Thyroid hormone synthesis, step by step
Six steps turn iodide into T₄ and T₃, and each antithyroid drug is defined by the step it blocks. Learn the sequence once and the drug map follows.
Trace thyroid hormone synthesis (iodide trapping, organification, coupling, release, peripheral T₄-to-T₃ conversion) and name the drugs that block each step.
The short version
- Trapping, pendrin efflux, peroxidase iodination, coupling, release, then deiodination to T₃: that is the order of thyroid hormone synthesis.
- Perchlorate and thiocyanate block iodide uptake; methimazole and propylthiouracil block thyroid peroxidase.
- Propylthiouracil, at high doses, also blocks peripheral conversion of T₄ to T₃.
- A large iodide load briefly shuts synthesis down (Wolff-Chaikoff effect) and pharmacological doses inhibit release.
- TSH drives every step and makes the gland grow, so iodine lack means low hormone, high TSH and a goitre.
A gland that cannot make hormone, and keeps growing
A woman in a remote mountain village has a neck swollen to the size of a grapefruit. Her blood tests show she is hypothyroid, and her TSH is very high. A gland that cannot make enough hormone is growing. Why?
The answer lies in thyroid hormone synthesis. Trace the steps, place the drug that blocks each one, and the puzzle resolves.
Work through it in order. Each step has its own transporter or enzyme, and each drug is defined by the single step it blocks. Keep the sequence in mind and the drug list stops being a list to memorise.
The axis, the follicle and why iodine lack causes a goitre
The hypothalamus releases TRH, which drives TSH from the pituitary, and TSH drives the thyroid. T₄ and T₃ then feed back and switch TSH off.[1][2]
TSH stimulates every step of synthesis, and it also makes the gland grow. So when iodine is scarce, hormone falls, TSH rises and the gland swells: a goitre.[2][9]
The thyroid is built of follicles: a ring of follicular cells around a lumen of colloid, which is rich in thyroglobulin. Hormone assembly takes place on the thyroglobulin in the colloid.[1][2]
Notice the logic: if a step inside the gland is blocked, whether by iodine lack or by a drug, hormone falls and TSH rises. Because TSH also stimulates growth, a blocked gland does not shrink. It swells.[2][9]
Steps 1 and 2: iodide trapping and pendrin efflux
Step 1, trapping. The sodium-iodide symporter (NIS) on the blood side of the cell actively pulls iodide in.[1][2]
Perchlorate and thiocyanate compete at this step and block iodide uptake.[2][5]
Step 2, efflux. Iodide leaves the apical side of the cell into the colloid through pendrin.[2][9]
Think of trapping as the gate into the cell and pendrin as the gate out into the colloid. Both are needed before the peroxidase can work on the iodide.[2][9] Back to the woman in the mountain village: her iodine-poor diet starves step 1, so hormone falls, TSH rises and the gland swells.[2][9]
Steps 3 and 4: organification and coupling in thyroid hormone synthesis
Step 3, organification. Thyroid peroxidase (TPO), using hydrogen peroxide, oxidises iodide and attaches it to tyrosines on thyroglobulin. This makes monoiodotyrosine (MIT) and diiodotyrosine (DIT).[1][2]
Step 4, coupling. One MIT plus one DIT makes T₃. Two DITs make T₄. The same enzyme drives it.[1][2]
Because the same enzyme drives both steps, one drug acting on thyroid peroxidase interrupts both organification and coupling.[3][6]
| Combination | Product |
|---|---|
| MIT + DIT | T₃ |
| DIT + DIT | T₄ |
Methimazole and propylthiouracil block thyroid peroxidase, so they inhibit organification and coupling.[3][6][7]
Step 5: release, and the Wolff-Chaikoff effect
The cell takes colloid back in by endocytosis, lysosomes digest the thyroglobulin, and T₄ and T₃ diffuse into the blood. T₄ is made far more than T₃.[1][2]
A large iodide load briefly shuts synthesis down. This is the Wolff-Chaikoff effect, and the gland escapes within days. Pharmacological doses of iodine also inhibit hormone release.[2][3][4]
Step 6: peripheral conversion of T₄ to T₃
Step 6 happens outside the gland. Deiodinases remove one iodine from T₄ to make T₃, the active hormone. Types 1 and 2 activate; type 3 makes inactive reverse T₃.[1][2]
At high doses, propylthiouracil also blocks that peripheral conversion.[3][6][8]
| Type | Action |
|---|---|
| Types 1 and 2 | Activate: T₄ to T₃ |
| Type 3 | Makes inactive reverse T₃ |
The drug map: which step each drug blocks
| Step | Process | Drug or agent |
|---|---|---|
| 1 | Iodide trapping (NIS) | Perchlorate, thiocyanate |
| 2 | Efflux into colloid (pendrin) | None of the antithyroid drugs |
| 3 | Organification (TPO) | Methimazole, propylthiouracil |
| 4 | Coupling (TPO) | Methimazole, propylthiouracil |
| 5 | Release (endocytosis, proteolysis) | Pharmacological iodide (a large load also briefly blocks organification: Wolff-Chaikoff) |
| 6 | T₄ to T₃ conversion | Propylthiouracil, at high doses |
Both antithyroid drugs can cause agranulocytosis, rarely and more often at higher doses. Propylthiouracil is the one with liver failure, and methimazole is the one rarely linked to birth defects.[3][4]
Practice question
Original · USMLE styleA 29-year-old woman comes to the clinic because of weight loss, heat intolerance and a tremor over the past 3 months. Her pulse is 118/min. Examination shows a diffuse, non-tender goiter and bilateral exophthalmos. Laboratory studies show a free thyroxine (T4) concentration of 5.6 ng/dL (reference 0.8-1.8) and an undetectable serum TSH concentration. She is diagnosed with Graves disease and treatment with methimazole is started.
