1. The Thyroid Gland Huiping Wang ( 王会平 ), PhD Department of Physiology Rm C516, Block C, Research Building, School of Medicine Tel: 88208252 Email: wanghuiping@zju.edu.cn

2. Outline Thyroid Hormones –Types –Biosynthesis –Storage and Release –Transport –Physiological Functions Mechanisms of TH action Regulation of thyroid hormone secretion Thyroid disorders

3. The Thyroid Gland Located at anterior part of neck on either side of trachea –The thyroid gland straddles the esophagus, just below the larynx, in the neck. One of the largest endocrine glands Comprised of 2 lobes; 20 g wt Rich in blood supply

4. The Thyroid Gland Thyroid follicular cell –T 4 and T 3 increase metabolic rate Parafollicular cell (C cell) –Calcitonin regulates calcium metabolism

5. Thyroid Gland Follicle The thyroid gland is composed of many follicles Each follicle contains colloid (thyroglobulin +hormones) Colloid is absorbed back into the follicle epithelial cells upon stimulation Follicular cells take part in almost all stages of TH synthesis and secretion

6. Types of Thyroid Hormones 90% of metabolically active hormones secreted by thyroid is thyroxine (T 4 ), 10% is triiodothyronine (T 3 ), and less than 1% is rT3 Iodide is required (1mg/week) for thyroid hormone synthesis

7. Thyroid Hormones Thyroxine (T 4 ) –Major hormone released from thyroid follicles –Contains 4 iodine atoms – More abundant than T 3 –Synthesis occurs in follicular cell colloid via the combination of DIT + DIT

8. Thyroid Hormones Triiodothyronine (T 3 ) –Generally formed from T4 by cleaving an iodine molecule (deiodinase in target cells) –4 times more potent than T 4 –Contains 3 iodine atoms –Synthesis occurs in the follicular cell colloid via the combination of DIT + MIT

9. Biosynthesis of Thyroid Hormones Materials –Iodine (in the form of iodide—I - ) 50mg/year Iodized table salt (1 sodium iodide/100,000 NaCl) –Tyrosine Thyroglobulin (TG) >70 tyrosines

10. Biosynthesis of Thyroid Hormones Iodine/iodide trapping –Iodide pump Maintains thyroid/plasma ratio of 30:1 Oxidation of iodide –Peroxidase: 2I - + H 2 O 2  I 2 Iodination of tyrosine –Peroxidase –MIT and DIT Formation of T 3, T 4 by coupling –Peroxidase –MIT + DIT  T 3 –DIT + DIT  T 4

11. Storage and Release of Thyroid Hormones Storage –In the follicles –In the form of TG (30 T 4 ) –For 2 ~3 months Release –Stimulated by TSH Concentration in plasma T 3 : 1.2 ~3.4 nmol/L T 4 : 85 ~142 nmol/L

12. Transport of T 4 and T 3 to the Tissues Binding form:99% –Most T 4 and T 3 bound to plasma proteins synthesized by liver: Thyroxine-binding globulin (TBG): mainly Thyroxine-binding prealbulmin (TBPA) albulmin –Slowly released to the tissue cells, slower for T 4 due to its higher affinity –Slow onset and long duration of action Free form:1% ( T 3 )

13. Physiological Functions of TH Effect on – Growth –Metabolism –Nervous System –Cardiovascular System –GI –Muscles, sexual function

14. Effects of TH on Growth Is essential for growth in children –Promote bone formation and maturation –Promote growth and development of brain (fetus and baby) Have synergistic effect with GH, IGF-1, insulin and other growth factors Tadpole  frog

15. Effects of TH on Growth Cretinism: deficiency of thyroid hormone during the period of fetal and early neonatal development short, stocky stature & mental retardation

16. Metabolic Effects of TH Increase cellular metabolic activity –Calorigenic action ↑ number & activity of mitochondria → ATP ↑ ↑ Na +, K + -ATPase and active transport of ions (Na, K) → heat production ↑ ↑ O 2 consumption & BMR

