3. Histology of the Thyroid Gland
• The thyroid gland contains numerous follicles,
composed of epithelial follicle cells and colloid.
• Between follicles are clear parafollicular cells,
which produce calcitonin.
5. 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- 80 micrograms/day
6. 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:
peroxidase
I- I+
• Oxidized iodine can then be used in production of
thyroid hormones.
7. 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 its tyrosine residues are iodinated by I+.
This results in tyrosine residues which have one
or two iodines attached (monoiodotyrosine or
diiodotyrosine).
9. Thyroid Hormones
There are two biologically active thyroid
hormones:
- tetraiodothyronine (T4; usually called
thyroxine)
- triiodothyronine (T3)
Derived from modification of tyrosine.
10. Differences between T4 and T3
The thyroid secretes about 80 micro gm of T4, but
only 5 micro gm 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.
T4
thyroid
I-
T3
11. TRIIODOTHYRONINE TETRAIODOTYROSINE
RAPID ACTION AND
DEGRADATION
SLOW TO RESPOND
10 x MORE RAPIDLY
BINDS TO RECEPTORS
SLOW BINDING
METABOLICALLY ACTIVE INACTIVE,CONVERTS TO
T3
DIFFERENCE IN ACTIONS OF T3 & T4
12. 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), (~14%)
- 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.
13. 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.
14. 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.
15. 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.
16. 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
17. 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+
I-
thyroglobulinfollicle
cell
gene
I-
endocytosis
thyroglobulin
T3 T4
colloid droplet
I-I+
iodination
thyroglobulin
Na+ K+
ATP
18. Mechanism of Action of TSH
TSH binds to a plasma membrane-bound, G
protein-coupled 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
Protein kinase
A
Follicle cell
20. 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.
TRH phospholipase C
G protein-coupled
receptor
IP3 calcium
DAG PKC
calmodulin
• Thyroid hormones also inhibit TRH synthesis.
21. Negative Feedback Actions of Thyroid
Hormones on TSH Synthesis and Release
hypothalamus
TRH
TRH receptor
TSH synthesis
pituitary
T3/T4
+
-
-
-
TRH synthesis
Thyroid gland
follicle cell receptors
TSH binds
23. Other Factors Regulating Thyroid Hormone
Levels
Diet: a high carbohydrate diet increase 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.
Any condition that increases body energy
requirements (e.g., pregnancy, prolonged cold)
stimulates hypothalamus TRH TSH (Pit)
24. conversion
T4 can convert to T3 through deniodenation in
peripheral tissues as well as in the thyroid.
(catalyzed by deiodinase).
25. 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.
26. 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)
27. 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)
28. 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).
29. 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).
30. 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
31. Thyroid Hormone Actions which
Increase Oxygen Consumption
Increase mitochondrial size, number and key enzymes
Increase plasma membrane Na-K ATPase activity
Decrease superoxide dismutase activity
T3 /T4 can increase oxygen consumption, promote
metabolism and BMR(basal metabolic rate) ,↓utility.
32. 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
33. Effects of Thyroid Hormones on the
Respiratory System
Increase resting respiratory rate
Increase minute ventilation
Increase ventilatory response to hypercapnia and
hypoxia
34. Effects of Thyroid Hormones on the
Renal System
Increase blood flow
Increase glomerular filtration rate
35. Effects of Thyroid Hormones on
Oxygen-Carrying Capacity
Increase RBC mass
Increase oxygen dissociation from hemoglobin
36. 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
37. 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
38. 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
39. 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
42. 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….)
43. Hypothyroidism Symptoms
Tiredness and weakness
Dry skin
Feeling cold
Hair loss
Difficulty in concentrating and poor memory
Constipation
Weight gain with poor
appetite
Hoarse voice
Menorrhagia, later
oligo and amenorrhoea
Paresthesias
Impaired hearing
45. Causes of Hypothyroidism
Autoimmune
hypothyroidism
(Hashimoto’s, atrophic
thyroiditis)
Iatrogenic (I123treatment,
thyroidectomy, external
irradiation of the neck)
Drugs: iodine excess,
lithium, antithyroid drugs,
etc
Iodine deficiency
Infiltrative disorders of the
thyroid: amyloidosis,
sarcoidosis,haemochroma
tosis, scleroderma
46. Causes of Hyperthyroidism
Most common causes
Graves disease
Toxic multinodular
goiter
Autonomously
functioning nodule
Rarer causes
Thyroiditis or other causes
of destruction
Thyrotoxicosis factitia
Iodine excess (Jod-Basedow
phenomenon)
Struma ovarii
Secondary causes (TSH or
ßHCG)
47. Hyperthyroidism Symptoms
Hyperactivity/ irritability/ dysphoria
Heat intolerance and sweating
Palpitations
Fatigue and weakness
Weight loss with increase of appetite
Diarrhoea
Polyuria
Oligomenorrhoea, loss of libido
48. Hyperthyroidism Signs
Tachycardia (AF)
Tremor
Goiter
Warm moist skin
Proximal muscle
weakness
Lid retraction or lag
Gynecomastia