Common questions
What are the steps of thyroid hormone synthesis?
Trapping of iodide by NIS, efflux into the colloid through pendrin, organification by thyroid peroxidase, coupling to T₃ and T₄, release by endocytosis and proteolysis, then deiodination of T₄ to T₃ outside the gland.
How do methimazole and propylthiouracil work?
Both block thyroid peroxidase, so they inhibit organification and coupling. At high doses, propylthiouracil also blocks the peripheral conversion of T₄ to T₃.
What is the Wolff-Chaikoff effect?
A large iodide load briefly shuts thyroid hormone synthesis down, and the gland escapes within days. Pharmacological doses of iodine also inhibit hormone release.
Why does iodine deficiency cause a goitre?
Hormone falls, so TSH rises. TSH stimulates every step of synthesis and also makes the gland grow, which produces a goitre.
Transcript
Read the full narration, by chapter606 words
0:00A goitre and a high TSH
A woman in a remote mountain village has a neck swollen to the size of a grapefruit. Her blood tests show she is hypothyroid, and her TSH is very high. A gland that cannot make enough hormone is growing. Why? Today: trace thyroid hormone synthesis step by step, and place the drugs that block each step.
0:21The axis: TRH, TSH, T4 and T3
The hypothalamus releases TRH, which drives TSH from the pituitary, and TSH drives the thyroid. T4 and T3 then feed back and switch TSH off. TSH stimulates every step we are about to see, and it also makes the gland grow. So when iodine is scarce, hormone falls, TSH rises, and the gland swells: a goitre.
0:48The thyroid follicle and step 1: iodide trapping (NIS), perchlorate
The thyroid is built of follicles: a ring of follicular cells around a lumen of colloid, which is rich in thyroglobulin. Step one, trapping. The sodium iodide symporter on the blood side of the cell actively pulls iodide in. Perchlorate and thiocyanate compete here, and block iodide uptake.
1:10Steps 2 and 3: pendrin, then organification by TPO
Step two, iodide leaves the apical side into the colloid, through pendrin. Step three, organification. Thyroid peroxidase, using hydrogen peroxide, oxidises iodide and attaches it to tyrosines on thyroglobulin, making monoiodotyrosine, MIT, and diiodotyrosine, DIT. Step four, coupling.
1:34Step 4: coupling to T3 and T4
One MIT plus one DIT makes T3. Two DITs make T4. The same enzyme drives it. Methimazole and propylthiouracil block thyroid peroxidase, so they inhibit organification and coupling.
1:53Step 5: release, and the Wolff-Chaikoff effect
Step five, release. The cell takes colloid back in by endocytosis, lysosomes digest the thyroglobulin, and T4 and T3 diffuse into the blood. T4 is made far more than T3. A large iodide load briefly shuts synthesis down, the Wolff-Chaikoff effect, and the gland escapes within days. Pharmacological doses also inhibit hormone release.
2:21Step 6: peripheral conversion (D1, D2, D3)
Step six happens outside the gland. Deiodinases remove one iodine from T4 to make T3, the active hormone. Types one and two activate; type three makes inactive reverse T3. At high doses, propylthiouracil also blocks that peripheral conversion.
2:42Antithyroid drug adverse effects, and back to our patient
Both antithyroid drugs can cause agranulocytosis, rarely and more often at higher doses. Propylthiouracil is the one with liver failure, and methimazole is the one rarely linked to birth defects. Back to our patient: an iodine-poor diet starves step one, hormone falls, TSH rises, and the gland swells.