17. Metabolic Effects of TH Carbohydrate metabolism –  glucose oxidation –  gluconeogenesis and glycogenolysis Too much   blood glucose (Diabetes) Fat metabolism –  lipolysis （ Triglyceride  FFA + glycerol ） –  Oxidation of free fatty acid –  serum cholesterol （ excretion into GI ） Protein metabolism –  Protein synthesis (normal) –  Protein catabolism (hyperthyroidism) hyperthyroidism

19. Effects of TH on Nervous System Important for maturation of CNS in perinatal period Enhance wakefulness, alertness, responsiveness to various stimuli, auditory sense, awareness of hunger, memory and learning capacity Normal emotional tone also depend on proper thyroid hormone Increase the speed and amplitude of peripheral nerve reflexes Hyperthyroidism: hyperexcitability, insomnia, loss of concentration Hypothyroidism: mental retardation, sleepiness

20. Effects of Thyroid Hormones on Cardiovascular System Increase blood flow and cardiac output –↑ metabolism → ↑ utilization of O 2 & ↑ metabolic end products from tissue → vasodilatation –↑ cardiac output ensures sufficient O 2 delivery to the tissues Increase heart rate (easy to detect!) –increase adrenergic activity （  response to adrenaline/noradrenaline ） –increase enzymatic activity Affect heart strength –slightly increase of thyroid hormone increases heart strength –marked increase of thyroid hormone decreases heart strength ↑stroke volume + ↓peripheral resistance → pulse pressure ↑

21. Effects of Thyroid Hormones on GI Increase appetite and food intake Increase secretion of digestive juices Increase mobility of GI –Diarrhea often results from hyperthyroidism

22. Effects of Thyroid Hormones On muscles –hyperthyroidism → muscle weakening (catabolic effect) –fine muscle tremor is a characteristic sign for hyperthyroidism –hypothyroidism → muscles sluggish On other endocrine glands –↑ secretion of insulin and cortisol On sexual function –loss of libido –impotency –abnormal menstruation

23. Mechanisms of TH action –T 3 and T 4 act by binding to nuclear receptors which are expressed in most tissues –T 3 has 10 times the affinity for thyroid receptor as T 4 –  Transcription of large numbers of genes –  Synthesis of great numbers of proteins

24. Regulation of thyroid hormone secretion Hypothalmico-pituitary-thyroid axis –TRH  TSH  T 3 /T 4 –Negative feed-back of T 3 /T 4 Environmental factors –cold, stress Wolff-Chaikoff Effect –autoregulation by I

25. Hypothalmico-pituitary-thyroid axis Hypothalamus –TRH Tripeptide  TSH secretion –Cold:  TRH release

26. Hypothalmico-pituitary-thyroid axis Pituitary –TSH Glycoprotein  T 3, T 4 synthesis and release  Size of the thyroid cells cAMP mediated mechanism –Hyperthyroidism thyroid stimulating immunoglobulin (TSI)

27. Hypothalmico-pituitary-thyroid axis Thyroid –Feedback effect of thyroid hormone T 4 is converted into T 3 in pituitary and T 3 acts as the final effector to turn off TSH

28. Iodine-Deficient Goiter TSH is a trophic hormone, it stimulates not only T 3 /T 4 secretion but also protein synthesis in follicular cells. Therefore,  exposure in thyroid  size

29. Wolff-Charkoff effect autoregulation by I –low I intake stimulates synthesis of iodide trap –high I intake (>2 mg/day) inhibits trap function and synthesis

30. Thyroid disorders Hyperthyroidism Hypothyroidism

31. Hyperthyroidism The most common cause –B lymphocytes synthesize immune globulins (Ab called thyroid stimulating immunoglobulin, TSI) that bind to and active the TSH receptor, producing all the actions of TSH on thyroid (Graves’ disease).

