3. Thyroid gland  One of largest pure endocrine glands in the body (  20gms).  Its size depends on: 1. age …  age   size. 2. sex … female > male. 3. physiological condition … (pregnancy, lactation)  Site: Located in the neck just below the larynx, on either side of & anterior to the trachea.

4. Thyroid gland Thyroid gland … (Continued)

5.  Thyroid gland is well vascularized (rich in blood supply).  Embryologically: Originates from an envagination of the floor of the pharynx.

6. Thyroid gland Thyroid gland … (Continued)  Formed of 2 lobes (Rt & Lt), that are connected by band of tissue called “isthmus”.  Not visible under normal conditions, but can be felt during swallowing.

8. Thyroid gland structure - Euthyroid (normal thyroid) 1. Multiple Follicles (Acini):  Are the functional unit.  Thousands in no.   100 to 300 µmeters in diameter.  Each follicle is spherical in structure.  Follicular wall is lined with a single layer of cuboidal epithelioid cells that secrete into the interior of the follicles.

9. Structure of thyroid follicle – Euthyroid follicle  Each follicle is filled with pink-staining proteinaceous material called colloid. ● When the gland is INACTIVE: colloid is abundant, follicles are large, & lining cells are flat. ● When the gland is ACTIVE: follicles are small, lining cells are cuboid or columnar, & the edge of colloid is scalloped, forming many small “ reabsorption lacunae ”.

10. Structure of thyroid follicle - Euthyroid follicle Thyroid C-cell Basal membrane of epithelial cells Apical membrane of epithelial cells Cuboidal epithelial cells Basement membrane Colloid (glycoprotein) Capillary (Rich blood supply)

11. Structure of thyroid follicle - Euthyroid follicle ● Each follicle is surrounded by a good & rich blood supply. ● Individual thyroid cells rest on a basal lamina that separates them from the adjacent capillaries. ● Endothelial cells are attenuated at places, forming gaps (fenestrations) in the walls of the capillaries. ● There are microvilli projections into the colloid from apex of thyroid cells, & canaliculi extend into them. ● Prominent endoplasmic reticulum ( a common feature in most glandular cells), & secretory droplets of thyroglobulins.

12. Structure of thyroid follicle - Euthyroid follicle 2. Colloid: Jell-like substance that contains large glycoproteins (proteins linked by carbohydrates) called thyroglobulin, which stores thyroid hormones within its molecules. 3. Parafollicular cells or “ C-cells: - Spherical cell, which has no relation to colloid or cuboidal cells. - Secrete Calcitonin, which is involved in calcium homeostasis.

13. Thyroid gland secretions Parafollicular cells - Secreted by Parafollicular cells. - Important hormone for Ca 2+ metabolism & homeostasis. ● 2 important thyroid hormones: ● Thyroxine (T 4 ) or tetraiodothyronine ● Triiodothyronine (T 3 ) Follicular cells. - Secreted by Follicular cells. - Can be stored in thyroid gland for couple of months (2-3 months). - Having significant effect on  metabolic rate of the body. ● Calcitonin

14. Chemical nature of thyroid hormones I HO COOH CH 2 -CHO  T 3 has : - 2 benzene rings - 3 iodine atoms. - COOH & NH 2 groups like an amino acid. NH 2 I I  T 4 has : - 2 benzene rings - 4 iodine atoms. - COOH & NH 2 groups like an amino acid. O I I I CH 2 -CH HO I COOH NH 2

15. Thyroid hormones - Thyroxine (T 4 ) or tetraiodothyronine … 93% - Triiodothyronine (T 3 ) … 7%  Amount secreted:  Almost all T 4 is converted to T 3 in tissues. Target cell T4T4 T4T4 T4T4 Capillary (Rich blood supply) T3T3 Reverse T 3

16. Thyroid hormones Thyroid hormones … (continued)  T 3 is the active form of T 4.  T 3  4 times > potent (active/important) than T 4 in tissue, but it present in much smaller quantities in blood, & persists for a much shorter time than does T 4.  T 3 has great affinity to nuclear receptors than T 4.  Reverse T 3 (RT 3 ) is inactive.

