1. The Thyroid Gland

2. Figure 18.11a Largest endocrine glands in the body, Weighing ~ 20-25g. Functions early in life for the development of brain cells (forming nerve terminals/ synapse/ dendrites/ myelin)

3. The Thyroid Gland---Structure

4. Figure 18.11b, c

5. Figure 18.12b

6. The Thyroid Gland - Function 酪氨酸

7. Biosynthesis of Thyroid Hormones Iodine: - Distribution: the sea - Source: food (and drink), in the form of I -. The international recommended intake of iodine ： 150 mg/day (1/3 is absorbed in the thyroid) The total iodine in the thyroid: 8-10 mg (90% of the total iodine in body) Thyroglobulin (TG): - Homodimer glycoprotein - Carrier of iodotyrosine - The storage form of thyroid hormones

8. Biosynthesis of Thyroid Hormones

9. The Thyroid Gland - Production of T3 and T4

12. Figure 18.12a

13. The sodium/iodide symporter ( 同向转运体， NIS) is an intrinsic membrane protein that mediates the active transport of iodide into the thyroid and other tissues Iodide trap – active transport: thyroid peroxidase, TPO

14. The activation of the iodine is the precondition of tyrosine iodination:

15. Condensation of iodinated tyrosine:

16. The storage and release of thyroid hormones Storage –In the follicles –In the form of TG –For 2 ~3 months Release –Stimulated by TSH T3 = 1.8 ~2.9 nmol/L T4 = 65 ~156 nmol/L rT3 = 0.2 ~0.8 nmol/L

17. Binding form: 99% Thyroid hormones attached to thyroid binding globulins (TBG) –Some are attached to transthyretin （甲状腺素运载蛋白）, Thyroxine-binding prealbulmin (TBPA ，甲状腺素结合前白蛋白 ) or albumin –Slowly released to the tissue cells, slower for T4 due to its higher affinity –Slow onset and long duration of action Free form: 1% ( T3) Transport of thyroid hormones

18. Metabolism of thyroid hormones Deiodination Deiodinase T4 → T3 (45%), in coldness T4→ rT3 (55%), in pregnancy, hungry, stress, kidney failure Locations: liver, kidney, skeletal muscle

19. The Thyroid Gland - Regulation of Secretion

20. Effects of T3 and T4 on the Body Proper development of the nervous system in the fetus; Maintain a person's alertness, responsiveness, and emotional state.

21. Essential for growth in children - Promote bone formation and maturation, and the development of brain (fetus and baby) Synergistic effect （协同效应） with GH, IGF-1, insulin and other growth factors Cretinism: deficiency of thyroid hormone during the period of fetal and early neonatal development; short, stocky stature & mental retardation

22. Permissive Effects on catecholamines – Up-regulate beta-adrenergic receptors in many tissues (heart and nervous system) – Potentiate (↑the effect of, being synergistic) actions of catecholamines (i.e. hyperthyroidism resembles symptoms of hypersecretion of epinephrine/norepinephrine)

23. Effects of T3 and T4 on the Body: Calorigenic effect

24. Carbohydrate metabolism –↑glucose oxidation,↑effect of glucagon, cortisol and GH –↑glucogenesis and glycogenolysis Too much TH →↑blood glucose (Diabetes) Fat metabolism –↑lipolysis (Triglyceride → FFA + glycerol) –↑oxidation of FFA –↓serum cholesterol (excretion into GI) Protein metabolism –↑Protein synthesis (normal) –↑Protein catabolism (hyperthyroidism)

25. Effects on Nervous System A key role on the CNS-maturation during perinatal period ↑ wakefulness, alertness, responsiveness to various stimuli, auditory sense, awareness of hunger, memory and learning capacity Normal emotional tone also depends on proper thyroid hormone ↑ the speed and amplitude of peripheral nerve reflexes Hyperthyroidism: hyperexcitability, insomnia, loss of concentration Hypothyroidism: mental retardation, sleepiness myxedema

26. Effects on cardiovascular system ↑ blood flow and cardiac output –↑metabolism →↑utilization of O2 & ↑metabolic end products from tissue →vasodilatation –↑cardiac output ensures sufficient O2 delivery to the tissues ↑ heart rate – ↑ adrenergic activity (↑response to adrenaline/noradrenaline ） – ↑ 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 ↑

27. Effects on gastrointestinal system Increase appetite and food intake Increase secretion of digestive juices Increase mobility of GI tract – hyperthyroidism: diarrhea Effects on muscles hyperthyroidism →muscle weakening (catabolic effect), fine muscle tremor (characteristic sign) hypothyroidism →muscles sluggish Effects on other endocrine glands ↑secretion of insulin and cortisol Effects on sexual function – loss of libido – impotency – abnormal menstruation

28. Working mechanism of thyroid hormones – T3 and T4 act by binding to nuclear receptors – T3 has 10 times the affinity for thyroid receptor as T4 – ↑ Transcription of large numbers of genes – ↑ Synthesis of great numbers of proteins

29. The HPT axis Wolff - Chaikoff Effect (autoregulation by Iodine) – low Iodine intake stimulates ‘iodide trap’ – high Iodine intake (>2 mg/day) inhibits ‘iodine trap’ and TH synthesis T4 is converted into T3 in pituitary and T3 acts as the final effector to turn off TSH

30. – TRH Tripeptide;↑ TSH secretion; Cold TRH release ↑ PLC-DAG-PKC 途径调节靶基因 转录，促进 TSH 合成 IP3-Ca2+ 途径促进 TSH 爆发性 释放

31. – TSH Glycoprotein ↑ T3, T4 synthesis and release ↑ thyroid cell size cAMP mediated mechanism

32. The Thyroid Gland- Diseases: Goiter