Thyroid Hormones 1, 2, & 3 Mohammed Y. Kalimi, Ph.D.

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1 Thyroid Hormones 1, 2, & 3 Mohammed Y. Kalimi, Ph.D. Thyroid hormones are iodinated derivatives of tyrosine (Fig.1). Figure 1 I. Iodide (or iodine) turnover (fig 2): Because thyroid hormones are iodinated molecules, their production is closely related to iodide turnover. The following diagram represents the daily exchange of iodide and peptide-bound iodine in a euthyroid individual on a 500 :g iodide uptake. In this country daily iodide uptake (mainly as sodium and potassium iodide) may easily range from :g/day. Minimum daily requirement in the adult is about 150 :g. Over this range, a healthy individual can compensate by modulating renal iodide excretion so that other intercompartmental fluxes, and thus thyroid hormone output remain constant. Beyond this range, however, disease can result from too little, or too much, dietary iodide.

2 Figure 2: Iodine Metabolism Daily iodide balance under equilibrium conditions: 500 :g dietary intake (input) daily = 480 :g excretion daily in urine and 20 :g excretion daily in stool (output). A. Biosynthesis of thyroid hormones: There are four main step in the biosynthesis of thyroid hormones: 1. Iodine accumulation (Iodide Pump or trap ): The anion iodide (I - ) is actively transported into the gland against chemical and electrical gradients by a Na + -I - cotransport (symport) system located in the basal membrane of the thyroid epithelial cells. The Na + -I - symporter is stimulated by Na + /K + -ATPase.

3 CNS - (thiocyanate) and HClO 4 - (perchlorate) ions inhibit I - transport. a. Daily iodide requirement: 150 :g I -. b. T/S (thyroid: serum) ratio: Euthyroid (normal thyroid) T/S 20:1 TSH stimulation T/S 100:1 Hypophysectomized (no TSH) T/S 1:1 II. Conversion of I - (Iodide) to I 2 (Iodine): 2I - Thyroid peroxidase enzyme I 2 Hydrogen peroxide Drugs propylthiouracil (PTU) and methimazole are inhibitors of this reaction. III. Organification: Iodination of tyrosyl residues of thyroglobulin form two types of inactive iodotyrosines, monoiodotyrosine ( MIT) and diiodotyrosine (DIT). IV. Coupling reactions: Formation of active iodothyronines, T3 & T4: T3 is formed by the coupling of one MIT and one DIT. T4 is formed by the coupling of two DIT s. The unique tertiary structure of thyroglobulin exposes tyrosine residues for iodination and favors coupling reactions. Both organification and coupling reactions are catalyzed by thyroid peroxidase enzyme and require hydrogen peroxide. A. Organic binding and coupling reactions occur while tyrosine is an integral part of the thyroglobulin molecule. 1. Thyroglobulin (TG): a. Glycoprotein of follicular colloids. b. Dimer of MW 650,000 daltons and hence too large to be transported across acinar cell wall. 2. All of these steps (I-IV), and TG synthesis are stimulated by TSH. B. Hydrolysis of thyroglobulin (Fig 3):

4 TG containing the iodotyrosines (MIT and DIT) and iodotyronines (T3 and T4) is stored in the lumen of the follicle as colloids. T3 and T4 release from the thyroid gland by the degradation of TG within the follicular cells. Droplets of colloid are taken back into the follicular cells by pinocytosis and coalesce with lysosomes. Lysosomal enzymes release the iodinated constituent from peptide bonds by proteolysis. Figure Proteolysis (stimulated by TSH). 2. Liberation of active hormones, T3 and T4 3. Liberation of inactive I- compounds MIT and DIT 4. MIT and DIT deiodinase I - reuptake by the thyroid gland (congenital defects in deiodinase result in goitrous hypothyroidism). In response to large quantifies of iodide (2 mg or more) there is a sharp decrease in T3 and T4 biosynthesis due to expression of Na + - I - symporter and enzyme peroxidase genes. C. Secretion of thyroid hormones (T3 and T4): Plasma level of total T4 : 5-10 :g/100 ml. T4 bound to the plasma proteins = 99.97% T4 free = 0.03% Plasma level of total T3 : ng/100 ml.

5 T3 bound to plasma proteins = 99.7 % T3 free = 0.3% 1. Ten times (of the total) T3 in the blood is free compared to T4. 2. Plasma half-lives of T4 and T3 are about 7 days and 1 day respectively. 3. T3 is two to three times more biologically potent than T4. In the blood T3 and T4 are largely bound to proteins. The known binding proteins are: 1. Thyroxine binding globulin (TBG, MW 50,000-80,000 daltons). TBG binds about 70% of total T4 and about 50% of total T3. 2. Thyroxine binding prealbumin (TBPA or transthyretin): TBPA binds 20% of total T4. TBPA does not bind T3. 3. Albumin: Binds 10% of T4 and 50% T3. D. Degradation of thyroid hormones: Most important catabolic reaction is deiodination (catalyzed by deiodinase, a microsomal enzyme). Important catabolic organs are the liver and kidney. Much of the iodide removed by the liver or kidney is recycled through the thyroid. 1. About 35% of the circulating T4 is deiodinated peripherally to T3. (T4 5' Deiodinase T3). 2. About 45% is deiodinated to reverse T3 (Fig 4.) (T4 5-Deiodinase reverse T3). 3. The remainder is metabolized either by conjugation or oxidative deamination. The physiological importance of rt3 is not known at the present time. Figure 4. Acute and chronic illness, caloric deprivation and certain drugs such as corticosteroids and propranolol (a beta blocker) increase peripheral conversion of T4 to rt3.

