Download Thyroid Hormones

Hypothyroidism
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Hyperthyroidism
cretinism
goiter
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
What induces the above disease?
Imbalance of thyroxine
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Production, Regulation, and Action of Thyroid Hormones
Early Studies on the Thyroid Gland
Gross and Microscopic Anatomy of the Thyroid Gland
Production of Thyroid Hormones
Transport and Activities of T3 and T4
Regulation of Thyroid Hormone Production & Secretion
Actions of Thyroid Hormones
Hyper- and Hypothyroidism
Histology of the Thyroid Gland
• The thyroid gland contains numerous follicles,
composed of epithelial follicle cells and colloid.
• Also, between follicles are clear parafollicular cells,
which produce calcitonin (see coming lecture on
calcium balance).
Thyroid Gland: Hormones and Iodine Metabolism
The thyroid gland
Thyroid Hormones
• There are two biologically active thyroid hormones:
- tetraiodothyronine (T4; usually called thyroxine)
- triiodothyronine (T3)
• Derived from modification of an amino acid (tyrosine)
THYROID HORMONES
OH
OH
I
I
I
I
I
O
O
NH2
I
O
Tyrosine
OH
Thyroxine (T4)
NH2
I
O
OH
3,5,3’-Triiodothyronine (T3)
Differences between T4 and T3
• The thyroid secretes about 80 micrograms of T4, but only
5 micrograms of T3 per day.
• However, T3 has a much greater biological activity (about
10X) than T4.
• An additional 25 micrograms/day of T3 is produced by
peripheral monodeiodination of T4.
thyroid
T3
T4
I-
Why is Iodine Important in Thyroid Hormone Production?
• Thyroid hormones are unique biological molecules in
that they incorporate iodine in their structure.
• Thus, adequate iodine intake (diet, water) is required
for normal thyroid hormone production.
• Major sources of iodine:
- iodized salt
- iodated bread
- dairy products
• Minimum requirement: 75 micrograms/day
• US intake: 200 - 500 micrograms/day
Iodine Metabolism
• Dietary iodine is absorbed in the GI tract, then taken up
by the thyroid gland (or removed from the body by the
kidneys).
• The transport of iodide into follicular cells is dependent
upon a sodium/iodine cotransport system.
• Iodide taken up by the thyroid gland is oxidized by
peroxide in the lumen of the follicle:
I-
peroxidase
I+
• Oxidized iodine can then be used in production of
thyroid hormones.
The Next Step: Production of T3 or T4
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
The first Step: Production of thyroglobulin
• The follicle cells of the thyroid produce thyroglobulin.
• Thyroglobulin is a very large glycoprotein.
• Thyroglobulin is released into the colloid space,
where it’s tyrosine residues are iodinated by I+.
• This results in monoiodotyrosine (MIT) or
diiodotyrosine (DIT).
Initial Steps in Thyroid Hormone Synthesis
Na+
extracellular space
gene
follicle
cell
K+
I-
Na+
I-
thyroglobulin
thyroglobulin
oxidation I+
I
iodination
thyroglobulin with
monoiodotyrosines and
diiodotyrosines
colloid space
Second step: Production of Thyroid Hormones
from Iodinated Thyroglobulin
• The iodinated tyrosine residues on thyroglobulin are
modified and joined to form T3 and T4, still attached
to the thyroglobulin molecule.
Utilization of Thyroglobulin to Secrete Thyroid Hormones
• In order to secrete T3/T4, the thyroglobulin in the
colloid space is internalized by endocytosis back
into the follicle cell.
• This internalized vesicle joins with a lysosome,
whose enzymes cause cleavage of T3 and T4 from
thyroglobulin. Some T4 is converted to T3 at this
point.
• T3 and T4 are then released into the extracellular
space by diffusion.
• Only minute amounts of thyroglobulin are
released into the circulation.
Utilization of Thyroglobulin to Secrete Thyroid Hormones
extracellular space
T3/T4 (T4
T3)
(deiodinated, recycled)
lysosome
follicle
cell
colloid droplet
endocytosis
thyroglobulin
T3
T4
colloid space
Transport of Thyroid Hormones
• Thyroid hormones are not very soluble in water
(but are lipid soluble).
