Thyroid hormones

T3 is more active

RT3 is inactive

T4 is secreted in greatest portion

T4 is converted into T3 in peripheral tissues

Synthesis

Metabolism of iodine

Daily intake = 500 microgram

Thyroid uptake = 120 microgram

Secretion as T3 and T4 from thyroid = 80 microgram

Diffusion from thyroid into ECF = 40 microgram

Liver and other tissue metabolise T3 and T4
* 60 microgram of iodine released back to ECF
* 20 microgram of iodine excreted as bile

Urine excretion = 480 microgram

 

Iodide (I-) uptake

Thyroid cell membrane facing the capillaries
--> Na-I Symporter
--> I- is transported into thyroid cells with secondary active transport
--> I- diffuses into collids

 

Thyroglobulin

• Glycoportein
• 2 subunits
• 10% carbohydrate by weight
• 123 tyrosine residues
• Synthesized in thyroid cells and secreted into the colloid

 

Functions of thyroid cells

• Transportation and concentration of iodine
• Synthesis and secretion of thyroglobulin
• Remove thyroid hormone from thyroglobulin and release the hormone into circulation

 

Synthesis of thyroid hormone

• Tyrosine (bound to thyroglobulin) binds to iodine
  --> Forms monoiodotyrosine (MIT)
• MIT binds another iodine
  --> Diiodotyrosine (DIT)
• When 2 DIT couple together
  --> T4 forms
• When MIT + DIT
  --> T3 forms

Enzyme:
Iodination (and maybe coupling) are catalyzed by thyroid peroxidase

Secretion

Thyroid cells ingest colloid by endocytosis
--> Protease in lysosome breaks the peptide bond between iodinated residues and thyroglobulin
--> MIT, DIT, T3 and T4 are liberated

T3 and T4 released

MIT and DIT broken down by iodotyrosine deiodinase

 

Metabolism

T3 and T4 are heavily bound to plasma proteins

Plasma proteins

• Albumin
  * Halflife = 13 days
• Transthyretin (thyroxine-binding prealbumin)
  * Halflife = 2 days
• Thyroxine-binding globulin (TBG)
  * Halflife = 5 days

NB:

• Albumin has the highest capacity to bind T4
• TBG has the smallest capacity to bind T4, but has the highest affinity for T4

--> Most of the circulating T4 are bound to TBG

 

T4

99.98% of T4 is bound

Free T4 is only 2ng/dL

Halflife = 6-7 days (long)

 

T3

99.8% of T3 is protein-bound
* 46% to TBG
* Rest to albumin

Free T3 = 0.15 microgram/dL

Halflife = shorter ????

 

Metabolism

T4 and T3 are deiodinated in the liver, kidney and other tissues

3 deiodinases

• D1
  * Primarily responsible for conversion of T4 to T3
  * Present in liver, kidney, thyroid, and pituitary
• D2
  * Present in brain, pituitary, and brown fat
  * Also contribute to conversion of T4 to T3
• D3
  * Present only in brain and reproductive tissues
  * Probably the main source of RT3

Some T4 and T3 are conjugated in liver to form sulfates and glucuronides
--> Secretion into bile and excreted

Some T4 and T3 pass directly from circulation into intestinal lumen

 

Fasting

T3 reduced by 10-20% in 24 hours of fasting

T3 reduced by about 50% in 3-7 days of fasting

--> Conservation of calories and protein

 

Actions and regulation

Mechanism of action

T3 and T4 binds to thyroid receptors in the nuclei
--> Hormone-receptor complex binds to DNA via zinc fingers

T3 binds to receptor more avidly

 

Actions

Main actions

• Calorigenic effect
  --> Stimulation of O2 consumption
• Development
  * Essential for normal growth and skeletal maturation
  * Also potentiate effect of growth hormone
  --> Permissive role [WG21:p410]
• Lowers circulating cholesterol
  * Due to increased formation of LDL receptors in liver
  * Independent of calorigenic effect

Other actions

• Increase RBC 2,3-DPG
  --> Increase O2 dissociation
• Needed for hepatic conversion of carotene to vitamin A
• Needed for normal menstrual cycles and fertility
• Needed from brain development
  * Cerebral cortex, basal ganglia, and cochlea affected
• Increase GIT absorption of carbohydrate

Calorigenic effect

• Increase O2 consumption in all tissues except
  * Adult brain
  * Testes
  * Uterus
  * Lymph nodes
  * Spleen
  * Anterior pituitary
• Increase Na-K ATPase
• Increase nitrogen excretion
• Similar effect as catecholamines

 

Hypothyroidism

• Milk secretion decreased
• Myxoedema
  --> From accumulation of proteins, polysaccharides in skin
  --> Accumulation of water in kin
• Slow mental ability
• CSF protein level elevated
• Prolonged reflex reaction time
• Muscle weakness, cramps and stiffness

During development

Hypothyroidism during development causes

• Mental retardation
• Motor rigidity
• Deaf-mutism

 

Hyperthyroidism

• Shortened reflex reaction time
• Muscle weakness (thyrotoxic myopathy)
  * May be due to increased protein catabolism

 

Regulation

Hypothalamus release
--> Thyrotropin-releasing hormone (TRH)

TRH stimulates anterior pituitary to release
--> Thyroid-stimulating hormone (TSH)

TSH stimulates release of T3 and T4 from thyroid

Negative feedback

T3 and T4 feeds back on anterior pituitary and hypothalamus to inhibit TSH and TRH formation
* T3 is the principle feedback

Secretion is inhibited before synthesis

Other factors

TSH inhibited by

• Stress
• Glucocorticoids
• Dopamine and somatostatin

TRH increased by cold and decreased by heat

 

TSH

• 2 subunits: alpha and beta
• Halflife = 60minutes
• Degrades in kidney (mostly) and also liver
• Alpha unit is the same as that in LH, FSH, and hCG-alpha
  --> High levels of hCG can activate thyroid receptors

Action of TSH

• Increase iodine binding in thyroid
• Synthesis of T3 and T4
• Increased secretion of thyroglobulin
• Increased endocytosis of the colloid

TSH receptor

Activates adenylyl cyclase via Gs protein

Other notes

Large doses of iodides act directly on thyroid
--> Mild and transient inhibition of organic binding of iodide
--> Inhibition of synthesis