3:06Practice question
Your turn. A 29-year-old woman has weight loss, heat intolerance, tremor and a pulse of 118. She has a diffuse goitre and exophthalmos, her free T4 is high, and her TSH is undetectable. She is diagnosed with Graves disease and started on methimazole. Which of the following steps in the thyroid follicle is the primary target of this drug? A, iodide uptake by the sodium iodide symporter. B, iodide efflux into the colloid through pendrin. C, endocytosis of colloid and proteolysis of thyroglobulin. D, TSH receptor signalling on follicular cells. E, thyroid peroxidase catalysed iodination and coupling. Pause here and decide. A is out: that step is blocked by perchlorate and thiocyanate, not by this drug. B is out: pendrin only carries iodide into the colloid, and the antithyroid drugs do not target it. C is out: release is what pharmacological iodide inhibits, not methimazole. D is out: the drug works downstream of the receptor, on the enzyme that builds the hormone. So the answer is E.
4:26Answer and explanation
Methimazole blocks thyroid peroxidase, so it inhibits iodination and coupling. Propylthiouracil does the same, and at high doses it also blocks T4 to T3 conversion.
4:41Recap and next lesson
Three things to keep. One: trapping, pendrin efflux, peroxidase iodination, coupling, release, then deiodination to T3. Two: perchlorate blocks uptake, thionamides block the peroxidase, and propylthiouracil also blocks conversion. Three: TSH drives it all, so iodine lack means a goitre. Next, calcium balance: parathyroid hormone, vitamin D and calcitonin.
Sources
Numbers in the text, e.g. [1], point here- OpenStax. Anatomy and Physiology 2e, section 17.4, The Thyroid Gland. openstax.org/books/anatomy-and-physiology-2e/pages/17-4-the-thyroid-gland
- Critical role of iodine and thyroid hormones (review). Int J Mol Sci 2025. PMC12610087. pmc.ncbi.nlm.nih.gov/articles/PMC12610087/
- Hyperthyroidism. MSD Manual Professional Edition. msdmanuals.com/professional/endocrine-and-metabolic-disorders/thyroid-disorders/hyperthyroidism
- Antithyroid drug adverse effects (review). PMC13320707. pmc.ncbi.nlm.nih.gov/articles/PMC13320707/
- Propylthiouracil; Perchlorate (secondary reference). Wikipedia. en.wikipedia.org/wiki/Propylthiouracil · en.wikipedia.org/wiki/Perchlorate
- Preoperative preparation in hyperthyroidism (review, 2024). PMC11472198. pmc.ncbi.nlm.nih.gov/articles/PMC11472198/
- Guidelines for the treatment of childhood Graves disease (Japan, 2016). PMC5402306. pmc.ncbi.nlm.nih.gov/articles/PMC5402306/
- Thyroid storm, Japanese perspective (2018). PMC5770119. pmc.ncbi.nlm.nih.gov/articles/PMC5770119/
- Thyroid physiology review (TSH signalling, apical iodide efflux). PMC9519864. pmc.ncbi.nlm.nih.gov/articles/PMC9519864/
The thyroid panel and patient on screen are an invented teaching vignette. Values on screen are illustrative.
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (cropped, recoloured, outlined): woman, neck and thyroid, thyroid gland, pituitary gland, brain, tablet, eye. The thyroid follicle, molecules, lab slip, question card and all handwriting are drawn in code (original). No AI-generated images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-ENDO-003.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01Hypothalamic-pituitary axes and feedback: primary, secondary, tertiary5:05
- EP 02Primary vs secondary endocrine disorders: paired hormone levels5:13
- EP 03Insulin secretion in the beta cell: from glucose to granule5:06
- EP 04Insulin vs glucagon signalling: receptors and effects5:19
- EP 05DKA vs HHS pathophysiology: why only one makes acid5:58
- EP 06Diabetes drugs by mechanism: where each class acts5:58
- EP 07Thyroid hormone synthesis, step by step5:14
- EP 08Calcium homeostasis: PTH, vitamin D and calcitonin5:28
- EP 09Adrenal steroidogenesis: zones, enzymes and the 17α-hydroxylase fork5:29
- EP 10Congenital adrenal hyperplasia: three enzymes, three patterns5:44
- EP 11Cushing syndrome: the dexamethasone suppression test and ACTH5:29
- EP 12Primary hyperaldosteronism: high aldosterone, low renin5:27
- EP 13SIADH vs diabetes insipidus: central vs nephrogenic DI5:44
- EP 14MEN1, MEN2A and MEN2B: match the gene to its tumours5:13