• Thus, they are found in the circulation associated
with binding proteins:
- Thyroid Hormone-Binding Globulin (~70% of
hormone)
- Pre-albumin (transthyretin), (~15%)
- Albumin (~15%)
• Less than 1% of thyroid hormone is found free in
the circulation.
• Only free and albumin-bound thyroid hormone is
biologically available to tissues.
Transthyretin (TTR) is a serum
and CSF carrier of the thyroxine (T4)
and retinol. This is how transthyretin
gained its name, transports thyroxine
and retinol.
TTR was originally called
prealbumin because it ran faster than
albumins on electrophoresis gels.
In CSF it is the primary carrier of
T4, as albumin is not present. TTR
also acts as a carrier of retinol
(vitamin A) through an association
with retinol-binding protein (RBP).
Transthyretin (prealbumin, amyloidosis type I)
Conversion of T4 to T3
• T3 has much greater biological activity than T4.
• A large amount of T4 (25%) is converted to T3 in
peripheral tissues.
• This conversion takes place mainly in the liver and
kidneys. The T3 formed is then released to the
blood stream.
• In addition to T3, an equal amount of “reverse T3”
may also be formed. This has no biological
activity.
THYROID HORMONE METABOLISM
“Step up”
“Step down”
T4
R
R
T3
rT3
R
3,3’-T2
THYROID HORMONE DEIODINASES
• Three deiodinases (D1, D2 & D3) catalyze the
generation and/disposal of bioactive thyroid hormone.
• D1 & D2 “bioactivate” thyroid hormone by removing
a single “outer-ring” iodine atom.
• D3 “inactivates” thyroid hormone by removing a
single “inner-ring”iodine atom.
• All family members contain the novel amino acid
selenocysteine (Se-Cys) in their catalytic center.
BASIC ORGANIZATION OF THE
SELENODEIODINASES
extracellular domain
intracellular domain
NH2
COOH
Se-Cys
EXISTS AS A
DIMER
Thyroxine and its precursors: Structure & Synthesis
Thyroid hormones are made from tyrosine and iodine
Thyroxine and its precursors: Structure & Synthesis
Thyroid hormone synthesis
One Major Advantage of this System
• The thyroid gland is capable of storing many
weeks worth of thyroid hormone (coupled to
thyroglobulin).
• If no iodine is available for this period, thyroid
hormone secretion will be maintained.
Regulation of Thyroid Hormone Levels
• Thyroid hormone synthesis and secretion is
regulated by two main mechanisms:
- an “autoregulation” mechanism, which
reflects the available levels of iodine
- regulation by the hypothalamus and anterior
pituitary
Autoregulation of Thyroid Hormone Production
• The rate of iodine uptake and incorporation into
thyroglobulin is influenced by the amount of
iodide available:
- low iodide levels increase iodine transport into
follicular cells
- high iodide levels decrease iodine transport into
follicular cells
Thus, there is negative feedback regulation of iodide
transport by iodide.
Neuroendocrine Regulation of Thyroid Hormones:
Role of TSH
• Thyroid-stimulating hormone (TSH) is produced by thyrotroph cells
of the anterior pituitary.
• TSH is a glycoprotein hormone composed of two subunits:
- alpha subunit (common to LH, FSH, TSH)
- TSH beta subunit, which gives specificity of receptor binding and
biological activity
a
LHb
FSHb
TSHb
LH
FSH
TSH
Feedback regulation
the hypothalamic-pituitary-thyroid axis
Hormones derived from the pituitary that regulate
the synthesis and/or secretion of other hormones
are known as trophic hormones.
Key players for the thyroid include:
TRH - Thyrotropin Releasing Hormone
TSH - Thyroid Stimulating Hormone
T4/T3 - Thyroid hormones
T3 & T4 Control Pathways
& Diseases from Malfunction
Action of TSH on the Thyroid
• TSH acts on follicular cells of the thyroid.
- increases iodide transport into follicular cells
- increases production and iodination of thyroglobulin
- increases endocytosis of colloid from lumen into follicular cells
Na+ K+ I
Na+
gene
ATP
follicle
cell
colloid droplet
thyroglobulin
I1
3
endocytosis
thyroglobulin
2
thyroglobulin
iodination
T3
T4
I+
I-
Mechanism of Action of TSH
• TSH binds to a plasma membrane-bound, G proteincoupled receptor on thyroid follicle cells.
