Endocrine Physiology (2) The Thyroid Gland 甲状腺. Huawei Liang, PhD

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1 Endocrine Physiology (2) The Thyroid Gland 甲状腺 Huawei Liang, PhD

2 Anatomy of 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

3 Thyroid Gland Follicle

4 The Thyroid Hormones Types 90% of metabolically active hormones secreted by thyroid is thyroxine (T 4 ), 10% is triiodothyronine (T 3 ), and less than 1% is rt3

5 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

6 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

7 Biosynthesis of Thyroid Hormones Materials Iodine 碘 (in the form of iodide I - ) 1mg/week, 50mg/year for thyroid hormone synthesis Iodized table salt (1 sodium iodide/100,000 NaCl) Tyrosine 酪氨酸 Thyroglobulin (TG) 甲状腺球蛋白

8 Process of synthesis Iodine/iodide trapping Sodium-Iodide smportor 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 T3, T4 by coupling Peroxidase MIT + DIT T 3 DIT + DIT T 4

9 Storage In the follicles In the form of TG Available 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

11 Transport Binding form: 99% Most T 4 and T 3 bound to plasma proteins: Thyroxine-binding globulin (TBG): mainly Thyroxine-binding prealbumin (TBPA) albumin Slowly released to the tissue cells, slower for T 4 due to its higher affinity Free form: 1% (T 3 )

12 Physiological Functions of TH Effects of TH on Growth 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

13 Cretinism 呆小病 : deficiency of thyroid hormone during the period of fetal and early neonatal development short, stocky stature & mental retardation

14 Metabolic Effects of TH Increase cellular metabolic activity Calorigenic action 生热效应 number & activity of mitochondria ATP Na +, K + -ATPase and active transport of ions (Na, K) heat production O 2 consumption & BMR

Carbohydrate metabolism glucose oxidation gluconeogenesis and glycogenolysis Too much blood glucose (Diabetes) Fat metabolism lipolysis (Triglyceride FFA +

15 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) hyperthyroidism Protein metabolism Protein synthesis (normal) Protein catabolism (hyperthyroidism)

16 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 甲亢 : hyperexcitability, insomnia, loss of concentration Hypothyroidism: mental retardation, sleepiness

17 Effects of TH on Cardiovascular System Increase heart rate (easy to detect!) increase adrenergic activity increase enzymatic activity Affect heart strength slightly increase of TH increases heart strength marked increase of TH decreases heart strength Increase blood flow and cardiac output

18 Effects of Thyroid Hormones on GI Increase appetite and food intake Increase secretion of digestive juices Increase mobility of GI Diarrhea ( 腹泻 ) often results from hyperthyroidism

19 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

20 Mechanisms of TH action T 3 and T 4 act by binding to nuclear receptors 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

21 Regulation of thyroid hormone secretion Hypothalmico-pituitary-thyroid axis TRH TSH T 3 /T 4 Negative feed-back of T 3 /T 4 Autoregulation by I

22 TRH Tripeptide TSH secretion Cold: TRH release

23 TSH Glycoprotein T 3, T 4 synthesis and release Size of the thyroid cells camp mediated mechanism

24 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

25 Autoregulation by I low I intake stimulates synthesis of iodide trap high I intake (>2 mg/day) inhibits trap function and synthesis (Wolff-Charkoff effect 碘阻断效应 )

26 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

27 Hyperthyroidism The most common cause B lymphocytes synthesize a immune globulin, thyroid stimulating immunoglobulin (TSI), that bind to and active the TSH receptor, producing all the actions of TSH on thyroid (Graves disease)

28 Common Symptoms Associated with Hyperthyroidism Nervousness Heat intolerance Palpitation ( heart rate, >100 per minute) Muscle weakness Diarrhea Increased BMR Increased appetite Weight loss( protein) Goiter (enlarged thyroid ) Tremor Fatigue Moist skin ( metabolism) Exophthalmos (eye signs; extra-thyroidal)

Hypothyroidism Causes Primary (autoimmune disease, partial thyroidectomy) Secondary (pituitary gland) or tertiary (hypothalamus) Common cause an autoimmune

29 Hypothyroidism Causes Primary (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

30 Common Symptoms Associated with Hypothyroidism Decreased BMR Mental slowness Cold intolerance ( metabolism) Dry cold skin ( protein) Weight gain ( metabolism) Acroparesthesia 肢体感觉异常 (numbness/tingling of hands) Thick tongue Myxedema 粘液性水肿 (due to glycosaminoglycan accumulation in the interstitial space) Goiter Slow speech Amenorrhea 闭经 Constipation 便秘 ( GI motility) Low sex drive Arteriosclerosis prolongation of tendon reflex cardiac output (remember permissive effect of TH to epinephrine/norepinephrine)