32. Common Symptoms Associated with Hyperthyroidism Nervousness Heat intolerance Palpitation(  heart rate, >100 per minute) Muscle weakness Diarrhea Increased BMR Increased appetite Weight loss(  protein)

33. Common Symptoms Associated with Hyperthyroidism Goiter (enlarged thyroid ) Tremor Fatigue Moist skin(  metabolism) Exophthalmos(eye signs; extra- thyroidal)

34. Graves’ Eye Disease An abnormal protrusion of the eyeball in the orbit when observed from the side. Swelling within the orbital cavities and enlargement of the perorbital muscles behind the eyes Note the proptosis, lid retraction and stare Is not reduced by propranolol treatment

35. Diagnose of Hyperthyroidism Diagnoses –Assessment of thyroid function  serum T 4 and T 3  serum TSH

36. Treatment of Hyperthyroidism Drugs –Treatment of symptoms β-blocker (propranolol) –Inhibition of thyroid hormone synthesis by inhibiting thyroid peroxidase Propylthiouracil (PTU) Methimazole Radioactive iodine –to radiate the gland with high energy gamma rays, 3 months max. effect Surgery –partial thyroidectomy

37. Hypothyroidism Causes –Primary (thyroid; autoimmune disease, partial thyroidectomy) –Secondary (pituitary gland) or tertiary (hypothalamus) –Common cause an autoimmune disorder called Hashimoto’s thyroiditis. Antibodies against the thyroid are not stimulatory, but are part of an immune process that blocks and destroys thyroid function

38. Common Symptoms Associated with Hypothyroidism Decreased BMR Mental slowness Cold intolerance(  metabolism) Dry cold skin(  protein) Weight gain (  metabolism) Acroparesthesia (numbness/tingling of hands)

39. Common Symptoms Associated with Hypothyroidism Thick tongue Myxedema(due to glycosaminoglycan accumulation in the interstitial space) Goiter Slow speech Amenorrhea Constipation(  GI motility) Low sex drive Arteriosclerosis prolongation of tendon reflex  cardiac output (remember permissive effect of TH to epinephrine/norepinephrine).

40. Hypothyroidism Assessment of thyroid function –low serum free T4 –greatly elevated serum TSH Treatment –thyroxine (T4) replacement

41. An absence of thyroid hormones during fetal development leads to a. acromegaly. b. Cushing's Syndrome. c. cretinism. d. Grave's disease. e. Addison's disease. QUIZ

42. An absence of thyroid hormones during fetal development leads to a. acromegaly. b. Cushing's Syndrome. c. cretinism. d. Grave's disease. e. Addison's disease. QUIZ

43. A subject consuming a diet deficient in iodine is likely to have a. a low plasma concentration of thyroxine due to reduced secretion of TSH by the pituitary gland. b. a low plasma concentration of thyroxine and an enlarged thyroid gland. c. a high plasma concentration of TSH. d. a low plasma concentration of thyroxine due to reduced secretion of TSH by the pituitary gland and a low plasma concentration of thyroxine and an enlarged thyroid gland. e. a low plasma concentration of thyroxine and an enlarged thyroid gland and a high plasma concentration of TSH. QUIZ

44. A subject consuming a diet deficient in iodine is likely to have a. a low plasma concentration of thyroxine due to reduced secretion of TSH by the pituitary gland. b. a low plasma concentration of thyroxine and an enlarged thyroid gland. c. a high plasma concentration of TSH. d. a low plasma concentration of thyroxine due to reduced secretion of TSH by the pituitary gland and a low plasma concentration of thyroxine and an enlarged thyroid gland. e. a low plasma concentration of thyroxine and an enlarged thyroid gland and a high plasma concentration of TSH. QUIZ

45. Summary Types of Thyroid Hormones –thyroxine (T4) –triiodothyronine (T3) Biosynthesis of Thyroid Hormones –Iodine/iodide trapping –Oxidation of iodide –Iodination of tyrosine –Formation of T3, T4 by coupling Storage and Release of Thyroid Hormones Transport of T4 and T3

46. Summary Physiological Functions of TH –Effect on Growth, Metabolism, Nervous System, Cardiovascular System, GI Mechanisms of TH action Regulation of thyroid hormone secretion –Hypothalmico-pituitary-thyroid axis –Wolff-Chaikoff Effect Thyroid disorders –Hyperthyroidism –Hypothyroidism