[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Thyroid hormone synthesis [Biochemistry](https://durgical.com/en/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 ## Interactive map ## 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 → Iodide On 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 →](https://durgical.com/en/conditions/hypothyroidism/) - **Step 2 · Pendrin (SLC26A4)** irreversible Iodide → Iodide in the colloid On 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)](https://durgical.com/en/biochemistry/enzymes/thyroid-peroxidase/)** irreversible Iodide in the colloid + Hydrogen peroxide (H₂O₂) → Oxidised iodine (TPO-bound) + H₂O TPO 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 →](https://durgical.com/en/conditions/hypothyroidism/) - **Step 4 · [Thyroid peroxidase (organification)](https://durgical.com/en/biochemistry/enzymes/thyroid-peroxidase/)** irreversible Oxidised iodine (TPO-bound) + Thyroglobulin → MIT and DIT on thyroglobulin Activated 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 →](https://durgical.com/en/conditions/goitre/) - **Step 5 · [Thyroid peroxidase (coupling)](https://durgical.com/en/biochemistry/enzymes/thyroid-peroxidase/)** irreversible MIT and DIT on thyroglobulin → T4 and T3 on thyroglobulin Inside 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) →](https://durgical.com/en/conditions/graves-disease/) - **Step 6 · Lysosomal proteases (cathepsins)** irreversible T4 and T3 on thyroglobulin → [Thyroxine](https://durgical.com/en/biochemistry/molecules/thyroxine/) + Free MIT and DIT The 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](https://durgical.com/en/biochemistry/enzymes/iodothyronine-deiodinases/)** irreversible [Thyroxine](https://durgical.com/en/biochemistry/molecules/thyroxine/) → [Triiodothyronine](https://durgical.com/en/biochemistry/molecules/triiodothyronine/) + Iodide In 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 →](https://durgical.com/en/conditions/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. ## Related conditions - [Hypothyroidism](https://durgical.com/en/conditions/hypothyroidism/) - [Graves disease (hyperthyroidism)](https://durgical.com/en/conditions/graves-disease/) - [Goitre](https://durgical.com/en/conditions/goitre/) - [Thyroid nodule](https://durgical.com/en/conditions/thyroid-nodule/) ## Related - [Thyroid peroxidase (TPO)](https://durgical.com/en/biochemistry/enzymes/thyroid-peroxidase/) - [Iodothyronine deiodinases (DIO1, DIO2, DIO3)](https://durgical.com/en/biochemistry/enzymes/iodothyronine-deiodinases/) - [Thyroxine (T4)](https://durgical.com/en/biochemistry/molecules/thyroxine/) - [Triiodothyronine (T3)](https://durgical.com/en/biochemistry/molecules/triiodothyronine/) - [Iodine](https://durgical.com/en/biochemistry/topics/iodine/) - [Selenium](https://durgical.com/en/biochemistry/topics/selenium/) - [Tyrosine](https://durgical.com/en/biochemistry/molecules/tyrosine/) - [Hormone classes and mechanisms](https://durgical.com/en/biochemistry/topics/hormone-classes-and-mechanisms/) - [Nuclear receptors](https://durgical.com/en/biochemistry/topics/nuclear-receptors/) - [G protein-coupled receptors and cAMP](https://durgical.com/en/biochemistry/topics/g-protein-coupled-receptors-and-camp/) ## 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. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/thyroid-hormone-synthesis/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [SLC5A5 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/slc5a5/) (MedlinePlus, US National Library of Medicine, 2026); [SLC26A4 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/slc26a4/) (MedlinePlus, US National Library of Medicine, 2026); [TPO gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/tpo/) (MedlinePlus, US National Library of Medicine, 2026); [TG gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/tg/) (MedlinePlus, US National Library of Medicine, 2026); [DUOX2 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/duox2/) (MedlinePlus, US National Library of Medicine, 2026); [Congenital hypothyroidism: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/congenital-hypothyroidism/) (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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