18. Transfer of thyroid hormones in blood  Almost all THs are carried in the blood, mostly in an inactive form, bound to 3 different types of proteins: a. Thyroxine binding globulin … 80% b. Thyroxine binding pre-albumin …  10% c. Plasma albumin (serum albumin) …  10% N.B. T 4 has greater affinity to bind proteins than T 3.  Only very little T 3 (0.25-0.3%) & T 4 (0.03%) are carried in the blood in the free active form.

20. Mechanism of action of thyroid hormones  TH s are lipophilic amino acid derivative hormones.  Their receptors are located within the nucleus of target cells.

22. How thyroid hormones are synthesized?  T 3 & T 4 are synthesized in the colloid by: 1. Iodine formation. 2. Thyroglobulin formatiom. 3. Iodination. 4. Condensation (coupling). 5. Thyroid hormones secretion. 6. Deiodination.

23. How thyroid hormones are synthesized? 1. Iodine formation:  Iodine (I o ) is a raw material essential for THs synthesis.  Found in food, e.g. salt, & sea food, in the form of “iodide (I - )”.  120-150 µg of I - is needed daily to maintain normal thyroid fx in adults (or  1mg/wk).  Iodide (I - ) actively transported (trap) into the follicle (90 – 95%).  (I - ) will be 30X in thyroid cells > blood concentration.  (I - ) secreted into colloid along concentration gradient.  Peroxidase enzyme found near apex of follicular cells.  Peroxidase oxidize iodide (I - ) to iodine (I o ).

25. How thyroid hormones are synthesized? How thyroid hormones are synthesized? 2. Thyroglobulin formatiom:  Thyroglobulin is a glycoprotein, made up of 2 subunits, & has a MW of 660,000.  Synthesized in the thyroid cells following entry aa from ECF.  Secreted into colloid by exocytosis of granules that also contain thyroid Peroxidase.

27. How thyroid hormones are synthesized? How thyroid hormones are synthesized? 3. Iodination:  Iodine attach to tyrosine within thyroglobulin chain.  Iodinase enzyme is found in the apical membrane  Colloid  start iodination process. 1 Iodine + 1 tyrosine  Mono-iodo-tyrosine (MIT) iodinase 2 Iodine + 1 tyrosine  Di-iodo-tyrosine (DIT) Colloid

28. How thyroid hormones are synthesized? How thyroid hormones are synthesized? 4. Condensation (coupling):  MIT & DIT or 2 DIT molecules coupled together. MIT + DIT = T 3 DIT + DIT = T 4 N.B. - Not all DIT & MIT  thyroid hormones. - Only 25% of DIT & MIT give rise to thyroid hormones. - T 3 can also be formed by de-iodination (removing 1 iodine atom) of T 4 by deiodinase enzyme.

29. How thyroid hormones are synthesized? How thyroid hormones are synthesized? 5. Thyroid hormones secretion:  After formation of THs, they remain bound to thyroglobulin in the colloid until secreted.  Hormones are surrounded in colloid by acid pool, then converted into ‘ colloid droplet ’.  TSH stimulates pinocytosis of thyroglobulin into the follicular cell.  Lysozome enzymes hydrolyze peptide bonds & release T 3 & T 4 from thyroglobulin.  T 3 & T 4 will be discharged freely & secreted into the capillaries (blood), attaching to TBG.

31. How thyroid hormones are synthesized? How thyroid hormones are synthesized? 6. Deiodination:  Inside follicular cells, DIT & MIT forms are NOT secreted into the blood.  DIT & MIT will be deiodinized to (I o ) & tyrosine.  Deiodized tyrosine will recycled back to synthesize New MIT & DIT.

33. How thyroid hormones are synthesized?

34. Remember: ● All hormones are formed in colloid ‘ lumen ’. ● Colloid stores enough hormones for next 2 – 3 months.

36. Control of thyroid hormones secretions  Hypothalamus (TRH)  Anterior pituitary gland (TSH)  (+) thyroid gland  (+) THs via cAMP dependent mechanism.  THs  -ve feed back mechanism to Hypothalamus inorder to inhibit (TRH) secretion to anterior pituitary gland.

