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Unit 3 Physiology: Thyroid Gland (Rillema)
THYROID HORMONES:
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Chemistry:
Thyroxine (T4):
o Prohormone of T3 (remove I with deiodinase enzyme; not very specific so you can get T3 or reverse T3)
o Thyroid gland releases 10x more T4 than T3
3,5,3’ Trioodothryronine (T3): biologically active hormone (50% of T4)
3,3’5’ Trioodothryronine (reverse T3): not made by the thyroid gland and not biologically active (50% of T4)
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Synthesis (Net Reactions):
o 2 Tyrosines + 1 ½ I2  T3 + Alanine
o 2 Tyrosines + 2 I2  T4 + Alanine
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Thyroid Follicular Cell:
From Bloodstream:
o Na-I Symporter: pumps I- into follicular cell
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Very powerful (can pump against gradient of 250:1)
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Driving force from Na,K-ATPase (secondary active; requires ATP)
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Present in many other places in the body: intestine, mammary gland, salivary glands, Cori
plexus (no I- in the CSF), ciliary body (no I- in aqueous humor)
o Once iodide is in the cell, converted to iodine (I2) using thyroperoxidase enzyme
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Tyrosine enters follicular cell as well
To enter Colloid:
o Pendrin Iodide Transporter: pumps iodide into colloid
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Also in mammary gland
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Pendrin Syndrome: leads to hypothyroid, deafness
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Two Step Synthesis (Simplified):
1. Iodination:
Tyrosine  Mono-iodotyrosine (MIT) or Diiodotyrosine (DIT) using thryoperoxidase enzyme
2. Conjugation:
2 DITs can combine  T4 + Alanine (require coupling enzymes at apical surface)
1 DIT + 1 MIT combine  T3 + Alanine (require coupling enzymes at apical surface)
o Note: to be active T3 (and not reverse T3) MIT must be the molecule that loses the alanine
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Actual Synthesis from Thyroglobulin:
Thyroglobulin (TGB): glycoprotein with 2 peptide chains (~115 tyrosine residues)
o Peptide chains synthesized in ER, glycosylation occurs in Golgi
o Iodination and conjugation occur in TGB at the apical border of the cell (thyroperoxidase)
o Thyroid hormones are stored within TGB in colloid (~2 month supply)
Conjugation:
o Requires the use of coupling enzymes, which cleave pieces of MIT and DIT from A and B chains and
move them to other DIT residues to form T3 and T4
o Cleaving and moving a DIT to an MIT gives you reverse T3, which is not active
o Alanine is left at the cleavage sites after removal of the ring structure (maintains integrity of chains)
Colloid Content:
o 6 MIT : 5 DIT : 0.3 T3 : 3 T4
o 20% of 115 tyrosine residues get iodinated
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Mechanism of Secretion:
Endocytosis of colloid into follicular cells and condensation of endocytosed vesicles with lysosomes
Proteolytic cleavage of TGB to AA, MIT, DIT, T3 and T4
o T3 and T4 released into bloodstream
o MIT and DIT are deiodinated, and I- and AA are recycled into new TGB
Amount Secreted: 10x more T4 secreted than T3
o Fate of T4: 35% converted to T3, 45% converted to reverse T3, 20% destroyed
o Source of Plasma T3: 80% from T4 conversion, 20% from thyroid
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Transport in Plasma:
T3 and T4 bound to plasma proteins (99.9%)
o Thryoxine Binding Globulin (TBG):
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Binds T4 strongly; binds T3 1/3 as strongly
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Binds 45-60% of plasma T4; 75% of plasma T3
o Prealbumin: binds 15-35% T4, does not bind T3
o Albumin: binds 15% T4 and 25% T3
Free T3 and T4: only fraction available to target cells
o 0.5% plasma T4 is free (3 ng/100mL)
o 0.5% of plasma T3 is free (1.5 ng/100mL)
Metabolism of T3 and T4:
Have very long half-lives compared to other hormones
o 6 days for T4
o 1-3 days for T3
Details of degradation not known
o Probably occurs primarily in muscle, liver and kidney
o Probable mechanism: deiodination, conjugation, oxidation, deamination, decarboxylation or splitting
of ether linkage
Actions of Thyroid Hormones:
Only T3 is biologically active
o Binds to receptor in the nucleus and alters transcription (in concert with retinoic acid receptor, forms a
heterodimer)
Functions on all body cells, increasing hundreds of metabolic processes
Long acting (days)
Specific Functions of T3:
