hypothalamic-pituitary-thyroid axis

**Components and flow** - Hypothalamus (paraventricular nucleus): secretes TRH (thyrotropin-releasing hormone, a tripeptide) into the hypophyseal portal system. - Anterior pituitary thyrotrophs: TRH binds a Gq receptor (PLC → IP3/DAG → ↑Ca2+/PKC) and stimulates TSH release. TSH is a glycoprotein with an α subunit shared with LH, FSH, and hCG, and a unique β subunit. - Thyroid follicular cells: TSH binds a Gs-coupled receptor (↑cAMP/PKA). This increases iodide uptake (Na+/I− symporter, NIS), thyroglobulin synthesis, thyroid peroxidase (TPO) activity, and hormone release. Chronic TSH stimulation causes goiter and follicular hypertrophy/hyperplasia. - Feedback: T3 and free T4 inhibit TSH (mainly) and TRH. T4 is converted to T3 in the pituitary by type 2 deiodinase, which provides the feedback signal.

**Thyroid hormone synthesis (TSH-driven steps)** 1. Iodide uptake via NIS (Na+/I− symporter). 2. Oxidation of I− to I2 by TPO, using H2O2. 3. Organification: iodination of tyrosine residues on thyroglobulin, forming MIT and DIT. 4. Coupling (TPO): MIT + DIT → T3, and DIT + DIT → T4. 5. Endocytosis of colloid, proteolysis, and release of T3/T4. - Peripheral conversion: T4 → T3 (active) by 5'-deiodinase, or T4 → reverse T3 (inactive) by 5-deiodinase. - Transport: >99% is bound to TBG (thyroxine-binding globulin), transthyretin, and albumin. Only free hormone is active. - T3 acts through nuclear receptors (like steroid hormones) and increases Na+/K+-ATPase, BMR, β1 receptor expression, and protein synthesis. It is essential for growth and CNS development.

**Interpreting labs (high-yield patterns)** - Primary hypothyroidism (Hashimoto, iodine deficiency): ↑TSH, ↓free T4. - Primary hyperthyroidism (Graves, toxic adenoma/multinodular goiter): ↓TSH, ↑free T4/T3. In Graves, TSH-receptor-stimulating IgG autoantibodies bypass the feedback loop. - Secondary (central) hypothyroidism (pituitary failure, Sheehan syndrome, adenoma): ↓TSH, ↓free T4. - Tertiary hypothyroidism (hypothalamic): ↓TRH, ↓TSH, ↓T4. A TRH stimulation test can distinguish pituitary from hypothalamic disease. - Secondary hyperthyroidism (TSH-secreting adenoma, pituitary thyroid hormone resistance): ↑TSH, ↑T4. - Subclinical hypothyroidism: ↑TSH with normal free T4. - Sick euthyroid syndrome (nonthyroidal illness): ↓T3 (↑reverse T3) from decreased peripheral conversion, with normal or low TSH. Do not treat. - TBG changes: Estrogen (pregnancy, OCPs) raises TBG, so total T4 rises but free T4 and TSH stay normal. Androgens, glucocorticoids, and nephrotic syndrome lower TBG.

**Modulators and drug effects** - Dopamine, somatostatin, and glucocorticoids inhibit TSH secretion. - Iodine excess causes the Wolff-Chaikoff effect (transient inhibition of organification). Escape from it, or Jod-Basedow (iodine-induced hyperthyroidism in a patient with an autonomous nodule), is a classic question. - Propylthiouracil (PTU) inhibits TPO and peripheral T4 → T3 conversion. Methimazole inhibits TPO only. PTU is preferred in the first trimester of pregnancy and in thyroid storm. Methimazole is teratogenic (aplasia cutis). - Amiodarone can cause hypothyroidism (Wolff-Chaikoff effect) or hyperthyroidism. - Levothyroxine treats hypothyroidism. Titrate it to TSH in primary disease. In central hypothyroidism, TSH is unreliable, so titrate to free T4. - Lithium can cause hypothyroidism.

**Clinical pearls** - Hypothyroidism: fatigue, cold intolerance, weight gain, constipation, bradycardia, myxedema, delayed DTR relaxation. Congenital hypothyroidism causes cretinism (macroglossia, umbilical hernia, developmental delay). - Hyperthyroidism: heat intolerance, weight loss, tachycardia/AF, tremor, hyperreflexia. Graves also causes ophthalmopathy and pretibial myxedema. - Thyroid storm: fever, tachycardia, altered mental status. Treat with β-blocker, PTU, iodine (given after PTU), and steroids. - Hashimoto: anti-TPO and antithyroglobulin antibodies, Hürthle cells, lymphocytic infiltrate with germinal centers, and ↑ risk of B-cell lymphoma. - TSH is the best initial screening test for suspected primary thyroid disease. Order free T4 next if TSH is abnormal.