• Specifically, it activates a Gs-coupled receptor, resulting in
increased cyclic AMP production and PKA activation.
TSH
Gsa
Adenylyl
Cyclase
ATP
cyclic AMP
Follicle cell
Protein kinase
A
Regulation of TSH Release from the Anterior Pituitary
• TSH release is influenced by hypothalamic TRH, and by
thyroid hormones themselves.
• Thyroid hormones exert negative feedback on TSH release
at the level of the anterior pituitary.
- inhibition of TSH synthesis
- decrease in pituitary receptors for TRH
hypothalamus
+
TRH
TRH receptor
pituitary
TSH synthesis
-
T3/T4
Regulation of TSH Release from the Anterior Pituitary
• Thyrotropin-releasing hormone (TRH) is a hypothalamic
releasing factor which travels through the pituitary portal
system to act on anterior pituitary thyrotroph cells.
• TRH acts through G protein-coupled receptors, activating
the IP3 (calcium) and DAG (PKC) pathways to cause
increased production and release of TSH.
IP3
TRH
G protein-coupled
receptor
phospholipase C
calcium
calmodulin
DAG
• Thyroid hormones also inhibit TRH synthesis.
PKC
Negative Feedback Actions of Thyroid Hormones on
TSH Synthesis & Release
TRH synthesis
hypothalamus
+
TRH
TRH receptor
pituitary
TSH synthesis
-
-
T3/T4
PITUITARY-THYROTROPE CELL
TSH regulation of
thyroid function
• TSH binds to specific cell surface receptors that
stimulate adenylate cyclase to produce cAMP.
• TSH increases metabolic activity that is required to
synthesize Thyroglobulin (Tg) and generate peroxide.
• TSH stimulates both I- uptake and iodination of
tyrosine resides on Tg.
Ion transport by the thyroid follicular cell
BLOOD
I-
organification
I
NaI symporter (NIS)
Thyroid peroxidase (TPO)
COLLOID
Propylthiouracil (PTU)
blocks iodination of
thyroglobulin
PTU, a thioamide drug used to treat hyperthyroidism
THYROGLOBULIN SYNTHESIS IN THE
THYROID FOLLICULAR CELL
Iodination of
Tyr residues of Tg
COLLOID
TSH
TSH receptor
TPO
THYROID HORMONE SECRETION BY THE
THYROID FOLLICULAR CELL
T4
T3
COLLOID
DIT
MIT
TSH
TSH receptor
I-
Other Factors Regulating Thyroid Hormone Levels
• Diet: a high carbohydrate diet increases T3 levels,
resulting in increased metabolic rate (diet-induced
thermogenesis).
• Low carbohydrate diets decrease T3 levels, resulting in
decreased metabolic rate.
• Cold Stress: increases T3 levels in other animals, but
not in humans.
Actions of Thyroid Hormones
• Required for GH and prolactin production & secretion
• Required for GH action
• Increases intestinal glucose reabsorption (glucose
transporter)
• Increases mitochondrial oxidative phosphorylation (ATP
production)
• Increases activity of adrenal medulla (sympathetic;
glucose production)
• Induces enzyme synthesis
•
Result: stimulation of growth of tissues and increased
metabolic rate.
Actions of Thyroid Hormones
• Thyroid hormones are essential for normal growth
of tissues, including the nervous system.
• Lack of thyroid hormone during development
results in short stature and mental deficits
(cretinism).
• Thyroid hormone stimulates basal metabolic rate.
• What are the specific actions of thyroid hormone
on body systems?
Cardiovascular system: Thyroid hormones increases heart
rate, cardiac contractility and cardiac output. They also
promote vasodilation, which leads to enhanced blood flow to
many organs.
Central nervous system: Both decreased and increased
concentrations of thyroid hormones lead to alterations in mental
state. Too little thyroid hormone, and the individual tends to feel
mentally sluggish, while too much induces anxiety and
nervousness.
Reproductive system: Normal reproductive behavior and
physiology is dependent on having essentially normal levels of
thyroid hormone. Hypothyroidism in particular is commonly
associated with infertility.
Specific actions of thyroid hormone: development
• TH is critical for normal development of the skeletal
system and musculature.
• TH is also essential for normal brain development and
regulates synaptogenesis, neuronal integration,
myelination and cell migration.
