Thyroid Hormone
Function
Non-essential for life, however, crucial for normal metabolic function.
Activity exerted at the gene expression level.
- Responsible for the tight regulation of metabolic processes including:
- Cellular “housekeeping” functions
- Protein turnover
- Membrane maintenance
- Specialized functions
- Contraction
- Secretion
- Biosynthetic processes
- Cellular “housekeeping” functions
Thyroid Follicles
- Location of thyroid hormone synthesis and storage
- Lined by a single layer of epithelial cells
- Lumen filled with colloid
- Parafollicular cells located in the spaces between follicles
- Produce calcitonin
Colloid
- Gel-like solution composed of 10-25% thyroglobulin.
- Located in the lumen of thyroid follicles
- Actively taken in by cells during thyroid hormone secretion
- Stimulated by TSH
Thyroglobulin
(Tg)
- Large protein with many tyrosine residues
- Only a fraction of these are iodinated
- Site of synthesis and storage for thyroid hormones
- Immature form of thyroglobulin made by follicular cells and secreted into the lumen
Thyroid Hormones
- Iodinated derivatives of amino acid tyrosine
- Synthesized via conjugation of mono-iodotyrosine (MIT) and diiodo-tyrosine precursors (DIT)
- Precursors connected to the thyroglobulin protein backbone until secretion
- Conjugation occurs through an ether linkage between their phenol rings
- Triiodothyronine (T3)
- Contains three iodine atoms
- Formed by the conjugation of one mono-iodotyrosine and one diiodo-tyrosine
- Has a stronger effect compared to T4
- Free form has a half-life of 1 day
- Thyroxine (T4)
- Contains four iodine atoms
- Formed by the conjugation of two diiodo-tyrosines
- Free form has a half-life of 7 days
- Converted by target tissues into the active T3
Biosynthesis of Thyroid Hormones
Overview
- Iodide uptake and luminal transfer
- Oxidation of iodide into iodine
- Iodination of tyrosine residues
- Coupling of MIT and DIT via conjugation
- Endocytosis of thyroglobuin precursor
- Proteolysis, degradation, and recycling of thyroglobulin
- Secretion of T3 and T4
Biosynthesis of Thyroid Hormone
Step 1: Iodide uptake and transfer into the follicle
- Sodium/Iodide Symporter (NIS)
- Located on the basal plasma membrane
- Transports iodide from the blood into the follicle cell against its concentration gradient using the Na+ gradient
- TSH increases expression of NIS
- NIS activity can be stimulated by low levels of iodide in the blood
- Na+/K+-ATPase
- Located on the basal plasma membrane
- Extrudes Na+ from the cell in order to maintain it’s concentration gradient and membrane potential
- Pendrin
- Located on the apical plasma membrane
- Transports iodide into the follicle lumen
- Activity is not affected by TSH
- Iodide is essential in the diet
- Iodide deficiency can lead to patho-physiological hypothyroidism and goiter
Biosynthesis of Thyroid Hormone
Steps 2 and 3: Oxidation and Iodination
These two steps combined is known organification.
All steps are performed by thyroid peroxidase (TPO) located on the apical plasma membrane.
- Oxidizes iodide (I-) into iodine (I2)
- Requires H2O2 produced in the mitochondria
- Oxidizes a tyrosine residue on thyroglobulin and brings it close to the iodine
- Requires H2O2 produced in the mitochondria
- Iodine is transferred to the tyrosine residue side chain producing monoiodotyrosine (MIT)
- If another iodination occurs on the MIT molecule then a diiodotyrosine (DIT) is produced.
Biosynthesis of Thyroid Hormone
Step 4: Coupling
Coupling of two precursor molecules into the final hormones is also performed by the thyroid peroxidase (TPO) enzyme.
- MIT + DIT = triiodothyronine (T3)
- DIT + DIT = thyroxine (T4)
Both hormones remain linked to the thyroglobulin backbone until the thyroid gland is stimulated to secrete into the blood stream by TSH.
Only 20-25% of MIT and DIT are coupled into hormones.
Synthesis of T3 is slower than T4.
Thyroid secretes 5-10x more T4 than T3.
Biosynthesis of Thyroid Hormones
Steps 5 - 7: Endocytosis, Proteolysis, Secretion
Upon stimulation by TSH:
- Apical membrane of follicular cells will extend pseudopodia into the lumen to uptake colloid droplets.
- Both macro and micropinocytosis occurs
- Process mediated by Megalin
- Multipurpose endocytosis receptor with a high affinity for thyroglobulin
- Expression stimulated by TSH
- Endosomes migrate towards the basal region of the cell and fuse with lysosomes.
- Thyroglobulin hydrolyzed into amino acids, MIT, DIT, T3, and T4 which are released into the cytosol.
- T3 and T4 exit the basal membrane of follicular cells and are transferred into the blood via capillaries.
- All other components including iodide are recycled by the cell.
Plasma Transport of Thyroid Hormones
- Thyroxin-binding globulin (TBG) binds the majority of T3 and T4 in the blood.
- Secreted by the liver
- Increases during pregnancy due to the crucial role of thyroid hormones in embryonic development
- Secreted by the liver
- Transthyretin and Albumin bind the rest
- Less than 1% of T3 and T4 circulate in their free form
- Only free form active
- Only free form cleared from the body
- Equilibrium between free and bound forms regulated by the concentration of free form in the blood
- Half-life for T3 is 1 day and T4 is 7 days
- Determined by fraction that is bound to carrier protein and affinity for this binding
Interconversion of Thyroid Hormones
T4 is converted into active T3 by deiodination at the 5’ position of the thyronine ring ⇒ outer ring deiodination.
