1.1Anatomy of the thyroid Gland¶
- weight about 15g
- left and right lobes are connected by isthmus
- congential hypothyroism: sometimes due to thyroid remains attach to tongue.
- general structure: 2 benzene rings linked by ester bond. paraposition of outer ring is a hydroxyl group and paraposition of the inner ring is a alanine group.
- iodine at 5 position (C5 at inner ring) is vital for biological activity of thyroid hormone.
- $T_4$: 3,5,3'5' tetraiodothyronine , thyroxine : has four iodine, two on each rings
- $T_3$: 3,5,3' triodothyronine
- reverse $T_3$: doesn't have iodine at C5, so inactive. synthesized at hyperthyroism?
- produced in thyrocyte and stored in follicles
- Follicles have cavities surrounded by epithelial cells.
- that cavities are filled w/ colloids which are made of thyroglobulin
- thyroglobulin (Tg) are 330000 MW glycoprotein as a large monomer
- Tg also exist as dimer and polymerse, but dimers are more important.
- though huge, not particular rich in tyrosine.
- It's the spacial distribution of thyrosines creates hormonogenic sites (i.e sites of production).
-- tyrosine residue (MIT and DIT) are spatially very close to each other
-- this allow thyroid peroxidase, in presence of $H_2O_2$, to bring the coupling (oxidation )of the 2 thyroxine residues together.
1.2.2Biosynthesis and Secretion (Production in more details)¶
- On the basal surface of a thyroid cell there's NIS, a I-/Na+ symporter
-- it concentrates I against gradient, energy comes from Na/K ATPase, pumping Na+ in drags I- in.
-- I- in side the cell is 200 times that outside the cell
- I- is toxic so it's oxydized to $I_2$
- $I_2$ is incorporated into Tg, whose post translational modificatino includes glycosylation, dimerization, etc, before being dumped into the colloid.
--$I^-$ can also be dumped into the colloid via pendrin, a tranporter at the apical surface
- thyroid synthesis: Tg is endocytosed by the cell and broken down by lysosome:
-- $T_4$ and $T_3$ are released in the cells and send to the extracellular compartment
-- MIT and DIT are recycled by enzymes which remove iodine from them.
- btw, MIT + DIT = 1 $T_3$ and 2 X DIT = 1 $T_4$
- also, Tg is a large reservoir, storing I and thyroid hormones and is effective for 4~ 6 weeks
-- durgs that given to reduce hyperthyrodism don't take effect until after 4-6 weeks.
1.3Roles of Thyroid Hormones¶
- Growth and development and some specific functions in all vertebrae.
- For homeothermic species (warm-blooded animals): thermogenesis and ancillary metabolic effects
- Hormonal effects depend on the concentration in or around the cells
-- Increase in plasma concentration also increases effect.
2Hypothalamic Pituitary Thyroid Axis¶
- In short: TRH (hypothalamus) --> TSH (anterior pituitary) --> $T_4$ and $T_3$ (thyroid)
- Paraventircular nucleus secretes TRH which induces secretion of TSH in the anterior pituitary.
- Thyrotropes in anterior pituitary produces TSH which induces thyroid secretion in the thyroid.
- $T_4$ and $T_3$ negative feedback onto production of TRH and TSH on hypothalamus and ant. pituitary, respectively.
-- on TSH synthesis, processing (post-translational event) , etc
2.1Thyrotropin/Thyroid Stimulating Hormone (TSH)¶
- Normally $T_4$ and $T_3$ are high in plasma which correspond to low TSH. (physiological concentration)
- high TSH happens when there's hypothyroism.
- thyrotropes have a much greater secretory capacity than we normally observed.
- produced in ant. pituitary by basophilic cells (thyrotropes)
- a glycoprotein, just like FSH, LH, and CG.
-- alpha unit: common to all those 4 glycoproteins
-- beta : different for each glycoproteins. site of receptor recognition. also the target of immuno essay.\ -- CHO moitie (carbohydrate) is important for biological activity and half life (makes the half life shorter)
-- Gs: adenyl cyclase, PKA (major)
-- Gq/11: phospholipase C, PKC (minor
-- Cross-talking between signaling pathways.
- bovine TSH's two oligosaccharides are both sulfated
- In human, TSH has two different oligosaccharde chains: sulfated (SO4) and NeuAc
-- rhTSH: a recombinant human TSH, both chains are NeuAc --> prolong the halfh life so enlongate biological activity.
- high at night and early in the morning
- no difference between men and women
- However, older women display more robust TSH secretion than younger women.
-- Doesn't happen in men.
- What makes the diural pattern? Experiment in rodents show:
-- corticosterone has no effect on TSH's rhythm.
-- ablation of suprachiasmatic nucleus (site of biological clock) abolishes the rhythm.
