1. Production, Regulation, and Action

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.

4. The Thyroid Gland – Histology
I

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).

8. Thyroid Hormone Synthesis

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

19. Thyroid Follicles

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

40.  Calcium metabolism.
 Adrenal cortex.

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

44. Hypothyroidism Signs
 Dry skin, cool extremities
 Puffy face, hands and feet
 Delayed tendon reflex relaxation
 Carpal tunnel syndrome
 Bradycardia
 Diffuse alopecia
 Serous cavity effusions

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