Download The hypothalamo-pituitary-thyroid axis

The hypothalamopituitary-thyroid axis
Thyrotropin releasing hormone
(TRH):-
TRH is manufactured in the hypothalamus and
transported via the portal circulation to the
pituitary where it ultimately leads to exocytosis of
TSH.
TRH is a modified tripeptide synthesized as a 26kDa
prohormone by peptidergic hypothalamic nuclei
and transported, after activation, to the anterior
pituitary by the portal circulation.
Stimulates TSH synthesis and secretion by binding
to receptors on the pituitary thyrotroph cell
membranes that are linked to phospholipase C.
More chronic actions of TRH include stimulation of
TSH subunit biosynthesis and TSH glycosylation.
Thyroid stimulating hormone:TSH (also known as Thyrotropin) is a 28kDa
glycoprotein synthesized by the pituitary
thyrotroph. It consists of two noncovalently
linked subunits and contains about 15%
carbohydrate. The α-chain is identical to that
found in other pituitary glycoprotein hormones
and so the specificity is determined by the βchain and the three dimensional configuration.
The synthesis each subunit is directed by
separate messenger R ribonucleic acids (mRNAs)
encoded by separate genes on different
chromosomes.
The plasma half life of TSH is about 65 minutes.
TSH acts on the thyroid gland and influences
virtually every aspect of thyroid hormone
biosynthesis and secretion:TSH acts via a specific membrane receptor on
the target cell of the thyroid gland. The
receptor is a 85kDa glycoprotein with an
extracellular domain of approximately 400
amino acids, seven transmembrane domains
of about 250 amino acids. The binding of TSH
to the receptor activates adenylate cyclase.
How the TSH control of thyroid
metabolism:1- stimulation of iodide pump to increase ion
trapping.
2- stimulate oxidation of iodide.
3- stimulate glucose metabolism by pentose
shunt so increase production of NADPH which
is a factor of production H2O2 & also
deiodinase.
4- stimulate endocytosis to engulf & storage of
thyroglobulin.
Biosynthesis of T4 and T3
• The first step is transport of Iodide from blood to
thyroid follicle. This process against gradient because
the concentration of Iodide in thyroid gland 20 times
more than blood, this process needs energy thus it is
ATP driven, under control of TSH. It is linked to ATPasedependent Na/K pump.
• Follicle of thyroid gland composed of single epi. Cell
contain colloid inside lumen. The colloid contains
thyroglobulin which is a glycoprotein M.w 660 kd, CHO
account 8-10 of wt and iodide 0.2-1, it contain 115
tyrosine residues each of which is potential site of
iodination. About 70 percentage of the iodide is
thyroglobulin exist in the inactive precursors
MonoIodotyrosine(MIT) and DiIodotyrosine(DIT) while
30 percentage as T3andT4
• The second step is the oxidation of iodide to
iodine(active) by peroxidase in the presence of
H2O2 this is called free radical reaction and
occur in epi. Cell of follicle. This process
inhibited by thiourea drugs.
• The third step is iodination of tyrosine(tyrosyl
residues in thyroglobulin) , probably involves
thyroperoxidase.
• In 3 position------------- MIT
• I 3, 5 position------------ DIT . Both occur in
luminal thyroglobulin
• The 4th step
• DIT+ DIT--------- T4
• DIT+ MIT--------- T3 both occur within
thyroglobulin molecule.
• T4 is quantitatively the most important thyroid
hormone and it is produced exclusively by the
thyroid gland . T3 is the biologically active form of
thyroid hormone produced by 5- deiodination of
T4. This process may occur in thyroid gland, in
target tissues or in other peripheral tissues
Removal of an iodine from the 5 rather than the
5- position result in reverse T3, which biologically
inactive
• The daily production rate of T4 is approximately
110 nmol (90μg) and transported in the plasma
bound to a variety of specific and non specific
binding proteins .
• Approximately 80‰ of T4is converted into equal
amounts of T3 and reverse T3(rT3), the remaining
T4 is conjugated with sulfate or glucuronide and
deactivated by deamination or decarboxylation .
• The daily production rate of T3 is approximately
45 nmol (35μg) by extra thyroidal deiodination .
The turnover of T3 is much greater than that of
T4 , and the free form – is able to exert the
biological activity while the bound form – is not
able to exert the biological activity.
• Transport of T3 and T4
1/2 – 2/3 OF T3 and T4 in the body is
extrathyriodal and bound to 2 specific protein
Thyroxin binding globulin (TBG) and Thyroxin
binding pre albumin(TBPA). The TBG is
glycoprotein , bind to T3,T4 with 100 times the
affinity of TBPA.
TBG is produced in the liver and it is synthesis
increases by estrogen while it decreases by
androgen and glucocorticoid and some liver
diseases.
• Biochemical action of thyroid hormone
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By acting on a wide range of tissues :
1- They increase the basal metabolic rate
2- Increase ATP consumption
3- Increase O2 consumption
Most, if not all, of these actions result from
altered transcription brought about by the
binding of T3 to its nuclear receptor.
• Clinical disorders
• Thyroid disease can occur at any time from
birth to old age. Greater than 95 percentage
of thyroid disease originates in the thyroid
gland and much of this is autoimmune in
origin