37. Control of thyroid hormones secretions  THs  also -ve feed back mechanism to Anterior pituitary gland in order to inhibit responsiveness to Hypothalamus (TRH).

39. Functions of thyroid hormones  Generally, THs: 1. Increases metabolic rate.  Stimulates increased consumption of glucose, fatty acids and other molecules. 2. Increases metabolic heat, by  mitochondrial no & activity   ATP, 3. Stimulates rate of cellular respiration by:  Production of uncoupling proteins.  Increase active transport by Na + /K + pumps.  Stimulates O 2 consumption of most of cells in the body.

40. Functions of thyroid hormones 4. Necessary for normal growth & maturation. 5. Promotes maturation of nervous system. 6. Stimulates protein synthesis. 7. Help regulating lipid & CHO metabolism.

42. I: Hyperthyroidism (thyrotoxicosis)  Females > males (4:1).  Hyperthyoidism   THs.  Could be: 1ry hyperthyroidism … (diseases is in the gland), e.g. Grave’s disease Exerts TSH-like effects on thyroid. Not affected by negative feedback.  T 3 & T 4  reflex  TSH. 2ry hyperthyroidism … (disease is higher up)  TRH   TSH   T 3 & T 4.  Follicular cells become overactive.

43. I: Hyperthyroidism … ‘ Grave ’ s disease ’  90% of hyperthyoidism is due to “Grave’s disease”.  GD is an autoimmune disease   thyroid stimulating antibodies IgG  Symptoms of GD: - Exophthalmous, due to retro-orbital oedema (irreversible). - Lid lag, due to weakness of extraoccular muscles (reversible). - Anxiety & restlessness. - Sleeplessness. -  appetite,  weight & diarrhea. - Intolerence to heat.  Treatment: - drugs to  iodination process, such as PTU ‘ Propylthiouracil ’ ; MMI ‘ methylmercaptoimidazole ’.

44. II: Hypothyroidism Adult (Myxedema)  Hypothyroidism in adults   THs.  Could be: 1ry hypothyroidism … (diseases is in the gland) - autoimmune disease such as “Hashimoto’s throiditis”. - lack of iodine. - absence of deiodination enzyme.  T 3 & T 4  reflex  TSH. 2ry hypothyroidism … (disease is higher up)  TRH   TSH   T 3 & T 4.  Follicular cells become less active.

45. II: Hypothyroidism (myxedema) … cont.  If No Iodine   T 3 & T 4   TRH   TSH   growth (size) of the gland  simple goiter.

46. How goiter ‘swollen neck’ is formed? With lack of iodine … Hypothalamus Anterior pituitary NO or low feedback inhibition Poor Low T3 or T4 release  Growth of the gland Thyroid gland + + TRH TSH +++ COLD Lack of iodine

47. II: Hypothyroidism (myxedema) … cont.  If there is absence of deionization enzyme  NO recycle synthesis of DIT & MIT  accumulate.  DIT & MIT will not be used for new THs formation   THs.

48. II: Hypothyroidism (myxedema) … cont.  Symptoms of Hypothyroidism: - Decreased metabolic rate. - Slow heart rate & pulse. - Slow muscle contractions -  appetite,  weight gain, & constipation. - Prolonged sleep, & dizziness. - Coarse skin. - Slow thinking, lethargy, & mask face. - Intolerence to cold (  ability to adapt cold). - Myxoedema  swollen & puffy appearance of body, due to deposition of protein-carbohydrate complexes ‘ mucopolysaccharides ’ & fluid in subcutaneous tissue.

49. II: Hypothyroidism Children (Cretinism)  Hypothyroidism in children   THs. Hypothyroid from end of 1 st trimester to 6 months postnatally, or in the 1 st few years of life.  T 3 & T 4  reflex  TSH.  Additional Signs & Symptoms: - Severe mental retardation. - Short stature (due to  growth of bones, muscle, & brain).  Treatment: Thyroxine.