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