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What are the thyroid hormones and what are they derived from?

Tyrosine. Each different hormone has a different number of iodines in different positions (T4, T3, rT3).


Describe thyroid hormone synthesis

Made in the epithelial cells. TSH binds to TSHR and activates GalphaS pathway. AC and cAMP phosphorylate most of the enzymes involved in this pathway. Iodine is brought into the cell from the blood and IP3 stimulates production of thyrogobulin. As thyroglobulin is released into the colloid, THOX2 (thyroid oxidase) and TPO (thyroid peroxidase), iodinate thyroglobulin. Iodinated thyroglobulin is then stored in the colloid. TSH also stimulates production of microvilli at the apical membrane allowing reuptakes of thyroglobulin. Inside the cell T3 and T4 get released from thyroglobulin and D1/D2 play a role in converting T4-->T3. However, still more T4 (inactive) is released from the cell than T3 (active).


What is goiter?

Too much TSH leading to enlargement of the thyroid gland.


What are the causes of goiter?

1. iodine deficiency
2. defects in thyroid biosynthesis
3. TSH receptor defect
4. thyroid hormone resistance


How does iodine deficiency cause goiter?

not able to make T3 or T4 which means no negative feedback to inhibit TSH, so constant stimulation of TSHR leading to hypertrophy of the thyroid


What does thyroid hormone receptor defect lead to?

Goiter. Causes there to be increased TSH and T3/T4 in the blood. Since T3 and T4 aren't affecting their target organs, there is increased levels in the blood. But there are also increased TSH levels because the body is trying to get those effects to happen at the tissue and it isn't working, so it keeps secreting more TSH. It presents as hypothyroidism since no thyroid hormone effects are working, but there is both TSH and thyroid hormone present in the blood.


How are thyroid hormones carried in the blood?

by TBG (thyroxine-binding globulin), TTR (transthyretin) and albumin


Which binding protein is specific and nonspecific?

Specific=TBG, higher affinity for T4
Nonspecific= TTR and albumin, higher affinity for T4


What is the half life of T3 and T4?

thyroid hormone is mostly bound (1% unbound). T4 is more stable than T3 since the binding proteins have a higher affinity for T4 and therefore T4 has a much longer half life.


What does DI and DII do?

Are iodothyronine deiodinases that eliminate the 5' iodine converting T4 to T3.


What does DIII do?

Eliminates the 5' iodine on the N side to convert T4 to rT3 (inactive)


Which thyroid hormones are active and which are inactive?

T4, rT3, T2 are all inactive
T3 is active


Where is D1 located at the peripheral tissues?

D1 is on the plasma membrane where it is able to bind T4 and convert it to T3 and release T3 back out into the circulation.


Where is D2 located at the peripheral tissues?

D2 is near the nucleus and golgi. T4 enters the cell and is converted to T3 but this T3 can enter the plasma or stay in the cell and plays an important role in negative feedback in the anterior pituitary and hypothalamus. In the anterior pituitary there is only D2 so the T4 that comes in and is converted to T3 stays in the cell allowing anterior pituitary to sense how much thyroid hormone is in the blood and regulate TSH levels.


Where is D3 located at the peripheral tissues?

D3 is also located at the plasma membrane but converts T4 to rT3, inactivating it and making a hormone that cannot bind to the D receptors. Main inactivator receptor.


What are the main products of D1, D2 and D3?

D1=T3, rT3 and T2
D3=rT3 and T2


What is propylthiouracil (PTU)?

Inhibitor of D1, often used to treat hyperthyroidism.


What stimulates release of thyroid hormone?

1. Hypothalamus is stimulated and releases TRH
2. TRH stimulates anterior pituitary to make TSH
3. TSH binds to receptors at thyroid gland causing production and release of T3/T4
4. Elevated T4/T3 levels will have negative feedback at the anterior pituitary (D2) and hypothalamus (D2?) inhibiting release of TRH and TSH.


What results of a defective TSHR?

- high TSH
- low T4
This is a defect with the thyroid gland itself, so primary problem.


What results of a defective pituitary or hypothalamus (adenoma)?

- high TRH
- high TSH
- high T4
Secondary or tertiary problem.


What results from autoantibodies stimulating TSHR?

autoantibodies bind to TSH receptor acting as an agonist so you get:
- high T4
- low TSH


How does TRH lead to release of TSH?

1. TRH binds to TRHR at anterior pituitary
2. causes increase in PLC/IP3/DAG/Ca
3. leads to transcription and translation of TSH from the anterior pituitary


How does T4/T3 inhibit TSH release at the anterior pituitary?

1. T4 enters the cell and converted to T3 by D2.
2. T3 sits on the HRE in the nucleus, inhibiting transcription of TSH genes
3. T3 also down regulates the level of the TRHR


What are the thyroid receptors (TR)?

Ligand-activated transcription factors. In the DNA there are TRE (thyroid response elements) to which TR can bind. When no T3 (ligand) is present, TR binds to TRE and has conformational effects that only favor corepressors to bind. When T3 is present, TR binds to TRE and has a conformational change that only allows coactivators to bind leading to expression.


Where are thyroid hormone receptors (TR) found?

In the peripheral tissues, the thyroid receptors are found in the nucleus bound to the DNA (differs from MR and GR which were found in the cytoplasm)


What are the effects of thyroid hormone?

1. Increases BMR
2. Increases metabolism and fate of fuels
3. Essential for nervous system development and mental well-being
4. Bone growth and mass
5. Cardiovascular system


What are the effects of thyroid hormone on BMR?

- increased O2 consumption
- increase NaK ATPase
- increased thermogenesis


What are the effects of thyroid hormone on metabolism and fate of fuels?

- increased glycolysis and gluconeogenesis in liver
- increased lipolysis
- increase glucose upstate and protein degradation
- increase LDL-cholesterol clearance (increased LDL in the blood)


What are the effects of hypo and hyperthyroidism on mental well-being?

hypothyroidism=depression, memory loss, slow speech, dulled senses
hyperthyroidism= irritability, restlessness, hyper-excitability


What are the effects of hypo and hyperthyroidism on growth?

hypo=short stature (creatinism)
hyper=too much growth?