31 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

32 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

33 The Adrenal Glands 肾上腺

34 Adrenal cortex: 80% to 90% Adrenal medulla: 10% to 20%

35 The Adrenal Cortex 肾上腺皮质 Three distinct layers Zona glomerulosa 球状带 : 15% Aldosterone Zona fasciculata 束状带 : 75% Cortisol, corticosterone Zona reticularis 网状带 Androgens, estrogens and glucocorticoids

36 The Adrenocortical hormones Corticosteroids 皮质类固醇 Glucocorticoids 糖皮质激素 Cortisol 皮质醇 Mineralocorticoids 盐皮质激素 Aldosterone 醛固酮 Sex hormones 性激素 Androgens, estrogens

37 Synthesis

38 Transport of Adrenocorticosteroids 75% of cortisol bound to corticosteroidbinding globulins (CBG, transcortin) 15% of cortisol bound to Albumin 10% free

39 Glucocorticoids Activity Cortisol (hydrocortisone): very potent, 95% of all glucocorticoid activity Corticosterone(~4% of total glucocorticoid activity) Others Cortisone (synthetic, as potent as cortisol) Dexamethasone (synthetic, 30 times as potent as cortisol) Important to the long-continued life of the animals

40 Functions of Glucocorticoids Effects on carbohydrate metabolism Stimulation of gluconeogenesis 糖异生 (from amino acids) Glycogenolytic effects of glucagon & adrenaline Glucose uptake & utlilization Blood glucose concentration Adrenal diabetes (Excessive hyperglycaemia 高血糖 )

41 Effects on protein metabolism protein breakdown (e.g. from muscle) for gluconeogenesis Catabolic effect: bone and cutaneous tissue ( 皮肤 ) (Excessive muscle wasting, weakening of blood vessel wall)

42 Effects on fat metabolism Lipolysis and fatty acid mobilisation (from adipose tissue) Oxidation of fatty acids

43 Obesity caused by excess cortisol Excess deposition of fat in the trunk and head Buffalo-like torso 水牛背 Rounded moon face 满月脸

44 Cortisol is also important in resisting stress 应激 Stress stimulates ACTH increase in ant. pituitary gland and therefore cortisol secretion Types of stress include the following Trauma Infection Intense coldness and heat Surgical operation

45 Effects on blood cells RBC, neutrophils ( 中性粒细胞 ), monocytes ( 单核细胞 ) and platelets Lymphocytes, eosinophils ( 嗜酸性粒细胞 ), and basophils ( 嗜碱性粒细胞 ),

46 Effects on Vascular System Permissive action through inhibition of enzyme that destroys norepinephrine at sympathetic nerve endings optimize vascular responses to catecholamines Cortisol is necessary to maintain blood pressure Inhibits COMT -- if cortisol not present, the metabolism of CATS would be so rapid, not enough for vasoconstriction Also helps maintain blood volume by decreasing the permeability of the vascular endothelium

47 Effect on bone formation-inhibition Synthesis of type I collagen (the fundamental component of bone matrix) is reduced by cortisol Cortisol decreases absorption of calcium from the gut (antagonizes the action and synthesis of vitamin D3 metabolites) Ca excretion is also elevated because cortisol increases glomerular filtration rate in the kidney Cortisol increases the rate of bone resorption (excess cortisol osteoporosis 骨质疏松 )

48 Effects on nervous system Excitability of CNS Alters mood and behavior Insomnia, strikingly depress or elevate moods Effects on digestive system Digestive secretions

49 Anti-inflammatory effects Depress the immune response (stabilizing lysosomes) Glucocorticoids are widely used in therapy: to reduce the inflammatory destruction of rheumatoid arthritis ( 风湿性关节炎 ) and other autoimmune diseases to prevent the rejection of transplanted organs to control asthma 哮喘

50 Mechanism of action Binds to cytosolic receptor Cortisol-receptor complex migrates to nucleus and transferred to nuclear binding site and interacts with DNA Increase in RNA synthesis

51 Regulation of cortisol secretion Hypothalamus-pituitary- adrenal axis Stress CRH ACTH cortsiol

52 ACTH(corticotropin, adrenocorticotropin) Cortisol secretion Hypertrophy ( 肥大 ) and proliferation ( 增殖 ) of the adrenocortical cells Secretion: with MSH Diurnal rhythm high in the morning low in late afternoon and night

53 Negative feed-back long -loop by free cortisol short-loop by ACTH on CRH secretion

54 Stress Stress overrides negative feed-back i.e. cortisol secretion is stimulated even though cortisol level is high, but magnitude is diminished Virtually any type of physical or mental stress results in elevation of cortisol concentrations in blood due to enhanced secretion of CRH in the hypothalamus

The most important of them is the steroid aldosterone.

