Download Production, Regulation, and Action of Thyroid Hormones

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 and
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).
The Thyroid Gland
Thyroid Hormones
• There are two biologically active thyroid
hormones:
- tetraiodothyronine (T4; usually called thyroxine)
- triiodothyronine (T3)
• Derived from modification of tyrosine.
Differences between T4 and T3
• The thyroid secretes about 80 microg of T4, but only 5
microg of T3 per day.
• However, T3 has a much greater biological activity
(about 10 X) than T4.
• An additional 25 microg/day of T3 is produced by
peripheral monodeiodination of T4 (stay tuned….).
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
- shellfish
• 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 Na+/I- cotransport system.
• Iodide taken up by the thyroid gland is oxidized by
peroxide in the lumen of the follicle:
I-
peroxidas
e
I+
• Oxidized iodine can then be used in production of
thyroid hormones.
The Next Step: Production of Thyroglobulin
• Pituitary produces TSH, which binds to follicle cell
receptors.
• 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 tyrosine residues which have one or
two iodines attached (monoiodotyrosine or
diiodotyrosine).
The Thyroid Gland – Histology
Gland is composed of hollow spheres, called colloid follicles.
Squamous epithelial cells, cuboidal cells (follicle cells)
Colloid fills the follicle cavities
I
Follicle cells produce thyroglobulin ---- TH
Thyroid Follicles
Thyroid Follicles
Initial Steps in Thyroid Hormone Synthesis
ATPase
Na+ K+
extracellular space
gene
follicle
cell
I-
Na+
I-
Thyroglobulin
thyroglobulin
I+
iodination
thyroglobulin with
monoiodotyrosines and
diiodotyrosines
oxidation
I-
colloid space
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. [this is the
peripheral monoiodination of T4 mentioned earlier].
• 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
iodinated tyrosines (gets deiodinated,
recycled)
lysosome
follicle
cell
colloid droplet
endocytosis
thyroglobulin
T3
T4
colloid space
To Sum…
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.
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.
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
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-
gene
ATP
follicle
cell
colloid droplet
thyroglobulin
I-
endocytosis
thyroglobulin
thyroglobulin
iodination
T3
T4
I+
I-
Na+
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 cAMP 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
Influence of TRH on TSH Release
• 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 (Ca2+) 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 and Release
TRH synthesis
hypothalamus
+
-
TRH
TRH receptor
pituitary
TSH synthesis
TSH binds
Thyroid gland
follicle cell receptors
-
T3/T4
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.
• Other stresses: increased or decreased?
• Any condition that increases body energy
requirements (e.g., pregnancy, prolonged cold)
stimulates hypothalamus  TRH  TSH (Pit)
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?
Actions of Thyroid Hormone
• Required for GH and prolactin production and
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. Increased heat
production (calorigenic effect)
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)
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
hypervariable
DBD
HBD
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, but not in adult brain,
spleen, testes, uterus, and thyroid gland itself.
• Thyroid hormone inhibits thyroid hormone
receptor expression (TRE on THR genes).
One Major Target Gene of T3: The Na+/K+
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 hormones:
Key Points
• Held in storage
• Bound to mitochondria, thereby increasing ATP
production
• Bound to receptors activating genes that control
energy utilization
• Exert a calorigenic effect
Thyroid Hormone Actions which
Increase Oxygen Consumption
• Increase mitochondrial size, number and key
enzymes
• Increase plasma membrane Na-K ATPase
activity
• Increase futile thermogenic energy cycles
• Decrease superoxide dismutase activity
Effects of Thyroid Hormones on the
Cardiovascular System
•
•
•
•
•
Increase heart rate
Increase force of cardiac contractions
Increase stroke volume
Increase Cardiac output
Up-regulate catecholamine receptors
Effects of Thyroid Hormones on the
Respiratory System
• Increase resting respiratory rate
• Increase minute ventilation
• Increase ventilatory response to hypercapnia
and hypoxia
Effects of Thyroid Hormones on the
Renal System
• Increase blood flow
• Increase glomerular filtration rate
Effects of Thyroid Hormones on
Oxygen-Carrying Capacity
• Increase RBC mass
• Increase oxygen dissociation from
hemoglobin
Effects of Thyroid Hormones on
Intermediary Metabolism
• Increase glucose absorption from the GI
tract
• Increase carbohydrate, lipid and protein
turnover
• Down-regulate insulin receptors
• Increase substrate availability
Effects Thyroid Hormones in
Growth and Tissue Development
• Increase growth and maturation of bone
• Increase tooth development and eruption
• Increase growth and maturation of epidermis,hair
follicles and nails
• Increase rate and force of skeletal muscle
contraction
• Inhibits synthesis and increases degradation of
mucopolysaccharides in subcutaneous tissue
Effects of Thyroid Hormones on the
Nervous System
• Critical for normal CNS neuronal
development
• Enhances wakefulness and alertness
• Enhances memory and learning capacity
• Required for normal emotional tone
• Increase speed and amplitude of peripheral
nerve reflexes
Effects of Thyroid Hormones on the
Reproductive System
• Required for normal follicular development
and ovulation in the female
• Required for the normal maintenance of
pregnancy
• Required for normal spermatogenesis in
the male
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 TH
binding globulin….)
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.
Midwest – the Goiter Belt
• If goiter is due to decreased I, then thyroid
gland enlarges – called endemic or colloidal
goiter.
• Pituitary gland  TSH to stim thyroid gland to
produce TH, but the only result is that the
follicles accumulate more and more unusable
colloid.
• Cells eventually die from overactivity and the
gland atrophies.
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,…)
How is Goiter Related to Hyperthyroidism?
• Due to excessive stimulation by TSH
(thyroglobulin production, enlarged follicles…).
• In this case, excessive stimulation of the
thyroid gland by TSH DOES result in thyroid
hormone secretion, since iodine is available.