1. Physiology of Thyroid Gland

2. The thyroid gland, located below the larynx on each side of and anterior to the trachea, is one of the largest of the endocrine glands.

3. Histology of the Thyroid Gland
The thyroid gland contains numerous follicles, composed of epithelial follicle cells and colloid.
The major constituent
of colloid is the large glycoprotein thyroglobulin, which contains the thyroid hormones within its molecule.
Also, between follicles are clear parafollicular cells, which produce calcitonin

4. THYROID HORMONES TyrosineOH I
NH2
Thyroxine (T4)
3,5,3’-Triiodothyronine (T3)
Tyrosine
There are two biologically active thyroid hormones:
- tetraiodothyronine (T4; usually called thyroxine)
- triiodothyronine (T3)
Derived from modification of an amino acid (tyrosine)

5. 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. T4
thyroid I- T3

6. 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

7. 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 basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell.
This is called iodide trapping.
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 (via pendrin receptor):
Thyroid peroxidase
I- I+
Oxidized iodine (I+ ) can then be used in production of thyroid hormones.

8. Production of thyroglobulin
The follicle cells of the thyroid produce thyroglobulin.
Thyroglobulin is a very large glycoprotein.
Thyroglobulin is released into the colloid space (via pendrin receptor), where it’s tyrosine residues are iodinated by I+. (organification)
This results in monoiodotyrosine (MIT) or diiodotyrosine (DIT).

9. Ion transport by the thyroid follicular cell
organification
Propylthiouracil (PTU) blocks iodination of thyroglobulin
COLLOID
BLOOD
NaI symporter (NIS)
Thyroid peroxidase (TPO)
PTU, a thioamide drug used to treat hyperthyroidism

10. Initial Steps in Thyroid Hormone Synthesis
follicle
cell
extracellular space
colloid space I-
thyroglobulin with
monoiodotyrosines and
diiodotyrosines
iodination
thyroglobulin
gene I+
oxidation
Na+ K+
Pendrin

11. 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.

12. Utilization of Thyroglobulin to Secrete Thyroid Hormones
In order to secrete T3/T4, the thyroglobulin in the colloid space is internalized by endocytosis via megalin receptor back into the follicle cell. (receptor mediated endocytosis)
This internalized vesicle joins with a lysosome, whose enzymes cause cleavage of T3 and T4 from thyroglobulin.
*megalin, an endocytic receptor for follicular thyroglobulin

13. Endocytosis (via megalin)
T3 and T4 are then released into the extracellular space by diffusion.
Only minute amounts of thyroglobulin are released into the circulation.
follicle
cell
colloid space
Endocytosis (via megalin)
thyroglobulin
T T4
colloid droplet
lysosome
T3/T4
(deiodinated, recycled)
extracellular space
(T4 T3)

14. 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.

15. 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.

16. In addition to T3, an equal amount of “reverse T3” may also be formed.
This has no biological activity.

17. THYROID HORMONE METABOLISM
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.

19. 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.

20. 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

21. 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
Thus, there is negative feedback regulation of iodide transport by iodide.

22. Key players for the thyroid include:
Feedback regulation the hypothalamic-pituitary-thyroid axis
T3 & T4 Control Pathways
Key players for the thyroid include:
TRH
TSH
T3, T4

23. Action of TSH on the Thyroid
TSH acts on follicular cells of the thyroid.
TSH binds to specific cell surface receptors that stimulate adenylate cyclase to produce cAMP.
- increases iodide transport into follicular cells
- increases production and iodination of thyroglobulin
- increases endocytosis of colloid from lumen into follicular cells
Na+ I-
thyroglobulin
follicle
cell
gene
endocytosis
T T4
colloid droplet I+
iodination K+
ATP 1 3 2

24. 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

25. 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).

26. 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).

27. 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

28. 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.

29. 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?

30. 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

31. Stimulation of Carbohydrate Metabolism by Thyroid hormone
Stimulates all of carbohydrate metabolism:
including rapid uptake of glucose by the cells,
increased glycolysis,
increased gluconeogenesis,
increased rate of absorption from the gastrointestinal tract,
increased insulin secretion with its resultant secondary effects on carbohydrate metabolism.
All these effects probably result from the overall increase in cellular metabolic enzymes caused by thyroid hormone.

32. Stimulation of Fat Metabolism
Lipids are mobilized rapidly from the fat tissue, which decreases the fat stores and increases the free fatty acid levels in the plasma.
Increased thyroid hormone decreases the levels of cholesterol, phospholipids, and triglycerides in the plasma, and increases the free fatty acids.
But, decreased thyroid secretion greatly increases the plasma levels of cholesterol, phospholipids, and triglycerides.
TH decreases the plasma cholesterol concentration through increase the rate of cholesterol secretion in the bile and consequent loss in the feces.