• Cretinism is a condition of severely stunted physical
and mental growth due to untreated congenital
deficiency of thyroid hormones (congenital
hypothyroidism) due to maternal nutritional deficiency
of iodine.
Effects of Thyroid Hormone on Nutrient Sources
Effects on protein synthesis and degradation:
-increased protein synthesis at low thyroid hormone levels
(low metabolic rate; growth)
-increased protein degradation at high thyroid hormone levels
(high metabolic rate; energy)
Effects on carbohydrates:
-low doses of thyroid hormone increase glycogen synthesis
(low metabolic rate; storage of energy)
- high doses increase glycogen breakdown (high metabolic rate;
glucose production)
Effects on Lipids: Increased thyroid hormone levels stimulate fat
mobilization, leading to increased concentrations of fatty acids
in plasma. They also enhance oxidation of fatty acids in many
tissues. Finally, plasma concentrations of cholesterol and
triglycerides are inversely correlated with TH levels.
Mechanism of Action of T3
• T3/T4 acts through the thyroid hormone receptor
- intracellular, in steroid receptor superfamily
- acts as a transcription factor
- receptor binds to TRE on 5’ flanking region of genes as
homodimers and/or heterodimers.
- multiple forms (alphas and betas) exist
- one form (alpha-2) is an antagonist at the TRE
More on Receptor Coactivators and Corepressors
 When not bound to hormone, the thyroid hormone receptor
binds to target DNA (TRE on 5’ flanking region). It is
associated with corepressor proteins that cause DNA to be
tightly wound and inhibit transcription.
 Binding of hormone causes a conformational change,
resulting in loss of corepressor binding and association with
coactivator proteins, which loosen DNA structure and
stimulate transcription.
Expression and Regulation
of Thyroid Hormone Receptors
• Thyroid hormone receptors are found in many tissues of
the body.
• Thyroid hormone inhibits thyroid hormone receptor
expression (TRE on THR genes).
One Major Target Gene of T3:
The Sodium/Potassium ATPase Pump
• Pumps sodium and potassium across cell membranes to
maintain resting membrane potential
• Activity of the Na+/K+ pump uses up energy, in the form of
ATP
• About 1/3rd of all ATP in the body is used by the Na+/K+
ATPase
• T3 increases the synthesis of Na+/K+ pumps, markedly
increasing ATP consumption.
• T3 also acts on mitochondria to increase ATP synthesis
• The resulting increased metabolic rate increases
thermogenesis (heat production).
Thyroid Hormone Deficiency: Hypothyroidism
• Early onset: delayed/incomplete physical and mental
development
• Later onset (youth): Impaired physical growth
• Adult onset (myxedema) : gradual changes occur.
Tiredness, lethargy, decreased metabolic rate, slowing
of mental function and motor activity, cold intolerance,
weight gain, goiter, hair loss, dry skin. Eventually
may result in coma.
• Many causes (insufficient iodine, lack of thyroid gland,
lack of hormone receptors, lack of TBG….)
How is Hypothyroidism Related to Goiter?
• During iodine deficiency, thyroid hormone production
decreases.
• This results in increased TSH release (less negative
feedback).
• TSH acts on thyroid, increasing blood flow, and
stimulating follicular cells and increasing colloid
production.
Thyroid Hormone Excess: Hyperthyroidism
• Emotional symptoms (nervousness, irritability), fatigue,
heat intolerance, elevated metabolic rate, weight loss,
tachycardia, goiter, muscle wasting, apparent bulging of
eyes, may develop congestive heart failure.
• Also due to many causes (excessive TSH release,
autoimmune disorders,…)
Graves' disease:A condition usually caused by
excessive production of thyroid hormone and
characterized by an enlarged thyroid gland,
protrusion of the eyeballs, a rapid heartbeat, and
nervous excitability. Also called exophthalmic
goiter.
a thioamide drug used to treat hyperthyroidism
• Regulates of Basal Metabolic Rate (BMR).
• Increases oxygen consumption in most target tissues.
• Permissive actions: TH increases sensitivity of target
tissues to catecholamines, thereby elevating lipolysis,
glycogenolysis, and gluconeogenesis.
EXAMPLES OF THYROID DISEASES
Hypothyroidism
Hyperthyroidism
cretinism
goiter
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings