is low. Low radioactive iodine uptake and low thyroglobulin point to factitious thyrotoxicosis.

**Graves disease** - TSH receptor–stimulating IgG antibodies (type II hypersensitivity) mimic TSH, so T4 rises and TSH is suppressed. - Findings include diffuse goiter, exophthalmos, and pretibial myxedema. Radioactive iodine uptake is diffusely increased.

**Clinical pearls** - TSH is the best initial screening test for thyroid dysfunction when the hypothalamic-pituitary axis is intact. - Check free T4 along with TSH if central disease is suspected. - Levothyroxine dosing in hypothyroidism is titrated to TSH. Wait about 6 weeks between dose changes because of T4's long half-life (about 7 days). - Pregnancy: hCG shares the α subunit with TSH and can weakly stimulate the TSH receptor. This lowers TSH in the first trimester (gestational transient thyrotoxicosis, especially with hyperemesis gravidarum or molar pregnancy). - Biotin supplements can interfere with streptavidin-biotin immunoassays and cause falsely abnormal results. - Sick euthyroid syndrome (non-thyroidal illness): TSH may be low, normal, or transiently high during recovery, with low T3 (increased reverse T3). - Thyroid cancer: TSH suppression with levothyroxine is used after thyroidectomy for differentiated cancer. Recombinant TSH (thyrotropin alfa) is used to stimulate RAI uptake and thyroglobulin testing.