Thyroxine (T4)
Also known as: T4, tetraiodothyronine, levothyroxine, thyroid hormone
The main secretory product of the thyroid (≈90 % of output), a largely inactive prohormone with a week-long half-life that is converted in tissues to the active hormone T3.
Overview
T4 (3,5,3′,5′-tetraiodothyronine) is formed by coupling two diiodotyrosine residues on thyroglobulin and released when TSH stimulates colloid endocytosis and proteolysis (≈80–100 µg/day). Being lipophilic, >99.9 % circulates bound to proteins — thyroxine-binding globulin (TBG) ≈75 %, transthyretin ≈15–20 % and albumin ≈5–10% — leaving only ≈0.03 % free. This large bound pool buffers supply and gives T4 a half-life of ≈7 days, so dose changes of levothyroxine take ≈6 weeks to reach steady state.
T4 enters cells via transporters (MCT8, MCT10, OATP1C1) and is activated by outer-ring deiodination to T3 — by type 1 deiodinase (liver, kidney, thyroid; supplies plasma T3) and type 2 deiodinase (brain, pituitary, brown fat, muscle; supplies intracellular T3 and mediates pituitary feedback). Type 3 deiodinase (placenta, brain, and many tissues in critical illness) inactivates T4 to reverse T3 (rT3). Selenium is a cofactor for all deiodinases.
Its actions are those of T3 acting on nuclear thyroid-hormone receptors (see triiodothyronine): increased basal metabolic rate and heat production, sensitisation to catecholamines, and maturation of the brain and skeleton.
- Location
Source: thyroid follicular cells. Targets: nearly every tissue (after conversion to T3).
Function
- Serves as the circulating reservoir and prohormone for T3.
- Mediates negative feedback on TSH and TRH (after local conversion to T3).
- Indirectly (as T3) raises metabolic rate and drives growth and development.
- Physiology
Class: iodinated amine (tyrosine derivative) that behaves like a steroid. Receptor: nuclear TRα/TRβ (after conversion to T3). Half-life ≈7 days. Binding: TBG ≈75 %, transthyretin ≈15–20 %, albumin ≈5–10 %; free ≈0.03 %.
- Regulation
TSH (TRH) stimulates secretion; free T4/T3 inhibit TSH and TRH. Iodide supply, deiodinase activity, binding-protein concentrations and drugs (amiodarone, lithium, iodinated contrast) alter levels.
Clinical significance
Binding-protein changes
Pregnancy, oral estrogen and hepatitis raise TBG, so total T4 rises while free T4 and TSH stay normal; androgens, glucocorticoids, nephrotic syndrome and liver failure lower TBG. Always interpret free T4 with TSH.
Levothyroxine therapy
Synthetic T4 is the standard treatment for hypothyroidism; taken on an empty stomach (absorption reduced by iron, calcium, PPIs), titrated to TSH, with requirements rising ≈30–50 % in pregnancy.
Mnemonics
Actions of thyroid hormone — the 4 Bs
Brain maturation, Bone growth, β-adrenergic effects (heart rate, contractility), Basal metabolic rate ↑.
Test yourself
Which is NOT a direct or indirect action of parathyroid hormone?
- Increased Ca²⁺ reabsorption in the distal convoluted tubule
- Increased phosphate reabsorption in the proximal tubule
- Stimulation of renal 1α-hydroxylase
- Osteoclast activation via osteoblast RANKL
Answer: Increased phosphate reabsorption in the proximal tubule
PTH inhibits proximal tubular phosphate reabsorption (by internalising NaPi-IIa cotransporters), causing phosphaturia. This lets calcium rise without precipitating calcium phosphate.
Compiled from standard anatomy and physiology references — see the Endocrine System sources. For education only; not medical advice.