Dive deep into the fascinating world of thyroid hormones with our comprehensive online guide! From the intricate anatomy of the thyroid gland to the molecular mechanisms of hormone synthesis and action, this resource offers a detailed exploration suitable for healthcare professionals and enthusiast...
Thyroid Hormones
In the anterior part of the neck, around the thyroid cartilage, we find the thyroid gland together with
the parathyroid glands, the latter concerned with the secretion of parathormone and regulation of
calcium levels (and homeostasis in general). [Remember: other than the thyroid hormones, the thyroid
gland also produces calcitonin, which helps parathyroids with regulation of calcium].
The thyroid gland is a follicular organ: this implies that it is constituted
by a number of cavities/ follicles that are surrounded by a secretory
epithelium; a perfectly suitable organization to separate pro-hormones
from active hormones (creation of separate compartments). When we talk
about thyroid hormones, their pro-hormones form is crucial as iodine is
needed to create them and it is only taken up through the diet: when iodine is
in circulation, thyroid gland need to create pro-hormones even though
they are not needed at that time, but just to store them into its follicles.
Therefore, two key concepts need to be remarked:
a) 3 or 4 residues of iodine are needed for one hormone molecule. Thyroid hormones need
to be created when iodine is available (after we eat, with food): e.g., the opposite of steroids that
are synthetized and secreted when needed, instead thyroid hormones are stored (because iodine
is not always available).
b) Thyroid hormones are small very lipophilic molecules, they easily escape a membrane or
a barrier so they need to be synthetized in a non-diffusible form: pro-hormones.
Synthesis of thyroid hormones
• Iodine is actively captured from blood through a sodium-iodine symport (NIS), found on the
basolateral domain of follicular
cells.
• Follicular cells can concentrate
iodine up to 40 fold and secrete it in
the follicle through pendrin ion
exchanger (Cl-/I-), where they are
oxidized by peroxidase.
• Inside the follicles, thyroid
hormones are formed by iodinating
(adding iodine [I2]) to tyrosine
residues of a protein called
thyroglobulin.
Tyrosine residues can be mono or di-
iodinated: MIT and DIT.
• MIT + DIT à T3, three-iodinated hormone
• DIT + DIT à T4, four-iodinated hormone
The fusion happens through an ether bond between
iodinated tyrosine molecules: the order in which these two
fuses it’s important:
• if DIT (inner) fuses with MIT or DIT then there is
detachment of the amino-acid portion and formation of T3
and T4;
• instead if MIT (inner) fuses, then reverse T3 is produced.
23 Body At Work II
, Enrico Tiepolo
• Thyroid hormones are secreted in the follicular space to constitute the colloid.
Most of the hormones produced are T4, which will then be converted to T3 or reverse T3 (active form
of the hormone) once it enters the target cell.
Depending on which deiodinase enzyme is
activated and expressed in the target cells, each
cell can decide how strongly it will respond to the
thyroid hormone:
• If it expresses the DI01, T4 becomes T3
• If it expresses the DI03, T4 becomes the
reverse T3.
Regulation
TSH sustains thyroid trophism and the production and storage of the prohormone, but it also stimulates
release, which is obtained by activating pinocytosis at the luminal surface of the thyroid follicular cell,
that digests the thyroglobulin and releases T3 and T4 in the circulation.
The fact that these two aspects (stimulation of production and release) cannot be differentiated means
that the release happens even if the resulting hormones are ineffective (because of the lack of iodine) and
the stimulus continues: it is a perfect example the goiter; as there is not stopping in producing
thyroglobulin which fills the follicles.
The third form of deiodinase is DI02. It is mostly expressed in the hypothalamus and in the pituitary
gland, and has the function of transforming T4 into T3. These cells are very sensitive to the presence
of the hormone and, as a consequence, they can generate a proper negative feedback control. The
hypothalamus and the pituitary gland need to monitor the level of the thyroid hormones: either you
generate a transduction system that is able to sense the concentration of T4 or you provide them with
DI02 and, by transforming T4 into T3 (effective form), they can sense how much hormone there is.
We produce most of the thyroid hormones in the form of the T4 (unless we are lacking iodine). When
we get to the cells, T4 enters much more easily and then it is metabolized half into T3 and half into
reverse T3 (as a consequence, less than 50% of T4 will be functional). Changes in the expression of DI01
and DI03 will influence this mechanism.
Travelling
THs travel in the blood using plasma proteins.
Transport
• Classically considered lipophilic molecules (because they have 2 phenyl rings), they can easily
cross the membrane without keeping the polar amino acid region.
• T4 is the predominant form in the blood (80%), it crosses the membrane and enters the cell.
• T4 is de-iodinated (using deiodinase 1) to T3 or (using deiodinase 3) to rT3
• Specific transporters exist for THs from the blood to the target organs (e.g., MCT8 & SLC16A2)
and their defects are associated with severe X linked mental and locomotor developmental
defects (i.e., Allan Herndon Dudley syndrome), due to TH inadequate activity.
Transcriptional effects
T3 penetrates the nucleus and binds to its receptor.
T3 receptor is generally part of a heteromeric dimer, with retinoic
acid receptor RXR, and may already be bound to its target
sequences (hormone responsive elements, HRE) in the DNA, and starts
exerting its transactivating actions upon binding of the TH.
There are two subtypes of thyroid receptor (alpha & beta) expressed
in different tissues, which contribute to differences in tissue sensitivity to
thyroid hormone. TRα1 is the predominant isoform in bone, brain and
heart, whereas TR beta 1 is the major isoform in liver, kidney and
thyroid.
24 Body At Work II
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