L12 - Thyroid Hormones

Question 1

Thyroxine, T4, is hydrophobic (serum, synthesis)

Answer 1

• Insoluble in serum
• Therefore transported in serum in conjunction with specific binding proteins
• Binding proteins are synthesised in the liver
• Liver disease can lead to loss of effective T4 transport to peripheral tissues

Question 2

Thyroxine-binding globulin (TBG):

Answer 2

o Binds 70-75% of plasma T4
o Large circulating reservoir of T4
o Prevents loss in urine

Question 3

Transthyretin (TTR):

Answer 3

o Binds 20% of plasma T4

o Important for delivery to CNS

Question 4

Albumin

Answer 4

o Binds 5-10% of plasma T4

Question 5

Daily production (T3/T4)

Answer 5

8ug T3 / 90ug T4 daily production from gland

Question 6

Affinity and capacity of T4 binding proteins

Answer 6

• TBG has a high affinity and low capacity for T4
• Transthyretin has a low affinity and high capacity for T4
• Albumin has a very low affinity and high capacity for T4

Question 7

oxide-binding globulin (TBG): the principal T4-binding globulin (Chain, weight, half life, levels and tim/inhib)

Answer 7

• Single polypeptide chain
• 20% CHO by weight, molecular heterogeneity
• Increased by T4 and by oestrogens/androgens
• Stability and half-life are extended after T4 binding
• Doubles in concentration during pregnancy
• Level is lowered by corticosteroids, illness, stress, cirrhosis, nephrotic disorders

Question 8

Transport of T3 and T4 into cells

Answer 8

• Bound T3 and T4 cannot enter cells
• Free T3 and T4 can enter cells via specific transporters (e.g. MCT8, MCT10, OATP1c1)
• T4 is INACTIVE, and must be converted to T3 by intracellular iodothyronine deiodinases (DIO)

Question 9

Iodothryonine deiodinases

Answer 9

• Seleno-cysteine containing enzymes
• Selenium accepts iodide (takes on of the iodines from T4 => T3)
o DIO1+2 T4 = T3
o DIO1+3 T4 = rT3

Question 10

Iodothronine deiodinase 1 (DIO1)

Answer 10

o Predominates in liver, kidney and muscle
o Also found in thyroid
o Produces most of the circulating T3

Question 11

Iodothryonine deiodinase 2 (DIO2)

Answer 11

o Predominates in areas of the CNS, pituitary thryotropes
o Controls intracellular T3 concentration
o Important for feedback regulation
o Found in skeletal muscle in some species

Question 12

Iodothryonine deiodinase 3 (DIO3)

Answer 12

o Produces inactive rT3

o Prevents thyroid hormone access to specific tissues

Question 13

Thyroid hormone action (receptors, subunits, location, binding, affinity and transcription)

Answer 13

• Thyroid hormone receptors (TR)

• TRα and TRβ (THRA and THRB)
o Found in cytoplasm and translocate into nucleus

• Heterodimer with retinoid X receptor (RXR)
• Functions as transcription factor
• Binds to TRE
• 15-fold ↑ affinity for T3 than T4
• Increased gene transcription – BUT can also inhibit.

Question 14

In the anterior pituitary gland (T3)

Answer 14

• T3-responsive genes include those encoding:
• ↑growth hormone
• ↓prolactin
• ↓a- and b-subunits of TSH

Question 15

Biological actions of thyroid hormones: Control of basal metabolic rate

Answer 15

a. Increase transcription of Na/K ATPase – Mt resp enzymes – Other proteins
i. Increase O2 consumption (02 and Sub)
1. Increase metabolic rate

Question 16

Biological actions of thyroid hormones: Growth-regulating roles of thyroid hormones

Answer 16

a. Synergise with other hormones
b. Deficiencies lead to abnormal growth, development, reproduction, behaviour, metabolism - Exert effects on all organs and tissues throughout life

= arrest of bone elongation + reduction in GH secretion

Question 17

Biological actions of thyroid hormones: Role of thyroid hormone in foetal development

Answer 17

a. Key role in developing neural and skeletal systems

b. Loss of T4 supply to foetus leads to irreversible intellectual disability and dwarfism (previously cretinism).

Question 18

Biological actions of thyroid hormones: Cardiovascular effects

Answer 18

a. T3 increases:
i. Cardiac contraction and output
ii. Heart rate
iii. Oxygen supply to tissues
iv. CO2 removal from tissues

b. Direct Effects
i. ↑Myocardial Ca2+ uptake
ii. ↑expression of α-myosin heavy chain and ↓ β
iii. ↑expression of RYR in SR

c. Indirect Effects
i. ↑Metabolism, Thermogenesis, Vasodilation
ii. ↑ sensitivity to catecholamines

Question 19

Biological actions of thyroid hormones: Musculoskeletal effects

Answer 19

a. T3 has a potent stimulatory effect on bone turnover, increasing both formation and resorption
b. T3 increases linear bone growth after birth
c. T3 increases the rate of muscle relaxation
d. Normal skeletal muscle function requires T3