1. Dr. Ayisha Qureshi MBBS, Mphil.
THYROID HORMONE
Dr. Ayisha Qureshi
MBBS, Mphil.

2. THE THYROID GLAND
- The thyroid gland is the largest of the endocrine glands & is located at the base of the neck immediately below the Larynx on each side of & anterior to the Trachea.
- The thyroid gland consists of two lobes of endocrine tissue (lying on either side of trachea) joined in the middle by a narrow portion of the gland called, the Isthmus.
- In a normal adult male, it weighs g but is capable of enormous growth, sometimes achieving a weight of several hundred grams.
It looks like a bow tie & is even located in the appropriate place for a bow tie lying over the trachea just below the larynx!

3. LOCATION OF THE THYROID GLAND

4. THYROID GLAND The thyroid gland consists of 2 types of cells:
Follicular cells: These are more abundant, and the major secretory cells. They secrete Thyroid hormone.
Parafollicular cells or C-cells: These are fewer in number & interspersed. They secrete calcitonin.
These 2 secretory cells are derived embryologically from 2 different sources: Follicular cells from endoderm of primitive pharynx & C-cells from neuroectoderm.

5. THYROID GLAND AS A FUNCTIONAL UNIT:
- The functional unit of the Thyroid Gland is a Follicle which is composed of cuboidal epithelial (follicular) cells arranged around hollow vesicles of various shapes (size: mm in diameter).
Each follicle is a closed structure filled with a glycoprotein colloid called Thyroglobulin.
There are about 3 million follicles in an adult human thyroid gland.

6. THE THYROID HORMONE

7. Thyroxine or T4 having 4 atoms of Iodine &
THYROID HORMONES
The Thyroid gland secretes 2 major hormones:
Thyroxine or T4 having 4 atoms of Iodine &
2. Triiodothyronine or T3 having 3 atoms of Iodine

8. THYROID HORMONES
About 93% of secreted hormone is T4, while 7% is T3. However, almost all of the T4 is ultimately converted into T3.
The functions of the 2 hormones are the SAME but they differ in rapidity & intensity of action.
T3 is about 4 times as potent as T4, but is present in blood in much smaller quantities & for a much shorter time!

9. THYROID HORMONE BIOSYNTHESIS:

10. 1. INGESTION OF IODINE
Iodine in large amounts is required for thyroid hormone synthesis. This is acquired through diet & THERE IS NO OTHER USE OF THIS ELEMENT IN THE BODY!
50 mg of Iodine is required each year OR 1 mg/week.
To prevent deficiency, common table salt is iodized with about 1 part sodium iodide to every 100,000 parts sodium chloride.
Ingested iodide is absorbed from the GIT.

11. This pump transfers 2 Na ions with each Iodide ion.
2. IODIDE TRAPPING
This is done with the help of an electrogenic “Iodide pump” located in the thyroid cell membrane.
The Iodide pump is a Sodium Iodide Symporter (NIS) & is present in the follicular cell basolateral membrane. ↓
This pump transfers 2 Na ions with each Iodide ion.
(Under normal circumstances, iodine is times more concentrated in the cytosol of Thyroid follicular cells than in the blood plasma. Iodine moves into the thyroid cells against a steep concentration gradient!)
Na/ K pump then extrudes 3 Na ions in exchange for 2 K ions to maintain the electrochemical gradient for Na.
NOTE: Other ions as percholate & thiocyanate compete for binding sites on the symporter and can block the uptake of iodide.
Consequently, other ions as perchlorate & thiocyanate compete for binding sites on the symporter, can block the uptake of iodide. This property can be exploited for diagnostic purposes!

12. 3. THYROGLOBULIN SYNTHESIS
It is the matrix for thyroid hormone synthesis & is the form in which the hormone is stored in the gland.
It is a large glycoprotein with a m.w of 660,000 Da. And is synthesized in the Thyroid follicular cells.
Tyrosine becomes incorporated into Thyroglobulin while it is being formed.
Once produced, the tyrosine-containing thyroglobulin is exported from the follicular cells into the colloid by exocytosis.
For hormone synthesis to take place, Iodine must also be delivered to the follicular lumen.
The Iodine that has entered into the follicular cell from the blood stream diffuses across the follicular cell & exits it to enter the colloid of the Follicle. This is done with the help of a transporter protein called Pendrin.
The Follicular cell has 2 surfaces: a basolateral surface facing the blood stream & the ECF, & an apical surface facing the Follicular lumen, where hormone biosynthesis takes place!

