772
chapter
33
Endocrine Metabolism IV: Thyroid Gland
When follicle cells are stimulated by TSH or TSI
(see below), their luminal border ingests colloid (and
hence Tg) into endocytotic vesicles. These vesicles
fuse with lysosomes to form phagolysosomes, which,
during transit toward the basolateral surface of the
cell, hydrolyze Tg and release T4, DIT, MIT, and a
small amount of T
3
. These substances are released
into the cytosol, and T
4
and T
3
diffuse into the blood.
MIT and DIT do not enter the circulation in
significant amounts because they are rapidly
deiodinated by iodotyrosine deiodinase, an enzyme
complex that contains ferredoxin, NADPH:
ferredoxin reductase, and a deiodinase containing
flavin mononucleotide (FMN). This reaction
promotes recycling of iodide within the follicle cell.
Some of the iodide, however, diffuses into plasma and
constitutes the daily “iodide leak,” estimated to be
about 16 /rg/d. By mechanisms that are not clear, a
small amount of intact Tg also leaks out of the thyroid
and can be found circulating in plasma in normal
individuals. Tg leakage at a rate of 100 /ig/d has been
reported in euthyroid individuals, and a concentration
of 15-25
fi g
Tg per liter of serum is considered to be
normal. The route of Tg leakage is by way of the
lympathic drainage and is increased when the gland is
excessively stimulated. Increased entry of Tg into the
circulation may result in an immune response because
of the antigenic nature of this glycoprotein.
The release of thyroid hormone following endocytosis
of colloid is inhibited by iodide and is known to be reduced
with high dietary intake of iodine. This inhibition is due to
the inverse relationship between the iodide content of Tg
and the digestibility of iodo-Tg by lysosomal peptidase;
that is, poorly iodinated Tg is more readily digested than
richly iodinated Tg.
Regulation of Thyroid Hormone Synthesis
Thyroid-Stimulating Hormone (TSH)
TSH (also called thyrotropin), which is secreted by
the pituitary, plays a central role in the regulation of
growth and function of the thyroid gland. TSH receptors
are functionally coupled to G-proteins; thus, the extra-
cellular stimulus by TSH is transduced into intracellular
signals mediated by a number of G-proteins. Activation of
Gs-protein results in the stimulation of the adenylate
cyclase-cAMP-protein phosphorylation cascade. Other
G-proteins
coupled
to
TSH-receptor
activation
in-
clude GQ-protein, which mediates the phospholipase
C-phosphatidylinositol 4,5-bisphosphate-Ca2+ signaling
pathway (see Chapter 30 for a detailed discussion).
The TSH receptor is a glycoprotein that consists of
three major domains: a long amino-terminal extracellular
segment that confers binding specificity, a transmem-
brane segment, and a carboxy-terminal intracytoplasmic
segment that mediates G-protein interactions (see Fig-
ure 30-6). TSH-receptor activation promotes iodide trap-
ping, organification of iodide, and endocytosis and hydrol-
ysis of colloid by a mechanism that involves cAMP.
Thyroid disorders consisting of either hypofunction
or hyperfunction can result form constitutive inactivat-
ing or activating mutations, respectively, in the TSH
receptor. Similarly, Gs<*-inactivating (loss of function)
or activating (gain of function) mutations can result in
h y p o th y r o id ism
and
h y p e rth y ro id ism .
An example of the
former is
A lb r ig h t h e re d ita ry o s te o d y s tr o p h y
and the lat-
ter is
M c C u n e -A lb r ig h t sy n d ro m e .
Both syndromes are
discussed in Chapter 30. All of the effects of TSH on
the thyroid gland are exaggerated in hyperthyroidism due
to excessive stimulation of the TSH receptor whether or
not the ligand is TSH. For example, in
G r a v e ’s d ise a se
hyperactivity of the thyroid gland is due to a thyroid-
stimulating antibody that binds the TSH receptor and, in
so doing, activates it. This
th y r o id -s tim u la tin g im m u n o -
g lo b u lin (T S I)
or
lo n g -a c tin g th y r o id s tim u la to r (L A T S )
is an expression of an autoimmune disease that may be
hereditary, although in some cases it may be the result of
a normal immune response. For example, certain strains
of bacteria contain a membrane protein which is homol-
ogous to the TSH receptor and which elicits an immune
response in infected individuals. The antibodies gener-
ated resemble TSI. Thus, some cases of hyperthyroidism
may be due to cross-recognition across phylogenetic
lines (molecular mimicry).
Human chorionic gonadotropin (hCG), a placental hor-
mone, has some TSH-like activity. hCG synthesis is initi-
ated during the first week after fertilization and reaches its
highest level near the end of the first trimester, after which
levels decrease. The action of hCG on thyrocytes may help
meet the increased requirement of thyroxine during preg-
nancy. The total thyroxine pool is increased in pregnancy
due to elevated levels of thyroxine-binding globulin. How-
ever, the serum free T
4
level, which represents the biologi-
cally active form, remains the same compared to nonpreg-
nant status. During the first trimester, the fetal requirement
for thyroxine is met by maternal circulation until the fetal
pituitary-thyroid axis becomes functional late in the first
trimester. The maternal-fetal transport of thyroxine which
occurs throughout pregnancy minimizes the fetal brain
abnormalities in fetal hypothyroidism (discussed later).
Maternal hypothyroidism (e.g., due to women consum-
ing iodine-deficient diets) is associated with defects in the
neurological functions of offspring.