Normal Growth Processes: going above or below normal levels impairs growth
o T3 Deficiency: dwarfism (cretinism); open epiphyses
o T3 Excess: stunted growth; closed epiphysis
Required for normal function of nervous system:
o T3 Deficiency (Children): cretinism resulting in mental retardation (T3 required in first 3 months of life
or retardation is permanent)
o T3 Deficiency (Adults): listless, sleepy, weak, general decreased nervous system function, decreased
catecholamine function
o T3 Excess: hyperexcitable nervous system (increases beta adrenergic receptors on cells)
Increases basal metabolic rate:
o Increased O2 used in oxidative metabolism
Increased turnover of lipids and carbohydrates:
o Increased rate of glycogenesis and glycogenolysis:
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Stimulates both formation and breakdown, but no net change in glycogen stores
o Increased rate of gluconeogenesis
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Net decrease in protein (broken down to make glucose)
o Increased rates of lipogenesis and lipolysis
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Stimulates both formation and breakdown, with net decrease in fat stores
o Increased rate of cholesterol synthesis and degradation
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Stimulates both formation and breakdown, with net decrease in plasma cholesterol
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Cholesterol levels used in clinics to assess thyroid status
 Hyperthyroid- low cholesterol
 Hypothyroid- high cholesterol
Required for normal protein metabolism:
o Excess T3 results in protein loss (increased gluconeogenesis)
o T3 deficiency results in myxedema (accumulation of mucopolysaccharide in the skin resulting in
swelling and edema not due to fluid)
Required for heat production: needed to survive cold climates
Required for various other processes:
o Lactation
o Digestion
o Kidney function
o CV function
o Reproduction (infertility can result from excess or deficiency of T3)
Regulation of T3 Secretion:
Thyroid functions at 50% capacity without TSH input (but this is not enough to prevent hypothyroidism)
Feedback inhibition occurs at anterior pituitary (inhibits TSH release; major pathway) and at the hypothalamus
Neural inputs causing TRH release from hypothalamus: cold, stress, exercise
Wolff-Chaikoffe Effect: give oral slug of iodide release of T3 and T4 inhibited for 2-4 days (used in clinics)
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Pathological States:
Goiter: enlarged thyroid gland
o Can be associated with normal secretion of thyroid hormone
o Can be caused by dietary iodide deficiency
Hyperthyroidism:
o Symptoms:
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Irritability
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Increased basal metabolic rate
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Fatigue
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Weight loss
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Increased body temperature
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Exopthalmos
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Positive chronotropism (increased heart rate)
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Increased activity
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Loss of hair
o Causes:
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Graves Disease: autoimmune disease in which TSI (thyroid stimulating immunoglobulin; Ab
to TSH receptor) is produced; TSI stimulates the TSH receptor on the thyroid gland
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Tumor of thyroid gland
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Tumor of pituitary gland (increased TSH)
Hypothyroidism:
o Symptoms:
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Sluggishness
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Mental retardation
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Reduced growth rate
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Thick and dry skin
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Sensitive to cold
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Increased sleep
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Frog-like voice
o Causes:
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Poor development of thyroid
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Thyroid insensitive to TSH (no goiter)
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Thyroid with goiter but reduced production of thyroid hormones (metabolic defect in
hormone production)
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Hashimoto’s Disease: Abs formed against TGB result in breakdown of thyroid tissue