7. Thyroid hormones

Question 1

Which hormones are produced by the thyroid gland?

Answer 1

• calcitonin
• thyroxine (T4)
• triiodothyronine (T3)

Question 2

What is the chemical structure of T3 and T4?

Answer 2

2 tyrosines linked together with iodine at 3 or 4 positions on the aromatic rings:

• T3 = monoiodotyrosine (MIT) + diiodotyrosine (DIT)
• T4 = diiodotyrosine + diiodotyrosine

Question 3

Which protein acts as a scaffold for thyroid hormone formation and storage?

Answer 3

thyroglobulin - contains 134 tyrosines although only a handful of these are actually used to synthesise T4 and T3

Question 4

Describe the absorption and thyroid localisation of dietary iodine.

Answer 4

1. dietary iodine reduced to iodide before absorption, principally in small intestine
2. iodide (I-) taken up from blood by thyroid epithelial cells which have a sodium-iodide symporter (“iodide trap”)

Question 5

Describe the basic steps in the synthesis of T3 and T4 in the thyroid follicles.

Answer 5

1) (tyrosine-rich) thyroglobulin synthesis by epithelial cell using amino acids, and exocytosis into follicle lumen (colloid)
2) transport of iodide into thyroid epithelial cells against conc. gradient via sodium-iodide symporter, and movement into colloid
3) oxidation of iodide to iodine (requires presence of H2O2)
4) iodination of tyrosine residue side chains in thyroglobulin to form MIT and DIT
5) coupling of DIT with MIT/DIT to form T3/T4 within the thyroglobulin.

Question 6

Which enzyme is involved in thyroid hormone production and what are its roles?

Answer 6

Thyroid peroxidase - membrane-bound enzyme that regulates 3 separate reactions involving iodide:

1- oxidation of iodide to iodine
2- addition of iodine to tyrosine acceptor residues on thyroglobulin
3- coupling of MIT or DIT to generate thryoid hormones within the thyroglobulin protein

Question 7

Describe the storage of thyroid formones. How long would this store last?

Answer 7

Stored extracellularly in follicle lumens as part of thyroglobulin molecules.

Considerable amounts stored that would last for several months at normal secretion rates (due to relative scarcity of iodine in environment)

Question 8

How are thyroid hormones secreted?

Answer 8

1- Thyroglobulin taken into epithelial cells from lumen of follicles by endocytosis/pinocytosis.
2- Fusion of vesicle with lysosome (phagolysosome formation) and proteolytic cleavage of thyroglobulin to release T3 and T4.
3- Diffusion of T3 and T4 from epithelial cells into circulation.

Question 9

What is the ratio of T3:T4 production and secretion?

Answer 9

1:10 (i.e. 90% T4)

Question 10

What happens to most of the T4 outside of the thyroid? Why?

Answer 10

Most T4 converted to T3 in liver and kidneys as biological activity of T3 is 4x that of T4

Question 11

Describe the regulation of thyroid hormone secretion via the HPT axis.

Answer 11

1. paraventricular nucleus of hypothalamus secretes TRH (thyrotropin releasing hormone) into the hypothalamic/pituitary portal system…
2. stimulates thyrotropes in anterior pituitary to secrete TSH (thyroid stimulating hormone)…
3. binds follicle cell surface receptors to stimulate all aspects of synthesis and secretion of T3/T4.

Question 12

Which factors affect the secretion of TRH and TSH from the hypothalamus and AP?

Answer 12

Hypothalamus release of TRH:

i) circulating levels of T3/T4 - negative feedback (long loop)
ii) TSH - negative feedback (short loop)
iii) stress (increases release)
iv) temperature (fall in temp increases release

AP release of TSH:

i) circulating levels of T3/T4 - negative feedback (long loop)
ii) released in low-amplitude pulses following a diurnal rhythm with higher levels attained during the night and decreasing in early hrs of morning

Question 13

What is the hormone type and structure of TSH?

Answer 13

glycoprotein hormone composed of 2 non-covalently bound subunits (alpha and beta)

Question 14

What does TSH stimulate to trigger thyroid hormone release?

Answer 14

1. iodide uptake
2. iodide oxidation
3. thyroglobulin synthesis and iodination
4. colloid pinocytosis into cell
5. proteolysis of thyroglobulin
6. cell metabolism and growth

Question 15

How can TSH cause goitre formation?

Answer 15

TSH has trophic effects on thyroid gland resulting in:

i) increased vascularity
ii) increased size and number of follicle cells

Question 16

Describe the induction of second messenger pathways by TSH.

Answer 16

Can bind to GalphaS or GalphaQ GPCRs:

1. activates adenylyl cyclase… cAMP… protein kinase A…
2. activates phospholipase C… DAG and IP3… Ca2+ release via IP3 receptor and PKC activation…

… stimulation of thyroid hormone synthesis and release.