13. 4. OXIDATION OF THE IODIDE ION
Iodide ion is oxidized to form either nascent iodine (I°) or I3− .
This oxidation is catalyzed by the enzyme thyroid peroxidase and its accompanying hydrogen peroxidase.
These enzymes are located in the apical membrane of the cell or attached to it.

14. 5. ORGANIFICATION
Addition of iodine molecules to tyrosine residues in the thyroglobulin is called Organification of thyroglobulin.
This reaction is catalyzed by the enzyme Iodinase.
Tyrosine + 1 Iodine = Monoiodotyrosine
(MIT)
Tyrosine + 2 Iodines = Di-iodotyrosine
(DIT)

15. COUPLING DOES NOT OCCUR B/W 2 MIT MOLECULES!
It is the combination or coupling of 2 molecules of iodinated tyrosine molecules to form thyroid hormone:
- DIT + DIT = Thyroxine (T4)
- DIT + MIT = Tri-iodothyronine (T3)
COUPLING DOES NOT OCCUR B/W 2 MIT MOLECULES!
This mature hormone is formed while being a part of Thyroglobulin molecule, & remains a part of this large storage molecule till the stimulus for secretion arrives.
This reaction is catalyzed by Thyroperoxidase.

16. 7. STORAGE
In normal individuals, approximately 30% of the mass of thyroid gland is thyroglobulin, which is about 2-3 months supply of hormone.

17. 8. SECRETION
Before their release, T4 & T3 are still bound with the thyroglobulin molecule.
For secretion to occur, thyroglobulin must be brought back into follicular cells by a process of endocytosis.
Pseudopodia reach out form the follicular cells to engulf chunks of thyroglobulin, which are taken up in endocytic vesicles- this is also called “BITING OFF”.
The endocytic vesicles fuse with the lysosomes.
Lysosomes release enzymes that split off the biologically active hormones: T3 & T4, as well as the inactive iodotyrosines, MIT & DIT.
The thyroid hormones being very lipophilic, pass freely through the outer membrane of the follicular cells & into the blood!
. It is a complicated process for 2 reasons:

18. The follicular cells contain an enzyme
9. FATE OF MIT & DIT
The MIT & DIT are of no endocrine value. ↓
The follicular cells contain an enzyme
(deiodinase) that will swiftly remove the Iodine from MIT & DIT, allowing the freed Iodine to be recycled for synthesis of more hormone.
This highly specific enzyme will remove iodine only from the worthless MIT & DIT and not from T3 & T4. Deiodinase provides almost twice as much iodide for hormone synthesis as Iodide pump & is therefore is of great significance in hormone biosynthesis. Patients who are genetically deficient thyroidal tyrosine deiodinase suffer symptoms of iodine deficiency & excrete MIT & DIT in their urine. Normally, virtually no MIT & DIT escapes from the gland.

21. PASSAGE THROUGH BLOOD
This highly lipophilic thyroid hormone molecule binds with several plasma proteins.
The binding proteins are:
Thyroxine binding globulin (TBG)
Transthyretin (TTR)
Albumin
The majority (70%) bind to TBG, a plasma protein that selectively binds only Thyroid hormone.
Less than 0.1% of T4 and less than 1% of T3 is in the unbound (free) form.
It is remarkable that such less percentage is carried in free form as it is only the free pool of the hormone that has access to the target organ receptors & thus can exert its effect! Also the bound protein cannot escape the blood stream through the capillary endothelium as it is too large!
The other binding proteins are:
Thyroxine binding globulin (TBG) (binds 70% of the hormone)
Transthyretin (TTR) (binds 15% of hormone)
Albumin (binds 15%)
The bound hormone provides substantial reservoir of extrathyroidal hormone!
Therefore, when there is a deficiency of thyroid hormone due to a defect of the gland, the deficiency is not even noticed for weeks to months as the unbound form is slowly released. Also, the total amount of bound T3 & T4 will affected if the plasma protein concentration is decreased as with kidney & liver diseases.

