Explain synthesis of thyroid hormone

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Synthesis of Thyroid Hormone

The thyroid gland produces two main hormones: thyroxine (T4) and triiodothyronine (T3). Synthesis occurs in a unique two-compartment system involving thyroid follicular cells (thyrocytes) and the colloid-filled follicular lumen. The process has six major steps.

Anatomy of the Follicle

The thyroid is made up of spherical follicles, each a single layer of thyrocytes surrounding a lumen filled with colloid - a viscous material composed primarily of thyroglobulin. Synthesis of hormone occurs partly inside the cell and partly in this extracellular colloid space. Both phases are promoted by TSH (thyroid-stimulating hormone).

Step-by-Step Synthesis

Step 1 - Iodide Uptake (Trapping)

Iodide (I⁻) is actively transported from the blood into thyrocytes across the basolateral membrane by the Na⁺/I⁻ symporter (NIS). This transporter uses the electrochemical gradient of sodium to co-transport iodide against its own concentration gradient, achieving a 30-fold concentration of iodide in thyroid tissue relative to plasma.

NIS is stimulated by TSH and regulated by iodide availability - low plasma iodide triggers upregulation of NIS to compensate.
Once inside the cell, iodide is transported across the apical membrane into the colloid via an I⁻/Cl⁻ transporter called pendrin.

Clinically relevant: NIS is the basis for radioiodine (¹³¹I) therapy in thyroid cancer and hyperthyroidism. Thiocyanate and perchlorate competitively inhibit NIS.

Thyroid hormone biosynthesis diagram showing iodide transport via NIS, MIT, DIT formation, and coupling to form T3 and T4 within thyroglobulin

Ganong's Review of Medical Physiology, Fig. 20-6: Iodide is transported vectorially from plasma across thyrocytes by NIS. Iodine then reacts with tyrosine residues of thyroglobulin in the colloid.

Step 2 - Synthesis and Secretion of Thyroglobulin

In parallel with iodide trapping, thyrocytes synthesize thyroglobulin (Tg) - a large glycoprotein (660 kDa, made of two subunits). Tg is:

Synthesized on the rough ER
Glycosylated in the Golgi apparatus
Secreted by exocytosis via apical vesicles into the follicular lumen (colloid)

Thyroglobulin contains approximately 123-140 tyrosyl residues, which serve as the scaffold on which iodination occurs. Tg itself has no hormonal activity - it is purely a precursor matrix. Only 4-8 of its tyrosine residues are typically incorporated into thyroid hormones.

Step 3 - Organification (Iodination of Tyrosines)

At the apical border (colloid-cell interface), iodide undergoes organification:

Iodide (I⁻) is oxidized to iodine (I₀) by thyroid peroxidase (TPO), a membrane-bound heme enzyme on thyrocyte microvilli, using H₂O₂ as the oxidant.
Reactive iodine is then incorporated into tyrosyl residues on thyroglobulin:
- Addition of one iodine atom → Monoiodotyrosine (MIT)
- Addition of two iodine atoms → Diiodotyrosine (DIT)

The tyrosines remain covalently bound to thyroglobulin throughout this step - no free amino acids are involved.

Clinically relevant: Propylthiouracil (PTU) and methimazole block TPO, inhibiting both oxidation of iodide and the coupling reaction. This is the main mechanism of antithyroid drugs.

Lippincott biosynthesis diagram showing the 5 steps: iodide uptake, thyroglobulin synthesis, iodination, condensation, and proteolytic release

Lippincott Illustrated Reviews Pharmacology, Fig. 23.9: The 5 steps of thyroid hormone biosynthesis and sites of drug action.

Step 4 - Coupling (Condensation)

Still within thyroglobulin in the colloid, TPO also catalyzes the coupling reaction, where two iodinated tyrosines are covalently joined (oxidative coupling), forming an ether linkage between their phenolic rings:

Coupling	Product
DIT + DIT	T4 (thyroxine) + alanine
MIT + DIT	T3 (triiodothyronine) + alanine
DIT + MIT	Reverse T3 (rT3) + alanine

The newly formed T3 and T4 molecules remain embedded within the thyroglobulin polypeptide chain in the colloid, where they serve as a reserve. Humans can go up to 2 months on a completely iodide-free diet before circulating thyroid hormone levels fall, thanks to this stored colloid reservoir.

