Thyroid Gland - Physiology

1. Overview

2. Hormones of the Thyroid Gland

3. Thyroid Follicle Structure

• The colloid consists primarily of thyroglobulin (TG), a large glycoprotein (~335 kDa, ~70 tyrosine residues) that is the precursor and storage form of thyroid hormones
• The thyroid is the only endocrine gland that stores its hormones in large extracellular quantities - enough supply for up to 2-3 months without new synthesis
• The gland has an exceptionally rich blood supply (~5x gland weight per minute) - Guyton & Hall, p. 930

4. Thyroid Hormone Synthesis

Step-by-Step Process

• Dietary iodide is absorbed from the GI tract and circulates in blood
• The sodium-iodide symporter (NIS) on the basolateral membrane co-transports 1 I⁻ with 2 Na⁺ into the thyrocyte (driven by Na⁺-K⁺ ATPase gradient)
• This concentrates iodide ~30x the blood level normally; up to 250x when maximally stimulated
• TSH is the most important regulator of NIS activity
• Iodide then exits across the apical membrane via pendrin (chloride-iodide counter-transporter) into the follicular lumen - Guyton & Hall, p. 930

• Thyrocytes synthesize thyroglobulin in the RER and Golgi
• Thyroglobulin is secreted by exocytosis into the follicular lumen (an "exocrine" phase)
• Thyroglobulin contains ~70-140 tyrosine residues, but only 4-8 are normally incorporated into thyroid hormones - Ganong's, p. 370

• At the apical membrane, thyroid peroxidase (TPO) oxidizes iodide (I⁻ → I⁰ or I₃⁻) using H₂O₂
• Oxidized iodine rapidly incorporates into tyrosine residues on thyroglobulin within the colloid
• This process is called "organification"

• Monoiodotyrosine (MIT): Tyrosine + 1 iodine atom (position 3)
• Diiodotyrosine (DIT): Tyrosine + 2 iodine atoms (positions 3 and 5)
• T4 (Thyroxine): DIT + DIT coupling (TPO-mediated oxidative condensation)
• T3: MIT + DIT coupling
• rT3: DIT + MIT (but outer ring iodination)
• Ganong's, p. 370 and Guyton & Hall, p. 931

• Thyroid hormones remain covalently attached to thyroglobulin in the colloid as a large hormone reservoir

• When stimulated (by TSH), thyrocytes endocytose colloid containing thyroglobulin
• Lysosomes fuse with the endocytic vesicles; lysosomal proteases hydrolyze the peptide bonds
• Free T4 and T3 are released into the cytosol and then into capillaries
• MIT and DIT are deiodinated within the cell; iodine is recycled
• Ganong's, p. 370

5. Transport in Blood

• Only the free (unbound) fraction is biologically active (~0.03% of T4; ~0.3% of T3)
• Total plasma levels can change with binding protein levels (e.g., high TBG in pregnancy increases total T4 but free T4 remains normal - patient is euthyroid)
• Ganong's, p. 372-373

6. Peripheral Metabolism: T4 → T3 Conversion

• 87% of circulating T3 comes from peripheral T4 deiodination (only 13% directly secreted by the thyroid)
• 95% of circulating rT3 comes from peripheral deiodination
• Ganong's, p. 371

7. Regulation of Secretion - The HPT Axis

• Tripeptide secreted by paraventricular nuclei of the hypothalamus
• Stimulates thyrotrophs of anterior pituitary to secrete TSH
• Also stimulates prolactin secretion

• Glycoprotein; secreted by anterior pituitary thyrotrophs
• Actions on thyroid: stimulates NIS (iodide trapping), thyroglobulin synthesis, organification, endocytosis of colloid, and thyroid cell growth (trophic)
• Binds TSH receptor (GPCR) → activates Gs → ↑ cAMP → protein kinase A pathway
• Higher TSH concentrations also activate G-PLC pathway

• Free T3 (converted from T4 in anterior pituitary by local D2 deiodinase) down-regulates TRH receptors on thyrotrophs
• Reduces sensitivity to TRH stimulation → decreases TSH secretion
• This reciprocal system maintains a steady-state of thyroid hormone output