- Can occur in peripheral issues:
- Performed by Deiodinase Type I (D1)
- Located in liver, kidneys, and thyroid gland.
- Performed by Deiodinase Type I (D1)
- Can occur in the cytosol of target cells
- Performed by Deiodinase Type II (D2)
- Located predominantly in skeletal muscle, CNS, pituitary gland, and placenta.
- Less active in the human fetus.
- Performed by Deiodinase Type II (D2)
Decreased by fasting, trauma, or illness but resolution of these conditions will rapidly restore the activity of deiodinases.
Both T3 and T4 can be inactivated by iodine removal ⇒ inner ring deiodination.
- Performed by Deiodinase Type III (D3)
- Located in the liver and kidneys
About 40% of T4 deiodinated into the inactive reverse T3 (rT3)
T3 inactivated into diiodothryonine.
All deiodinases contain selenocysteine.
Thyroid Hormone
Feedback Control
- T3 and T4 exert a negative feedback on:
- Hypothalamus release of TRH
- Anterior pituitary release of TSH
- T3 and T4 exert a positive feedback on the hypothalamus release of somatotropin release inhibiting factor (SRIF)
- SRIF inhibits the production of TSH by thyrotroph cells in the pituitary
Effects of TSH
TSH receptors are located on the basal membrane of follicular cells.
Action exerted through cAMP production.
- Tropic
- Stimulates:
- Iodine uptake
- Oxidation of iodine and Tg
- Coupling of MIT and DIT
- Endocytosis of Tg
- Stimulates:
- Trophic
- Stimulates:
- Protein synthesis
- Overall growth and proliferation of follicular cells
- Continuous exposure to elevated TSH levels results in enlargement of the entire gland ⇒ goiter.
- Stimulates:
Thyroid Hormone
Mechanism
Only T3 metabolically active.
Modulation of Gene Expression
- T3 binds to the thyroid hormone receptor (TR)
- Type 2 receptor which is already bound to DNA acting as a transcription inhibitor.
- TR expressed in a tissue specific fashion to confer different effects of thyroid hormone on various tissues.
- Upon binding, TR forms a heterodimeric complex with Retinoid X Receptor (RXR).
- Complex binds to the Thyroid Responsive Element (TRE) and initiates transcription.
- Can be modulated by coactivators or corepressors.
Thyroid hormones also exert physiological effects that are not mediated by gene expression:
- Changes in cellular respiration
- Changes in morphology
- Ion homeostasis
Physiological Actions of Thyroid Hormones
- Table below
- Significant thermogenic action
- Stimulation of cytochrome, cytochrome oxidases, and Na+/K+-ATPase in selected cells
- May regulate the activity of mitochondria
- Alter oxygen usage
- Affects skeletal development
- Alters neurological functions
- Changes cardiac output
Hashimoto disease
Primary Hypothyroidism
- Autoantibodies against:
- Thyroid peroxidase
- TSH receptors
- can have initial moderate stimulatory effect on the receptor
- Eventually leads to distruction of the gland
- Can be diagnosed by measuring the levels of Ab in the plasma
Myxedema
Primary Hypothyroidism
- Caused by insufficient intake of iodide in the diet
- Most frequent cause of hypothyroidism
- Continuous production of TSH caused by the reduced negative feedback by T3/T4 will induce hypertrophy of the gland ⇒ goiter
- Symptoms include:
- Weight gain
- Reduced metabolic rate
- Fatigue
- Reduced thermogenesis
- Hypersensitivity to cold
- Peripheral edema
- In severe cases a substance composed of hyaluronic acid and chondroitin sulfate complexes with proteins in the extracellular spaces of the derma leading to osmotic water retention
- Causes a swollen appearance of the skin of face, hands, and feet
Secondary Hypothyroidism
Thyroid gland biosynthetic functions are reduced because of decreased TRH and/or TSH production.
Can be due to hypothalamic failure or pituitary failure.
Results in thyroid gland tissue atrophy.
See low TSH and low T3/T4
Graves Disease
Primary Hyperthyroidism
- Autoantibodies directed against TSH receptors stimulate the biosynthetic activity of the thyroid gland.
- Diffuse toxic goiter results.
- Diagnosis frequently involves increased accumulation of radioactive iodine in the thyroid
- Symptoms include:
- Hyperexcitability
- Fatigue
- Increased metabolic rate
- Weight Loss
- Increased thermogenesis
- Increased heart rate and cardiac output
- Muscle wasting
- Exophthalmos
- Protrusion of the eye bulb due to accumulation of connective tissue at the apex of the orbit
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Endocrine Principles and Signaling Mechanisms34
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Hypothalamic-Pituitary Axis26
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Thyroid Hormones20
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Adrenal Hormones35
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Pancreatic Hormones22
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Hormonal Regulation of Calcium Metabolism24
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Cardiovascular System172
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Cardiovascular Abbreviations25
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ANS Signal Transmission & Receptors12
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Pulmonary112
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Pulmonary Symbols, Terminology, and Normal Values63
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Gastrointestinal124
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Renal161
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Reproductive38