33. Increased Basal Metabolic Rate
Because thyroid hormone increases metabolism in almost all cells of the body,
excessive quantities of the hormone can increase the basal metabolic rate
Conversely, when no thyroid hormone is produced, the basal metabolic rate falls.

34. Effects of Thyroid Hormones on the Cardiovascular System
Increased metabolism in the tissues causes more rapid utilization of oxygen than normal and release of greater than normal quantities of metabolic end products from the tissues.
So, the increased blood flow leads to increased cardiac output and,
Increase heart rate
Increase force of cardiac contractions
Increase stroke volume
Up-regulate catecholamine receptors

36. Effects of Thyroid Hormones on the Respiratory System
Increase resting respiratory rate
Increase minute ventilation
Increase ventilatory response to hypercapnia and hypoxia

37. Effects of Thyroid Hormones on the Renal System
Increase blood flow
Increase glomerular filtration rate

38. Thyroid hormones affect renal function by both pre-renal and direct renal effects Pre-renal effects are mediated by the influence of thyroid hormones on the cardiovascular system and the renal blood flow (RBF) The direct renal effects are mediated by the effect of thyroid hormones on glomerular filtration rate (GFR), tubular secretory and re-absorptive processes, as well as the hormonal influences on renal tubular physiology.
Thyroid hormones influence Na reabsorption at the PCT primarily by increasing the activity of the Na/K ATPase  and tubular potassium permeability

40. Effects of Thyroid Hormones on Oxygen-Carrying Capacity
Increase RBC mass
Increase oxygen dissociation from hemoglobin

41. 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

42. 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,nhair follicles and nails
Increase rate and force of skeletal muscle contraction
Inhibits synthesis and increases degradation of mucopolysaccharides in subcutaneous tissue

43. Effects of Thyroid Hormones on the Nervous System
Enhances wakefulness and alertness
Enhances memory and learning capacity
Required for normal emotional tone
Increase speed and amplitude of peripheral nerve reflexes

44. TH in Intrauterin and infantil periods:
Critical for normal CNS neuronal development:
Development of cerebral and cerebellar cortex
Proliferation of axons
Branching of dendrite
Synaptogenesis
Myelinization
Migration of cells

45. Deficiency of TH in infant or intrauterin periods (Cretenism)
Mostly affected development of cerebral cortex, basal ganglia and cochlea, so:
Loss of hearing
CNS exitation,
motor activity,
learning capacity,
memory,
response to stimulus

46. 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

48. 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.

49. 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….)

50. 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.

51. 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,…)

52. 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.

53. Calcitonin
Calcitonin is a 32-amino acid polypeptide hormone that is produced in humans primarily by the parafollicular (also known as C-cells) of the thyroid.
It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone(PTH).

54. Biosynthesis
Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene (CALCA).
The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.
The calcitonin receptor, found primarily on osteoclasts, is a G protein-coupled receptor, which is coupled by Gs to adenyl cyclase and thereby to the generation of cAMP in target cells.

55. Physiology
The hormone participates in calcium(Ca2+) and phosphorus metabolism. In many ways, calcitonin has the counter effects of parathyroid hormone(PTH).
To be specific, reduces blood Ca2+ levels in three ways:
1) Decreasing Ca2+ absorption by the intestines.
2) Decreasing osteoclast activity in bones.
3) Decreasing Ca2+ and phosphate reabsorption by the kidney tubules.

57. These stimulate secretion of calcitonin:
Increased plasma Ca levels
Feeding ( Gis hormones, especially gastrin)
Β-adrenergic agonist drugs
Dopamine
Estrogens

58. High levels of blood Ca (>11mg)
When blood Ca levels are high, Calcitonin is released.
Causes bone deposit to occur
Ca from the blood is stored into bone.
(Osteoblasts and Osteocytes are working.)
99% of all Ca is found in bone.

59. Osteoclasts cause bone resorption
Controlled by PTH
Osteoblasts cause bone deposit
Controlled by calcitonin

60. Action 1) Bone mineral metabolism:
- Prevent postprandial hypercalcemia resulting from absorption of Ca2+ from foods during a meal
- Promote mineralization of skeletal bone.
- Protect against Ca2+ loss from skeleton during periods of Ca2+ stress such as pregnancy and lactation.
- It have hypophostatemic effects:
*inhibits of bone resorption
* stimulates of phosphate deposition in bone
* increases excretion of phosphate in tubules

61. 2) Vitamin D regulation
3) A satiety hormone:
- Inhibit food intake in rats and monkeys - May have CNS action involving the regulation of feeding and appetite.

62. In human, CT increases gastric acid and pepsin secretion and decreases pancreatic amylase and pancreatic polypeptide. 
The kidney is the principal site of CT degradation by neutral endopeptidase (NEP).
The effect of CT on the kidney is to stimulate diuresis and increase the fractional excretion rate of sodium and chloride.
In addition, in urine a calcium and phosphate excretion increases.