Question 17

How are T3 and T4 transported in the blood?

Answer 17

• Are hydrophobic so transported bound to protein: thyroxine binding globulin, pre-albumin and albumin.
• <1% of T3/4 is free in solution but it is this free hormone that is biologically active.

Question 18

Why does T3 have a shorter half life than T4?

Answer 18

T3 has slightly lower affinity for transport proteins than T4, so greater free % and shorter 1/2 life in circulation (2 days cf. 8 days)

Question 19

Why is the TOTAL amount of T3/T4 in blood increased during pregnancy?

Answer 19

Oestrogens increase synthesis of TBG during pregnancy… more T3/T4 bound so fall in free T3/T4… removes inhibitory feedback on hypothalamus and pituitary… more TRH and TSH produced… increase T3/T4 secretion - amount of free T3/T4 returns to normal but total amount in blood is increased.

Question 20

What are the 3 general actions of thyroid hormone?

Answer 20

1. increase in basal metabolic rate and heat production
   i) increase no. and size of mitochondria
   ii) stimulate synthesis of respiratory chain enzymes
2. stimulation of metabolic pathways, esp. catabolic pathways
   i) lipid metabolism: stimulates lipolysis and beta-oxidation of fatty acids
   ii) carb metabolism: stimulate insulin-dependent entry of glucose into cells and increase gluconeogenesis and glycogenolysis
3. sympathomimetic effects
   - increase target cell response to catcholamines by increasing adrenergic receptor no.

Question 21

In which tissues do thyroid hormones not stimulate the BMR and heat production?

Answer 21

brain, spleen and testis (would damage brain, affect sperm production…)

Question 22

How do thyroid hormones stimulate insulin-dependent entry of glucose into cells?

Answer 22

stimulate expression of Glut4 on cell membranes

Question 23

How are thyroid hormones important in physical development?

Answer 23

• directly affect bone mineralisation

- increase synthesis of heart muscle protein

Question 24

What is the effect of thyroid hormones on the CVS?

Answer 24

Increase heart’s responsiveness to catecholamines:

• increased cardiac output (increase in chronotropy and inotropy)
• increased peripheral vasodilation to carry extra heat to body surface

Question 25

What is the effect of thyroid hormones in the adult CNS? What is the lack of thyroid hormones characterised by?

Answer 25

essential for adult function: increase nerve myelination and dev. of neurons.

poor concentration, poor memory and lack of initiative

Question 26

Why can the absence of thyroid hormones in childhood lead to cretinism?

Answer 26

T3 and T4 essential for dev. of CNS, required for:

i) dev. of neuron cellular processes
ii) hyperplasia of cortical neurons
iii) myelination of nerve fibres

If deficiency within a few wks from birth, causes irreversible mental and physical retardation - cretinism.

Question 27

What is the effect of T3/T4 on ovulation?

Answer 27

T3/4 have permissive role in actions of hormones such as FSH and LH - ovulation fails to occur in absence of thyroid hormones

Question 28

What is the mechanism of action of T3 and T4?

Answer 28

1. Thyroid hormones are lipid-soluble but enter target cell through thyroid hormone transporters.
2. Nuclear thyroid hormone receptor is pre-bound to specific DNA sequences - hormone response elements - in promoter region of thyroid hormone regulated genes.
3. Thyroid hormone enters nucleus and binds receptor… conformational change in receptor causing it to act as trasncriptional activator… relieves repression of gene transcription.
4. i) Expression of new protein mediates effects of thyroid hormone… cellular response.
   ii) Increased rate of protein synthesis stimulates oxidative energy metabolism in target cell to provide extra energy required for protein synthesis.

Question 29

How can T4 be converted to T3 and why is this an important mechanism for the regulation of active hormone amount?

Answer 29

T4 converted to T3 in tissues by removal of 5’-iodide.

T3 has 10x activity of T4 as 10-fold greater affinity for receptors.

Question 30

What is the effect of removal of 3’-iodide of T4?

Answer 30

produces inactive reverse T3 (rT3) which can bind to thyroid hormone receptors without stimulating them, blocking effects of T3.

Question 31

Give examples of thyroid hormone activated genes.

Answer 31

Genes involved in upregulation of metabolism, e.g.

• cytochrome oxidase (key ETC component)
• Na+/K+ ATPase

Question 32

Describe the general levels of free T3 and T4, and TSH in the blood.

Answer 32

pM range

Question 33

Why do free T3/T4 and TSH serum levels vary (unrelated to thyroid disease)?

Answer 33

Free T4 and T3:

• methodological factors
• albumin changes
• dilution effects

TSH:

• diurnal variation
• pulsatile secretion
• medications