Pharmacology
Hormone modulators
1. Learning outcomes
Utilise knowledge of thyroid function to explain the use of thyroid hormone modulators.
Explain how the timeline of treatment and delay in symptom relief is affected by thyroid
physiology.
Describe mechanisms of action of contraceptive drugs and explain how these link to side effects.
Explain mechanisms regulating hormones with relation to cancer therapy, hormone replacement
and infertility
2. What do you remember about the thyroid
Two main hormones: T3 (active form) and T4
(goes around the blood and when it gets to
where it’s needed it gets converted to T3)
Iodine is important for these hormones and is
transported into the cells that line the colloid and
that’s the major function of the thyroid
Main steps in the synthesis, storage & secretion
of thyroid hormone are:
- uptake of plasma iodide by the follicle cells
- oxidation of iodide and iodination of tyrosine
residues of thyroglobulin
- secretion of thyroid hormone.
In the picture at the bottom we find the blood
plasma and the little balls are iodide molecules
that need to get transported into our thyrocytes
(iodine trapping).
Once iodine is in the cell it needs to move
through the cell and be stored in the colloid, the
thyrocytes will produce and secrete thyroglobulin
(TGB). TGB is a very sticky substance and has
loads of tyrosine residues which will bind to
iodide ions and it will store it there. This protein
has about 115 tyrosine residues for every protein
particle produced so it can take a lot of iodide. It
will stay there for a long period of time
Once it’s required something will stimulate it to
be taken up back into the thyrocyte, degraded
and then released into the blood again
T3 and T4 are really similar to the steroid
hormones and they need to be bound to a thyroxine binding globulin (TBG) to get oved around
the body and the blood because they’re not soluble in aqueous solutions
, Pharmacology
Hormone modulators
3. Thyroid hormone synthesis and iodine storage
NIS (sodium/iodide symporter) is the
transporter the iodide from the blood to the
thyrocyte, normally there’s more iodide in blood
than in the thyrocyte so it needs to move it
against it concentration gradient, it requires ATP
generated from and ATPase. One of the reasons
people have problems with the thyroid is
because there’s a mutation in NIS. That iodide is
then transported out into the colloid using PDS
(also can have a mutation and make iodide sit in
the cell). It can either be incorporated as MIT
(monoidotyrosine) or DIT (di idotyrosine). MIT +
DIT= T3, DIT +DIT= T4
Once we’ve got our iodide in the cell it’s then converted
by thyroperoxidase (organification process) and H2O2
making it into the surrounded radical. It’s thought that
there are two different sites in the thyroperoxidase, one
allows for iodide to be converted and the other one
allows for tyrosine residues to be made into radicals by
the removal of that hydrogen group leaving our lone
electron and that means that then when we bring these
and the surrounded radical together we can form
monoidotyrosine or MIT and that's then able to be
incorporated into the thyroid globulin, stored.
4. How is thyroid hormone released regulated
Thyrotrophin-releasing hormone (TRH) stimulates thyroid stimulating
hormone (TSH) release from anterior pituitary.
TSH Mechanism:
- stimulates G-protein coupled receptors on thyrocyte (follicle cell)
surface, leading to cAMP accumulation and PI3K signalling
- → increase in expression of Na+/I- symporter (NIS) present in
basolateral membrane of thyrocytes
- → increased I- uptake into thyrocytes
Circulating I- concentration
5. Stop and think
It will take between 1 and 4 weeks for your medication to take its effect
There’s a lot of iodide sitting in the colloid so it will take a while for tat to get completely broken
down and emptied of the iodide stored there.
A patient has hypothyroidism: “your thyroid is enlarged due to low levels of plasma iodide”
There’s no iodide n the blood, the thyroid needs to search for iodide and best way to take it up is
to make the cells of the thyroid proliferate because then that gives you even the smallest
amount of iodide that might be in the blood is going to get taken up relatively quickly so by
having very low levels you're going to cause hyperplasia (lots of growth) increasing the number
of cells and therefore potentially increasing how much you can take up
Hormone modulators
1. Learning outcomes
Utilise knowledge of thyroid function to explain the use of thyroid hormone modulators.