22. MECHANISM OF ACTION

23. M.O.A
Thyroid hormone receptors are members of a large family of nuclear hormone receptors
Location: Thyroid hormone receptors are either attached to the DNA genetic strand or located in close proximity to them.

24. M.O.A
The receptor usually forms a heterodimer with retinoid X receptor (RXR) at specific thyroid hormone receptor elements (THR) on the DNA. ↓
The thyroid hormone receptor binds to the response elements in the absence of the hormone.
When the thyroid hormone becomes available, the receptor becomes activated & initiates the transcription process.
Large number of mRNA are formed
Within minutes or hours: RNA translation on the cytoplasmic ribosomes takes place
Hundreds of new intracellular proteins are formed
Most of the actions are exerted through these proteins

26. ACTIONS OF THYROID HORMONE

27. 1. GENES
Thyroid hormone increases the transcription of large number of genes. ↓
Thus, in all cells of the body, there is increased production of:
Protein enzymes
Structural proteins
Transport proteins
Other substances
Net result: there is generalized increase in functional activity throughout the body!

28. 2. GROWTH & MATURATION
It stimulates growth of the skeletal system by affecting bone maturation.
It stimulates normal synthesis & secretion of the GH.
It is essential for the normal growth of the children.
It stimulates & promotes normal growth & development of the brain during the perinatal period (nerve myelination & brain vascularity).
Its deficiency during postnatal period can lead to irreversible mental & physical retardation in infants & a small sized brain.
In the adult, it has excitatory effects on the nervous system.
REMEMBER: skeletal maturation is distinct from skeletal growth. Maturation of bone results in the ossification & eventual fusion of the cartilaginous growth plates, which occurs with sufficient predictability in normal development that individuals can be assigned a specific “bone age” from radiological examination of the ossification centers.
In Hyperthyroid children, excessive skeletal growth may occur, causing the child to become considerably taller at an earlier age. However, the bones mature more rapidly and the epiphysis close at an early age, so that the duration of growth & the ultimate height of the child is shortened!

29. 3. AUTONOMIC NERVOUS SYSTEM
Interactions b/w thyroid hormone & ANS are important throughout life.
↑ secretion of thyroid hormone exaggerates many responses of the sympathetic neurons.
It ↑ the number of receptors for epinephrine & NE (beta- adrenergic receptors) in the myocardium & other tissues.
Thus, many symptoms of hyperthyroidism resemble sympathetic nervous system.
Increased thyroid secretion exaggerates many of the responses that are mediated by the NT NE and E, which are released from the sympathetic neurons & the adrenal medulla. Also it may also increase expression of excitatory G-proteins and cAMP.

30. 4. Carbohydrate metabolism
It stimulates all aspects of carbohydrate metabolism:
↑ hepatic glucose production
↑ gluconeogenesis
↑ glycogenolysis
The plasma glucose levels remain normal provided the pancreas respond by ↑ Insulin secretion.

31. 5. LIPIDS
It stimulates lipid mobilization from fat stores of the body.
↑ Lipogenesis
↑ Lipolysis (to provide glycerol for gluconeogenesis)
Increased levels of TH shift the balance in favor of lipolysis, mobilizing fat stores.
↑ secretion of cholesterol into bile, thus decreasing the cholesterol levels in the blood.

32. 6. PROTEIN METABOLISM
↑ Proteolysis (to provide the amino acids for gluconeogenesis)
↑ Protein synthesis
Usually the Proteolysis outweighs the protein synthesis and there is a net increase in Protein catbolism.
Body proteins are constantly being degraded & resynthesized. In the hyperthyroid subject, the effects of degradation predominate and often there is severe catabolism of muscle. Body protein mass decreases despite increased appetite and ingestion of dietary proteins.

33. 7. BASAL METABOLIC RATE BMR is highly sensitive to thyroid status.
HYPOthyroidism decreases BMR & HYPERthyroidism increases BMR.
TH is “calorigenic” which means that it promoted heat production.
It is not surprising that one of the classical signs of hypothyroidism is decreased tolerance to cold, whereas excessive heat production & sweating are seen in hyperthyroidism.
BMR is a measure of oxygen consumption under defined resting condition. Oxygen consumption in all tissues except brain, testis and spleen is sensitive to thyroid status. Physiologically, oxygen consumption is proportional to energy utilization. Thus, if there is increased oxygen consumption, there must be increased utilization of energy.