55 Mineralocorticoids The mineralocorticoids get their name from their effect on mineral metabolism. The most important of them is the steroid aldosterone. Accounts for about 90% of all mineralocorticoid activity About 60% are bound to plasma proteins Half life is about 20 min

56 Functions of aldosterone Renal reabsorption of sodium in the principal cells of the collecting tubules and also in the distal tubules and collecting ducts Excretion of potassium and hydrogen ions in the distal tubules and collecting ducts Control of blood volume Excess hypokalemia 低血钾, alkalosis, hypertension Deficient hyperkalemia 高血钾, acidosis, hypotension

57 Regulation of aldosterone secretion 1. Increased K 2. Increased activity of Renin-angiotensin system. 3. Increased sodium through renin. 4. ACTH

58 Abnormalities of adrenocortical secretion Hypoadrenalism 肾上腺功能减退 Clinical features excessive urinary loss of Na and Cl ions diuresis (dehydration ) 多尿 hypoglycaemia muscle weakness skin pigmentation 色素沉着 (due to ACTH) hypotension inability to withstand stress

Hyperadrenalism 肾上腺功能亢退 Cushing s syndrome moon face plethora (reddish face & neck) trunk obesity purple abdominal striate (loss of collagen in subcutaneous tissue and increases tearing) poor wound

60 Hyperadrenalism 肾上腺功能亢退 Cushing s syndrome moon face plethora (reddish face & neck) trunk obesity purple abdominal striate (loss of collagen in subcutaneous tissue and increases tearing) poor wound healing hypertension (mineral effects of cortisol) hyperglycaemia osteoporosis,loss of protein in bone) muscular weakness mental abnormalities hirsutism 多毛症 (due to adrenal androgens) skin pigmentation (due to ACTH)

61 The Adrenal Medulla Sympathoadrenal system

62 Epinephrine (E): 80% Norepinephrine (NE): 20% Adrenomedullin 肾上腺髓质素

63 Synthesis of Catecholamines (DA, NE, E)

64 Physiologic Actions of E and NE Cardiovascular effects Metabolic effects Glucose production BMR Emergency reaction ( 应急反应 ) Stress response

65 Adrenergic Receptors and Mechanism of Action Receptor Effectively Binds Effect of Ligand Binding Alpha 1 Adrenaline, Noradrenaline Increased free calcium Alpha 2 Adrenaline, Noradrenaline Decreased cyclic AMP Beta 1 Adrenaline, Noradrenaline Increased cyclic AMP Beta 2 Adrenaline Increased cyclic AMP

67 Regulation Sympathetic nervous system ACTH and glucocorticoids Feedback end-product inhibition

68 Summary Glucocorticoids Functions Effects on carbohydrate, protein and fat metabolism Resisting stress Effects on blood cells, vascular system, bone formation Effects on nervous system, digestive system Anti-inflammatory effects Regulation of cortisol secretion Hypothalamus-pituitary- adrenal axis

69 Summary Mineralocorticoids Functions Regulation of aldosterone secretion Disorders of the adrenal Hypercortisolism (Cushing s syndrome) Primary hypoadrenalism (Addison s disease) The Adrenal Medulla Physiologic Actions of E and NE Regulation sympathoadrenal system

70 Summary Terms Thyroid Hormones Glucocorticoid Stress List the main physiological actions of thyroid hormones Describe the mechanisms that regulate secretion of glucocorticoids

71 General question What are the endocrinologic causes of dwarfism and cretinism, and how does each lead to short stature? What are the advantages and disadvantages of longterm, high dose treatment with glucocorticoids in diseases such as rheumatoid arthritis and asthma? What problems occur when steroid treatment is stopped suddenly?

Thyroid Gland 甲状腺. Huiping Wang ( 王会平 ), PhD Department of Physiology Rm C541, Block C, Research Building, School of Medicine Tel:

Thyroid Gland 甲状腺. Huiping Wang ( 王会平 ), PhD Department of Physiology Rm C541, Block C, Research Building, School of Medicine Tel: Thyroid Gland 甲状腺 Huiping Wang ( 王会平 ), PhD Department of Physiology Rm C541, Block C, Research Building, School of Medicine Tel: 88208292 Outline Thyroid Hormones Types Biosynthesis Storage and Release