Normal iodinated compound distribution in thyroid:

MIT: ~3%
DIT: ~33%
T4: ~35%
T3: ~7%

Step 5 - Endocytosis of Thyroglobulin

When thyroid hormone is needed, iodinated thyroglobulin is retrieved from the colloid back into thyrocytes by:

Receptor-mediated endocytosis (predominant with TSH stimulation)
Fluid-phase pinocytosis

The endocytic vesicles (colloid reabsorption droplets) fuse with lysosomes, which contain proteases that hydrolyze peptide bonds throughout the thyroglobulin molecule.

Step 6 - Proteolysis and Secretion

Lysosomal proteases cleave thyroglobulin, releasing:

Free T4 and T3 → secreted across the basolateral membrane into adjacent capillaries
Free MIT and DIT → these are NOT secreted; instead, they are deiodinated by iodotyrosine deiodinase (in the ER), which recovers iodine for reutilization within the gland

This recycling is efficient: recovered iodine from MIT/DIT normally supplies twice the amount of iodide that NIS brings in from plasma.

Clinically relevant: Congenital absence of iodotyrosine deiodinase causes MIT and DIT to spill into the urine, leading to iodine deficiency despite normal iodide intake.

Junqueira's detailed thyrocyte diagram showing all 6 steps: thyroglobulin synthesis (1), NIS uptake (2), pendrin transport (3), peroxidase iodination, coupling, endocytosis (5), lysosomal degradation, and T3/T4 release (6)

Junqueira's Basic Histology, Fig. 20-21: Complete thyrocyte synthesis cycle, showing both the exocrine (synthesis/secretion into colloid) and endocrine (hormone release into blood) phases.

Regulation of Synthesis

TSH (Primary Regulator)

TSH from the anterior pituitary is the main driver of thyroid hormone synthesis. It acts via TSH receptor (TSHR) on thyrocytes, coupled to:

cAMP pathway → stimulates iodide uptake, thyroglobulin synthesis, and hormone secretion
Phospholipase C/Ca²⁺ pathway → involved in synthesis steps

TSH stimulates every step: iodide uptake, thyroglobulin synthesis, iodination, coupling, endocytosis, and secretion.

TRH - TSH - T3/T4 Feedback Axis

Hypothalamus releases TRH (thyrotropin-releasing hormone)
TRH stimulates the anterior pituitary to release TSH
Elevated free T3 and T4 feed back to inhibit both TRH and TSH (classic negative feedback)

Wolff-Chaikoff Effect

When plasma iodide is acutely elevated (as with iodinated contrast agents or amiodarone), organification is transiently inhibited. This is the Wolff-Chaikoff effect, a protective mechanism against excessive thyroid hormone production. The gland normally "escapes" from this effect within days by downregulating NIS.

Products Secreted by the Thyroid

Hormone	Daily secretion	Notes
T4 (thyroxine)	~80 µg/day	Predominant product (90% of circulating TH); prohormone
T3	~4 µg/day	Biologically more active; 80% derived from peripheral T4 deiodination
Reverse T3 (rT3)	~2 µg/day	Biologically inactive
MIT, DIT	Not secreted	Deiodinated and recycled within the gland

Summary of Steps

Step	Location	Key Player
1. Iodide uptake	Basolateral membrane	NIS (Na⁺/I⁻ symporter)
2. Iodide transport into colloid	Apical membrane	Pendrin (I⁻/Cl⁻ transporter)
3. Thyroglobulin synthesis	rER → Golgi → apical secretion	Thyroglobulin
4. Oxidation + Organification	Colloid (apical surface)	Thyroid peroxidase + H₂O₂
5. Coupling	Colloid	Thyroid peroxidase
6. Endocytosis	Apical membrane	Receptor-mediated + pinocytosis
7. Proteolysis + release	Lysosomes → basolateral	Lysosomal proteases
8. Iodine recycling	ER	Iodotyrosine deiodinase

Sources:

Ganong's Review of Medical Physiology, 26th Ed., pp. 369-370 - thyroid hormone biosynthesis section
Lippincott Illustrated Reviews: Pharmacology - thyroid hormone synthesis and secretion
Junqueira's Basic Histology, 17th Ed. - thyrocyte synthesis cycle

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