34. 8. HEART Blood Flow & Cardiac Output: Increased BMR ↓
Increased & more rapid oxygen consumption by the tissues
Greater than normal metabolic end products
Vasodilatation in most tissues
Increased blood flow
Increased cardiac output
Increased Heart Rate
Heart Strength:
Small increase in thyroid hormone secretion: Increase in heart strength due to increased enzymatic activity (as occurs in mild fevers during exercise)
Large increase in thyroid hormone secretion: heart strength becomes depressed b/c of long term protein metabolism
Some severely Thyrotoxic patients die of severe cardiac decompensation (due to myocardial failure b/c of increased cardiac output causing increased cardiac load)

35. 9. RESPIRATION Increased rate of metabolism ↓
Increased utilization of oxygen +
Increased formation of carbon dioxide
Increased rate & depth of Respiration

36. 10. GASTROINTESTINAL TRACT
Increased appetite
Increased food intake
Increased GI motility
Increased GI secretions
SO, Hypothyroidism causes:__________
& Hyperthyroidism causes: __________

37. 11. SLEEP Increased thyroid hormone secretion ↓
Exhaustive effect on the musculature & CNS
Constant tiredness
BUT, b/c of the excitable effects on synapses, IT IS DIFFICULT TO SLEEP

38. 12. Effect on Other Endocrine Glands
Increased rate of secretion of thyroid hormones ↓
Increases the need of the tissues for the hormones
Increases the rate of secretion of various hormones
For normal sexual development and function, thyroid hormone production needs to be normal.

39. THYROID HORMONE SECRETION
CONTROL & DIAGNOSIS
THYROID HORMONE SECRETION

40. THYROID STIMULATING HORMONE (TSH)/ THYROTROPIN
Is a glycoprotein with a mw of 28, 000 and secreted by the anterior pituitary.
Main function: It increases the secretion of both T3 & T4by the thyroid gland.
Mechanism of Action:
TSH + TSH receptors on the thyroid follicular cell membrane ↓
Adenylyl cyclase is stimulated
ATP→ cAMP
Protein kinase A is activated
Multiple phosphorylations throughout the cell
Immediate increase in thyroid hormone secretion
Stimulates growth of the thyroid glandular tissue

41. THYROID STIMULATING HORMONE
EFFECTS ON THE THYROID GLAND:
Increased proteolysis of the Thyroglobulin already stored in the follicular cells
Increased activity of the “Iodide pump”
Stimulates Organification
Increased size & secretory activity of the thyroid cells
Increased number of the Thyroid cells (with change into columnar from cuboidal)
IN SUMMARY: TSH increases all the known secretory activities of the thyroid gland!
MOST IMPORTANT IS PROTEOLYSIS WHICH CAUSES RELEASE OF THE TH INTO THE BLOOD STREAM WITHIN 30 MINUTES!

42. ANTERIOR PITUITARY SECRETION OF TSH IS REGULATED BY THYROTROPIN-RELEASING HORMONE FROM THE HYPOTHALAMUS

43. THYROTROPIN RELEASING HORMONE (TRH)
A tripeptide amide (pyroglutamyl-histidyl-proline-amide)
Secreted by the nerve endings in the median eminence of hypothalamus
Mechanism of secretion:
TRH + TRH receptor in the pituitary cell membrane ↓
Phospholipase C second messenger system activated
TSH released

44. HYPOTHALAMIC-HYPOPHYSIAL PITUITARY AXIS
Hypothalamus ↓
TRH
Hypothalamic-Hypophysial portal blood system
Anterior pituitary
TSH
Thyroid gland
Tri-iodothyronine & Thyroxine Secretion

45. Hypothalamic-Hypophysial Feedback System
IF TYROID HORMONE DEFICIENT, THEN THE SECRETION IS STIMULATED THROUGH THIS FEEDBACK SYSTEM!
&
VICE VERSA!
When the rate of TH secretion increases by 1.75 times normal, the rate of TSH secretion falls essentially to zero!
This effect on the anterior pituitary is seen even when ant. Pituitary has been separated from hypothalamus!