-- so SON is responsible for TSh's circadian pattern. but it's also due to differnetial expression of Type 2 DIOD-2 (will be discussed later)
2.1.3Effects on the thyroid glands¶
- Earliest effect is on the released of thyroid hormones (ready-made) by stimulating
--Digestion and release of iodoaminoacids
-- intrathyroidal deiodination of iodotyrosines (MIT and DIT)
- stimulate synthesis of thyroid hormones
-- NIS (the transporter) level and activity
-- I- oxidation and organification
-- Coupling of iodotyrosines (MIT and DIT)
-- Tg synthesis and processing
-- Deiodination (by D1)
- thyroid cell replication and differentiation
-- therefore it's responsible for goiter (enlargement of thyroid)
- It however does NOT increase expression/activity of pendrin (that transporter on the apical surface）
2.2TRH (thyrotropin releasing hormone)¶
- TSH structure: three amino acid neuropeptide ! (pyroglutamyl-histidyl-prolinamide .. )
2.2.1Hypothalamic pituitary connections¶
- TRH is released from paraventircular (PVN) and arcuate (ARC) nuclei and transport via infundibulum (stalk that connects hypothalamus and ant. pituitary) to reach thyrotropes.
-- PVN is superior to ARC, which is right above the median eminence. All three are at the level of third ventricle.
-- Not all cells in PVN makes TRH. Only those that line the third ventricle do.
- pituitary gland rests in sella turcia, a saddle-shaped depression in the sphenoid bone. the stalk is outside of sella turcia
-- post. pituitary receives arterial blood but ant. pituitary receives venous blood from venux plexus in the stalk (infundibulum)
-- basically for ant pituitary: arterial blood --> super hypophyseal artery --> venous plexus at the level of the stalk (where hormones from hypothalamus are dumped into) --> secondary venous plexus in ant. pituitary --> hormones in the venous blood act on ant. pituitary --> ant. pituitary secrete its hormones and dump them into the portal blood.
- innervation of TRH neurons in PVN
-- C1/A1 nuclei project onto PVN nucleus and secrete norepinephrine and epinephrine upon cold exposure
-- ARC secrete neuropeptins onto PVN on appetite control: Orexigenic (NPY and AGRP) and anorexogenic (MSH , CART)
2.2.2Effects of TRH on TSH-producing cells¶
- stimulates secretion of TSH, synthesis of new TSH
- glycosylation of TSH at post-translational stage
-- if TRh is blocked from reaching TSH producing cells --> hypothyroisim (low T3 and T4) because TSH has very little biological activity when it's w/o the carbohydrate moitie.
- There are tons of non-hypophysiotropic effects of TRH/TRH derived peptides but you don't need to memorize them unless you want to.
2.2.3TRH, TSH, thyroid hormone interactions in thyrotrophs###¶
- T3 can suppress TRH at level of hypothalamus, TSH gene and mRNA translation at ant. pituitary gland and post translational events of TSH.
- TRH upregulate TSH in thyrotroph.
-- Action via transcription factors: CBP and Pit1, which act on transcription of the beta subunit specific for TSH
-- Pit 1 is also important for prolactin and growth hormone expression.
- TSH's pulses:
-- stimulatory: TRH and AVP (vasopressin)
-- 2 inhibitory: dopamine and somatostatin
3T3 and T4#¶
- Most T3 in human is made outside of the thyroid
-- T4 is made exclusively in thyroid
-- 20% T3 comes from thyroid, 80% comes from T4 being converted into T3 by D2 and D1 in the periphery.
- T4 ---(D2,D1)--> 5' deiodination --> T3 ---(D3, D1) --> 5-deionization -->T2 (inactive)
- T4 ---(D3,D1)--> 5 deiodination --> reverse T3 ---(D2, D1) --> 5'-deionization -->T2 (inactive)
T3 is 10X more potent, stronger in affinity, and more abundant than T4.
-- so T3 is ultimately responsible for most of the thyroid hormone activity
-- since most T3 comes from T4, T4 can be seen as T3 prohormone
in liver and kidney, 40% of receptor is occupied and most of them are by T3 from thyroid.
- In ant. pituitary, 90% receptor is occupied
-- strong negative feedback on TSH secretion --> euthyroid (i.e. normal thyroid) TSH secretion (minimal fraction of maximal secretion potential)
-- most T3 that bind to pituitary derives from T4 because pituitary likes converting T4 to T3, allowing it to modulate amount of T3 to bind to its receptors.
-- There's very little T4 found in pituitary nuclei as most of them got converted to T3:
-- T4 contributes a large fraction of the nuclear T3 in the TSH producing cells.
- T4's importance for TSH regulation can be seen in hypothyroism.
-- as individuals become more and more hypothyroid-y, T4 would fall while T3 is maintained relatively constant
-- basically body tries to maintain the higher potency T3 in response to increase need of T3
-- and ofc, TSH will greatly increase (because receptor occupancy at ant. pituitary falls
-- as TSH goes up, thyroid produces more T3 (contrary to usually produce 20% of circulating T3) by upregulating D2/D1
- in situ hybridization shows cerebral T3 autoregulation
-- in hypothyroism, D3 mRNA level is low in hippocampus. In hyperthyroism, it's very high.
-- upregulation of D2 on surface of ventricle and ant. pituitary in hypothyroism --> an effort to maintain T3 level in the brain while circulating level is low
-- Astrocyte: has OATP (organic anion transport protein) which pumps T4 from serum into the cell.
--astrocyte has D2 , converting T4 to T3. It also has UPS (ubiquitin protein system) which can degrades D2 (in event of hyperthyroism)
-- T3 then acts on astrocyte's nucleus or go into neuron via MCT8 (another transport protein)
-- neuron either inactivate T3 by expressing D3 or T3 acts on nucleus to decrease D3 transcription.
*There are other factors that act on hypothalamus in regulating thyroid hormone --> next class.