Explain how the timeline of treatment and delay in symptom relief is affected by thyroid
physiology.
Describe mechanisms of action of contraceptive drugs and explain how these link to side effects.
Explain mechanisms regulating hormones with relation to cancer therapy, hormone replacement
and infertility
2. What do you remember about the thyroid
Two main hormones: T3 (active form) and T4
(goes around the blood and when it gets to
where it’s needed it gets converted to T3)
Iodine is important for these hormones and is
transported into the cells that line the colloid and
that’s the major function of the thyroid
Main steps in the synthesis, storage & secretion
of thyroid hormone are:
- uptake of plasma iodide by the follicle cells
- oxidation of iodide and iodination of tyrosine
residues of thyroglobulin
- secretion of thyroid hormone.
In the picture at the bottom we find the blood
plasma and the little balls are iodide molecules
that need to get transported into our thyrocytes
(iodine trapping).
Once iodine is in the cell it needs to move
through the cell and be stored in the colloid, the
thyrocytes will produce and secrete thyroglobulin
(TGB). TGB is a very sticky substance and has
loads of tyrosine residues which will bind to
iodide ions and it will store it there. This protein
has about 115 tyrosine residues for every protein
particle produced so it can take a lot of iodide. It
will stay there for a long period of time
Once it’s required something will stimulate it to
be taken up back into the thyrocyte, degraded
and then released into the blood again
T3 and T4 are really similar to the steroid
hormones and they need to be bound to a thyroxine binding globulin (TBG) to get oved around
the body and the blood because they’re not soluble in aqueous solutions
, Pharmacology
Hormone modulators
3. Thyroid hormone synthesis and iodine storage
NIS (sodium/iodide symporter) is the
transporter the iodide from the blood to the
thyrocyte, normally there’s more iodide in blood
than in the thyrocyte so it needs to move it
against it concentration gradient, it requires ATP
generated from and ATPase. One of the reasons
people have problems with the thyroid is
because there’s a mutation in NIS. That iodide is
then transported out into the colloid using PDS
(also can have a mutation and make iodide sit in
the cell). It can either be incorporated as MIT
(monoidotyrosine) or DIT (di idotyrosine). MIT +
DIT= T3, DIT +DIT= T4
Once we’ve got our iodide in the cell it’s then converted
by thyroperoxidase (organification process) and H2O2
making it into the surrounded radical. It’s thought that
there are two different sites in the thyroperoxidase, one
allows for iodide to be converted and the other one
allows for tyrosine residues to be made into radicals by
the removal of that hydrogen group leaving our lone
electron and that means that then when we bring these
and the surrounded radical together we can form
monoidotyrosine or MIT and that's then able to be
incorporated into the thyroid globulin, stored.
4. How is thyroid hormone released regulated
Thyrotrophin-releasing hormone (TRH) stimulates thyroid stimulating
hormone (TSH) release from anterior pituitary.
TSH Mechanism:
- stimulates G-protein coupled receptors on thyrocyte (follicle cell)
surface, leading to cAMP accumulation and PI3K signalling
- → increase in expression of Na+/I- symporter (NIS) present in
basolateral membrane of thyrocytes
- → increased I- uptake into thyrocytes
Circulating I- concentration
5. Stop and think
It will take between 1 and 4 weeks for your medication to take its effect
There’s a lot of iodide sitting in the colloid so it will take a while for tat to get completely broken
down and emptied of the iodide stored there.
A patient has hypothyroidism: “your thyroid is enlarged due to low levels of plasma iodide”
There’s no iodide n the blood, the thyroid needs to search for iodide and best way to take it up is
to make the cells of the thyroid proliferate because then that gives you even the smallest
amount of iodide that might be in the blood is going to get taken up relatively quickly so by
having very low levels you're going to cause hyperplasia (lots of growth) increasing the number
of cells and therefore potentially increasing how much you can take up
