Biochemistry · Metabolic pathway

Thyroid hormone synthesis !

The thyroid takes up iodine, attaches it to thyroglobulin and forms T4 and T3; tissues then turn T4 into T3, the active form.

Updated 2026-11-01

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Key facts

Iodide enters through NIS, leaves into the colloid through pendrin, and thyroid peroxidase (TPO) oxidises it, attaches it to tyrosines and couples the iodotyrosines.
The hormone is stored ready-made inside thyroglobulin in the colloid: a reserve for several weeks.
TSH stimulates every step through the Gs/cAMP pathway; T3 and T4 hold back TRH and TSH.
Thionamides block TPO; propylthiouracil also slows peripheral conversion of T4 to T3.
Iodine deficiency is still the most important preventable cause of brain damage from hypothyroidism worldwide; iodised salt prevents it.

Also called: Thyroid hormonogenesis

Regulation

TSH, through its Gs-coupled receptor, raises NIS, TPO, H₂O₂ production, colloid endocytosis and gland growth.
An acute iodide excess holds back organification (Wolff–Chaikoff effect) and hormone release; the normal gland escapes the brake within days.
T3 holds back hypothalamic TRH and pituitary TSH; in the pituitary T3 is made locally by DIO2.
Antibodies that stimulate the TSH receptor (Graves disease) switch on the whole pathway without control.

The steps, one by one

Step 1 · Sodium–iodide symporter (NIS) irreversible Plasma iodide → IodideOn the thyrocyte basolateral membrane it brings in one iodide with two sodiums, using the Na⁺/K⁺ pump gradient.If it fails: SLC5A5 mutations block iodine uptake: congenital hypothyroidism with no uptake on the scan. Hypothyroidism →
Step 2 · Pendrin (SLC26A4) irreversible Iodide → Iodide in the colloidOn the apical membrane it passes iodide from the cytoplasm into the colloid, where thyroglobulin is.If it fails: Pendred syndrome: congenital deafness with goitre, because iodine organification is incomplete.
Step 3 · Thyroid peroxidase (oxidation) irreversible Iodide in the colloid + Hydrogen peroxide (H₂O₂) → Oxidised iodine (TPO-bound) + H₂OTPO uses H₂O₂ from DUOX2 to oxidise iodide to an enzyme-bound reactive form.If it fails: DUOX2 or TPO defects cause congenital hypothyroidism with goitre (dyshormonogenesis). Hypothyroidism →
Step 4 · Thyroid peroxidase (organification) irreversible Oxidised iodine (TPO-bound) + Thyroglobulin → MIT and DIT on thyroglobulinActivated iodine attaches to thyroglobulin tyrosines: it forms monoiodotyrosine (MIT) and diiodotyrosine (DIT).If it fails: Too little dietary iodine leaves thyroglobulin poorly iodinated: goitre and hypothyroidism. Goitre →
Step 5 · Thyroid peroxidase (coupling) irreversible MIT and DIT on thyroglobulin → T4 and T3 on thyroglobulinInside thyroglobulin, DIT + DIT form T4 and MIT + DIT form T3; they stay stored in the colloid.If it fails: Thionamides block this step and the one before; that is why they are used in Graves disease. Graves disease (hyperthyroidism) →
Step 6 · Lysosomal proteases (cathepsins) irreversible T4 and T3 on thyroglobulin → Thyroxine + Free MIT and DITThe thyrocyte engulfs colloid; in lysosomes cathepsins cut thyroglobulin and free T4 (and some T3), which leaves for the blood through MCT8.If it fails: The freed MIT and DIT lose their iodine through iodotyrosine deiodinase (IYD); if it is missing, iodine is lost in urine and hypothyroidism follows.
Step 7 · Deiodinases DIO1 and DIO2 irreversible Thyroxine → Triiodothyronine + IodideIn liver, kidney, muscle, brain and pituitary the outer-ring 5' iodine is removed: T4 becomes active T3.If it fails: In severe illness conversion falls: low T3 and high reverse T3 with normal TSH. Hypothyroidism →

Clinical notes

Congenital hypothyroidism: gland dysgenesis or defects of NIS, pendrin, TPO, DUOX2, thyroglobulin or IYD; newborn TSH screening detects it.
Endemic goitre and cretinism from lack of iodine; iodine excess (contrast media, amiodarone) can cause hypo- or hyperthyroidism.
Radioactive iodine enters through NIS and destroys thyroid tissue: it is used in Graves disease and differentiated thyroid cancer.
Serum thyroglobulin is used as a recurrence marker after treating differentiated thyroid cancer.

Test yourself

Think of the answer, then tap the question to see it.

Which transporter brings iodide into the thyrocyte, and which drug blocks it?

The sodium–iodide symporter (NIS), blocked by perchlorate.

Which three synthesis steps does thyroid peroxidase perform?

It oxidises iodide, attaches it to thyroglobulin tyrosines (organification) and couples MIT and DIT to form T3 and T4.

What is the Wolff–Chaikoff effect?

The temporary brake on iodine organification when an acute iodide excess reaches the thyroid.

Where is most T3 made?

Outside the thyroid, by deiodination of T4 in peripheral tissues.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: SLC5A5 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); SLC26A4 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); TPO gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); TG gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); DUOX2 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Congenital hypothyroidism: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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