The Thyroid Gland

1. The Thyroid Gland

2. The Thyroid Gland 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) Figure 18.11a

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. Iodide trap – active transport: 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 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. Transport of thyroid hormones 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)

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

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