unit 5, lesson 3, Thyroid Gland: Development, Anatomy, and Structure

• Thyroid hormones are the focus of the material

Thyroid Gland Development

• The thyroid gland appears very early in life
• Development begins ~4 weeks post-conception via tongue epithelial invagination
• It moves down the neck, forms a bilobular structure, and completes by the 3rd trimester

Anatomy of Thyroid Gland

• The thyroid gland comprises two 20-25g lobes on either side of the trachea, below the larynx, joined by the isthmus
• It has a 'Butterfly shape'
• A pyramidal lobe is often present
• The thyroid gland has a rich blood supply from thyroid arteries
• The autonomic nervous system innervates it

Cellular Structure of Thyroid Gland

• Distinct cellular organisation is related to its function
• It has cells arranged in follicles
• Over a million follicles exist here
• Follicles are spherical bodies of epithelial cells around the colloidal storage protein, thyroglobulin

Histology of Thyroid Gland

• Epithelial cell height differs based on gland activity
• Inactive epithelial cells are flattened with a large colloidal mass
• Active cells are columnar with a small colloidal lumen
• Epithelial cells are exocrine, absorptive and endocrine
• Larger epithelial cells lie between follicles as parafollicular C cells make calcitonin
• Connective tissue, blood vessels, and nerves form the lobule by surrounding follicle groups

Thyroid Hormone Synthesis

• Dietary iodide (I-) is uptaken from the blood by an iodide pump
• I- concentrates to 25-50 times plasma concentration, which is 600µg/g of tissue
• Thyroid Stimulating Hormone (TSH), iodine deficiency, and TSH receptor antibodies enhance iodide uptake
• The iodide pump is inhibited by I-, perchlorate (ClO4-), thiocyanate (SCN-), pertechnetate (TcO4-)
• H₂O₂ oxidizes I- from thyroid peroxidase to I₂ at the apical surface
• I₂ incorporates into tyrosyl residues covalently bound to thyroglobulin (TG) molecules at the apical border
• This forms monoiodotyrosine (MIT) and diiodotyrosine (DIT)
• Thyroid peroxidase couples MIT and DIT to form T3 (3,5,3'-triiodothyronine) and T4 (3,5,3',5'-tetraiodothyronine, thyroxine)
• T3 is the active hormone, and reverse T3 is not active
• Cells continually produce TG as secretory vesicles and exocytose it into the colloid
• Thyroid hormones are stored in the colloid until secretion
• TSH uses lysosomes of the TG-hormone complex to cause endocytosis and proteolysis
• T3 and T4 are released into the bloodstream
• Halogenases de-iodinate MIT and DIT, reusing free iodine and tyrosine

Transport of Thyroid Hormones

• T4 constitutes ~90%, and T3 constitutes ~10% of thyroid hormones, equalling to 80-100µg/day
• T3 and T4 are transported in plasma bound with thyroid-binding globulin, transthyretin, and albumin
• T3 is less avidly bound compared to T4
• Only the free hormone not bound to plasma proteins is biologically active

Metabolism of Thyroid Hormones

• In the periphery (liver/kidney), T4 de-iodinates to T3; most T3 comes from this pathway
• T4 plasma t1/2 life is 6-7 days, and T3 is 24-36 hours
• T3 is ~10 times more potent than T4
• T3 and T4 conjugate to glucuronide or sulphate in the liver
• This results in the excretion of conjugated forms through bile
• Iodide excretes via urine or re-circulates back to the thyroid

Regulation of Thyroid Hormone Release

• The regulation gets influenced by cold, trauma, and stress
• The hypothalamus secretes TRH
• Somatostatin and dopamine inhibit the thyroid system
• The anterior pituitary secretes TSH
• T3 and T4 act as direct negative feedback on the anterior pituitary and hypothalamus

Control of Synthesis and Release

• Thyrotrophin Releasing Hormone (TRH) is a tripeptide from the hypothalamus
• TRH stimulates release of thyrotrophin or Thyroid Stimulating Hormone (TSH) from the anterior pituitary
• TRH also releases prolactin
• Synthetic TRH (Protirelin) gets administered by intravenous injection to test thyroid function

Thyroid Stimulating Hormone (TSH)

• TSH acts on specific receptors on the basal membrane
• It increases synthesis of iodide pumps and thyroglobulin
• Synthesis and secretion of T3 and T4 increases too
• Follicular epithelium and vascularity thickness increases
• Thyroid hormones, cortisol, growth hormone, oestrogens, dopamine, and somatostatin inhibit TSH release

Mechanism of Action of Thyroid Hormones

• T3 and T4 enter cells via passive diffusion or active uptake
• T4 de-iodinates to T3 or rT3
• T3 gets transported to the nucleus, plus binds to cytosolic thyroid hormone-binding protein (CTBP)
• T3 binds to thyroid receptors (TR) in the nucleus that are bound to regulatory thyroid hormone response elements (TREs)
• Thyroid hormone receptor auxiliary protein (TRAP) is necessary to stabilize TR binding to DNA
• Stimulation/inhibition occurs of target genes
• Several TR (α1-3, β1-2) exist, with different distributions, and undetermined functions
• T3 binds to membrane-associated receptors to activate Na+/K+ ATPase pump, leading to rise of glucose and amino acids
• T3 activates mitochondria to increase energy production

Physiological Actions of Thyroid Hormones

• Increase basal metabolic rate (BMR)

Calorigenesis

• Oxygen consumption increases in all tissues except the brain, spleen, testes, and anterior pituitary, thus, heat production increases
• Important for thermoregulation
• It involves synthesis of new Na+/K+ ATPase pumps in the cell membrane and direct activation of mitochondria
• It takes 4-5 days to occur
• Blockers of Na+/K+ ATPase pumps inhibit actions of thyroid hormones

Carbohydrate, Protein and Fat Metabolism

• There is a direct effect on carbohydrates that involve increased Gl glucose absorption and synthesis of metabolic enzymes
• Indirect effects sensitize tissues to insulin, catecholamines and GH
• It boosts gluconeogenesis and glycogenolysis in the liver
• This raises glucose utilization in fat, liver, and muscle cells
• Synthesis and degradation of protein balances at low thyroid hormone levels, yet degradation predominates at high levels
• Both fat synthesis and lipolysis occur
• Lipolysis is more key
• Potentiation of catecholamine activity occurs on adipocytes
• Free fatty acids oxidation and calorigenesis increases
• Plasma cholesterol decreases by increasing liver uptake through increasing LDL receptors and bile acid formation

Maturation of the Central Nervous System

• Essential for normal CNS development during foetal and early neonatal life
• T3 and T4 do not cross the placenta
• Growth of cortical and cerebellar neurones and myelination of nerve fibres result

Skeletal Growth and Maturation

• Synergistic effects occur with GH that are essential for bone growth, development, and normal stature
• Also essential for normal functioning of nervous and cardiovascular systems, Gl tract, development of teeth, skin and hair

Need for Thyroid Hormones

• Aids responses to extremes of temperature
• The body gets maintained at 37.2°C
• When the body detects low temperature, T3 and T4 immediately release from the thyroid gland
• Tissues and mitochondria use more O2, creating heat
• Underactive thyroid gland (people feel cold) is a useful symptom

Summary of Thyroid Hormones

• Thyroid gland has a location, structure and cells
• Needs I- for hormone synthesis and storage
• Regulation of synthesis and release occurs via negative feedback, TRH, TSH
• Molecular mechanism of action has nuclear and membrane receptors
• Physiological actions increase BMR and are needed for standard development