• Somatostatin (inhibits TRH action)
• Dopamine
• High-dose glucocorticoids
• Costanzo Physiology, p. 426 and Ganong's, p. 373

8. Mechanism of Action at Target Cells

1. T4 enters target cell and is converted to T3 by 5'-deiodinase (D1 or D2)
2. T3 enters the nucleus and binds to a thyroid hormone nuclear receptor (TR-alpha or TR-beta)
3. The T3-receptor complex binds to thyroid hormone response elements (TREs) on DNA (often as a heterodimer with RXR - retinoid X receptor)
4. Stimulates transcription → new mRNAs → new protein synthesis
5. New proteins mediate all physiological effects - Costanzo Physiology, p. 428

9. Physiological Effects of Thyroid Hormones

a) Basal Metabolic Rate (BMR)

• Most pronounced effect: ↑ BMR, ↑ O₂ consumption, ↑ heat production
• Mechanism: induction of Na⁺-K⁺ ATPase in most tissues → more ATP consumed → more O₂ required → more heat generated
• This is the basis of "calorigenesis" - Costanzo Physiology, p. 428

b) Metabolism

• Carbohydrate: ↑ GI glucose absorption, ↑ glycogenolysis, ↑ gluconeogenesis (potentiates catecholamines and glucagon)
• Fat: ↑ lipolysis (releases free fatty acids), ↑ cholesterol synthesis AND degradation (net: ↓ cholesterol - hypothyroidism → hypercholesterolaemia)
• Protein: Both synthesis and degradation increased, but net effect is catabolic → decreased muscle mass at high levels
• Key enzymes induced: cytochrome oxidase, α-glycerophosphate dehydrogenase, malic enzyme, proteolytic enzymes

c) Cardiovascular System

• ↑ Heart rate and ↑ contractility → ↑ cardiac output
• Mechanism: induction of cardiac β₁-adrenergic receptors, cardiac myosin heavy chain, and sarcoplasmic reticulum Ca²⁺-ATPase
• Also causes peripheral vasodilation (due to ↑ tissue O₂ demand and heat) → ↓ SVR
• Net: ↑ pulse pressure, bounding pulse (classic hyperthyroid sign)

d) Growth and Development

• Acts synergistically with growth hormone (GH) and somatomedins (IGF-1) to promote linear bone growth
• Promotes ossification, fusion of bone plates, and bone maturation
• In hypothyroidism: bone age < chronological age

e) Central Nervous System (CNS)

• Critical age-dependent effects:
  • Perinatal period: Essential for CNS maturation. Hypothyroidism → irreversible mental retardation (cretinism) - this is why neonatal thyroid screening is mandatory
  • Adults: Hypothyroidism → listlessness, somnolence, impaired memory, slowed reflexes; Hyperthyroidism → hyperexcitability, hyperreflexia, irritability

f) Sympathetic Nervous System Interaction

• Thyroid hormones up-regulate β₁-adrenergic receptors on myocardium and other tissues
• Effects of thyroid hormones on heart rate, cardiac output, lipolysis, and gluconeogenesis are synergistic with catecholamines
• Clinical significance: β-blockers (propranolol) effectively relieve many symptoms of hyperthyroidism (tachycardia, tremor) - Costanzo Physiology, p. 429

10. Calcitonin (from C Cells)

• Secreted by parafollicular (C) cells derived from neural crest (via ultimobranchial body)
• Released in response to elevated blood Ca²⁺
• Action: inhibits osteoclast activity → ↓ bone resorption → ↓ plasma Ca²⁺
• In humans, this role is less physiologically important than parathyroid hormone (PTH) and vitamin D for calcium homeostasis - Ganong's, p. 369

11. Pathophysiology Summary

• T4 is the main secretory product but is a prohormone; T3 is the active hormone
• The thyroid is unique in extracellular, long-term hormone storage (2-3 months reserve)
• Synthesis requires iodine, thyroglobulin, and thyroid peroxidase - block any one and you block hormone production
• Free T3 exerts negative feedback on the anterior pituitary
• Thyroid hormones act genomically via nuclear receptors to increase Na⁺-K⁺ ATPase and β₁-adrenergic receptors in key tissues