Thyroid Hormone Phys/Pharm [TRH] Flashcards
What form is TRH translsated in?
WI its mature form?
translated as: preprohormone
mature= tripeptide
Besides the thyroid/hypothalmus/pit, where can you find TRH in the body?
What are the major roles of TRH?
- TRH is also in the cerebral cortex, GI, & pancreas
- Roles/regulation:
- regulates energy homeostasis [thru stimulation of TSH & regulating circulating thyroid H levels]
- feeding behavior
- thermogenesis
- autonomic regulation
What is the structure of TSH?
- alpha chain: same as other pit. H’s [listed below]
- beta chain: specific to TSH [and each gonadotropin; LH, FSH, hCG]
- confers specificity of H action
What is the structure of T4?
What is the structure of T3?
- T4: 2 tyrosines + 4 Iodine
- T3: 2 tyrosines + 3 iodine
7 steps of thyroid H synthesis?
- dietary iodide required & active transport of I- into thyroid follicular cell
- Oxidation of I- [iodide] to I2 [iodine]…aka organification
- Iodination of tyrosines bound to thyroglobulin backbone–>
- MIT & DIT
- conjugation of MIT & DIT –> TriiodoT [T3] & TetraiiodT [T4]
- dependendent on thyroid peroxidase
- endocytosis of conjugates
- proteolysis of conjugates into mature T3 & T4
- move T3 & T4 out of cell
Compare T3 & T4?
- activity
- circulation []
T3:
- more active
- shorter circulating half life [1 day]
- binds thyroid H R’s
T4:
- less active
- longer circulation half life [6 days]
- binds thyroid H R’s
- converted intracellularly to T3!!!!
What are the 3 main thyroid H carrier proteins?
-what do they bind respectively?
Thyroxine binding globulin [TBG]
- binds 75% of T3 & T4
- 1 binding site for 1 thyroid H molecule
Transthyretin
- binds 20% of T4, 5% of T3
- 2 binding sites
Albumin
- binds 5% T4 & 20% T3 [has several binding sites]
When are serum [thyroid H] carrier proteins highest?
lowest?
increased: in pregnancy OR estrogen/androgen Tx
Decreased: hyperthyroidism, malnutrition & nephritic syndrome [diseases that cause protein loss]
note: 99.98% of T4 & 99.95% of T3 are bound to carriers
What does total H mean?
bound + free = total
***total can fluctuate
What molecules deactivate & activate T4 & T3?
Deactivate:
- DI & III
- converts T4 –> rT3 = not active
Activate:
- DI & II
- convert T4 –> T3 =active
Which Deiodinase is responsible for both activation & deactivation of thyroid H’s?
- where is it most abundant?
- one more unique thing about it?
Deiodinase I:
- highly prevalent in liver and kidney
- converts T4 to T3 [more active] & increases T3 in cell/circul8
- converts T4 to rT3 [inactive] for disposal
- drug target for **prophylthiouracil **
What are DII & III responsible for repectively?
-where are they most abundant?
DII:
- in brain, pit, sk. & cardiac muscles
- converts T4 to T3 [activates intracellularly]
DIII:
- in brain, skin, placenta
- deactivates hormones
What process does TSH stimulate?
- secretion/release of mature H’s [T3 & T4]
- thyroid peroxidase synthesis
- Na+/I- symporter activity [^^ I- availability to follicular cell]
- Thyroglobulin transcription
Biochemically, how is T4 converted to T3?
DI removes a 5’ iodine!
Which has a higher thyroid H [], intracellular or plasma/serum?
Why is this?
intracellular [] > serum/plasma []
**this is due to 10+ different energy-dependent thyroid H transporters –> help maintain the above gradient
What effects are seen in congenital hypothyroid [caused often by maternal hypothyroidism] in infants
- profound mental retardation
- short stature
- delay in motor development
- coarse hair
- protuberant abdomens
What are the causes of maternal hypothyroidism?
- lack of Iodine in maternal diet [rare now]
- mother has Hashimoto’s thyroiditis –> makes anti-TSH R antibodies
- exposure to radioactive Iodine or antithyroid drugs during pregnancy
What is the RDA of iodine?
-where can we get it in our diets?
RDA: 150 mcg/day for men & women
TUL: 1,100 mcg/day
dietary sources: sea food, esp. kelp, & plants grown in iodine-rich soil
**iodized salt too
HYpothyroid effects/**cretinism **in infants
respiratory difficulty
cyanosis
jaundice
poor feeding
hoarse cry
umbilical hernia
slowed bone maturation: prox. tibial & distal femoral epiphysis lengths shorter than expected indicate hypoThyroidism
How do we Tx hypoThy in infants?
if hormone replacement occurs w/in few days of birth, development will proceed normally
***if delayed Tx; physical development will be fine but mental development will be retarded
thus we should screen newborns [although not all states have made this mandatory yet]
HypoThy effects in adults
lethargy
somnolence
slowed intellect fxn’s; speech!
stiff & aching muscles
cold intolerance
delayed deep tendon reflexes
anovulation & amenorrhea common, menorrhagia less common
HyperThy effects in adults
- promote rapid contraxn & relax of muscles –>^^HR
- ^^# if Beta adrenerguc R’s in heart, Sk.M, fat & lymphocytes –>^^catecholamine sensitivity
- amplified post-R axn of catecholamines
- ^^contrxn–>^^O2 demand –>^^EPO prdxn –> ^^erythropoesis
- ^^GI motility–> D
- promote bone turnover w/ net bone loss & hyperCa+
- ^^protein turnover –> net loss of Sk.M & myopathy
- heat intolerance
- ^^hepatic GluNeo & GlyLys & intestinal absorption of Glu
- ^^ LDL-R #’s –> ^^LDL clearance –> decreased LDL levels
- alters prdxn, responsiveness, & met. clearance of many H’s
- precocious puberty
- ^^aromatization of androgens to estrogens & ^^sex H binding globulins –> gynecomastia in men
- impairs GnRH & regulation of ovulation –> infertility
WI thyrotoxicosis?
WI thyroid storm?
How do we Tx/prevent?
Thyrotoxicosis: any cause of excessive thyroid H [] & its effects
Thyroid storm: extreme manifestation of thyrotoxicosis & one of most critical endocrine illnesses [less than 10% of pts with tox get storm]
Thus we Tx thyrotoxicosis as if they will progress to a STORM:
- B-adrenergic blockers, thioamides [antithyroid], corticosteroids [covers fxnl hypoadrenalism induced by thyrotox]
What are the causes of 1’ Hypothyr?
2’/tertiary?
1’: problem in thyroid gland itself
- congenital
- gland destrxn [surg, radiation, external rad]
- Iodine deficiency
- Autoimmune [hashimoto]
2’/tertiary: problem in pit gland or hypothalamus
note: you can also have thyroid H resistance syndromes [norm thyroid H prodxn]