6 1. There is a decrease in T3 production with fasting with reciprocal increase in rt3. 2. The decrease of T3 production with fasting may be an important adaptive response contributed to the observed lack of substrate and decreased metabolic rate. 3. During fasting, total T4, and free T4 concentrations remain normal. E. THYROID PHYSIOLOGY: General Aspects: 1. Acts on most tissues. 2. Action-slow in onset and long in duration: a. Large dose of T4: BMR seen after 2-3 days and reaches a maximum in days. b. Large dose of T3: BMR seen after 6-12 hours, maximum cellular activity in approximately 2-3 days. c. TH (T3 and T4) is not necessary for life but improves the quality of life. Specific Actions: 1. Normal Growth and Development: TH Promotes normal bone and skeletal development. TH deficiency - bone remains infantile, premature epiphyseal closure, stunting of growth. GH secretion is deficient in the absence of TH. Mental development: congenital TH deficiency responsible for cretinism (mental retardation, dwarf stature). Deficiency during the first year of neonatal life produces irreversible brain damage 2. Metabolic (regulation of the overall rate of body metabolism): TH influences BMR and intermediary metabolism through mitochondrial ATP synthesis and the expression of genes encoding various metabolic enzymes. a. Calorigenic action: BMR, 0 2 consumption. Activation of the membrane sodium-potassium pump ( Na + - K + -ATPase activity). b. Thermogenic action: Rapid generation of heat.

7 Acute response to cold by BMR, heat production, catecholamines, cardiac adjustments, lipolysis, muscular activity. TH exerts a permissive effect on catecholamine action. Chronic cold: cold adaptation causes an increased conversion of T4 to T3. c. Carbohydrate, protein and lipid metabolism: Increased carbohydrate metabolism, gluconeogenesis, glycolysis, absorption of carbohydrates from the GI tract. Muscle: Increased rate of protein synthesis, increased rate of protein degradation (overall negative nitrogen balance). Adipose tissue: Increased lipolysis, increased fatty acid synthesis, increased free fatty acid oxidation, decreased total and LDL cholesterol. Overall increased demand for vitamins. 3. Neural: Promotes normal neuronal development. 4. Cardiovascular effects: TH, in the rate and strength of the heartbeat, ventilation and cardiac output. Thyroid hormone induces the synthesis of cardiac beta adrenergic receptors. F. Mechanism of Thyroid Hormone Action (Fig. 5): T4 converts to T3 by the enzyme 5 deiodinase in peripheral tissues (T4 5 deiodinase T3). T3 enters the nucleus and binds with high affinity to the nuclear receptor. The thyroid hormone receptor dimer (homodimer) or thyroid hormone receptor + 9 cis retinoic acid (RXR) receptor complex (heterodimer) along with coactivator bind to the thyroid response element (TRE) and stimulates transcription of specific m-rnas with induction of a multitude of specific proteins such as growth hormone, malic enzyme, β adrenergic receptor, TBG, Na+,K+-ATPase, cytochrome oxidase etc. resulting in various physiological responses as described above.

8 Figure 5. G. Control of Thyroid Hormone (TH) Secretion (Fig. 6): The secretion of TSH is regulated by TH, in such a way that high TH suppresses TSH, but low TH allows TSH to be secreted. Since TSH causes TH to be secreted, but TH inhibits TSH secretion, we have a Negative Feedback regulation. Figure 6.

9 1. Hypothalamus: Thyrotrophic Releasing Hormone (TRH): Tripeptide -Pyroglutamine - Histidine - Proline amide. TRH is the first hypothalamic releasing factor isolated, structurally defined and synthesized. TRH is synthesized in the hypothalamus and secreted into hypophyseal portal circulation and carried to the anterior pituitary. TRH stimulates TSH secretion by thyrotrophs of the anterior pituitary. Thyroid hormones may reduce the effectiveness of TRH by inducing a loss of receptors for TRH on the membranes of the thyrotrophs ( T3, T4, TRH receptors, TSH). It is also surprising that TRH is found outside the hypothalamus, and sometimes outside the central nervous system. This suggests that TRH may act also as a neurotransmitter. 2. Anterior Pituitary: Thyroid stimulating hormone (TSH): TSH is a glycoprotein of MW 28,000 daltons composed of two noncovalently linked subunits α and ß. α - subunit - identical with LH, FSH, hcg ß - subunit - specific (immunologically and biologically) to TSH. Both α and β subunits are required for receptor binding and hormone action. Plasma T ½ life of TSH = 1 hour. Plasma level of TSH = :U/ml (normal values). TSH stimulates growth and metabolism of the thyroid gland including biosynthesis of T3, T4 and TG. TSH secretion declines during sleep and fasting and increases upon exposure to cold. TRH ( TRH, TSH) and somatostatin ( somatostatin, TSH) are important factors in the control of TSH secretion.

10 leptin, TSH, T3,T4. The mechanism of action of TSH is through the activation of adenylyl cyclase. TSH-membrane receptor complex, adenylyl cyclase, camp, phosphokinases and the biological responses. Prolonged (and excessive) TSH stimulation of thyroid gland results in a goiter (enlargement of the thyroid gland). Prolonged normal TSH stimulation by TSH occurs constantly and does not cause a goiter. Consequences of disrupting normal thyroid hormone regulation: Thyroid hormones are regulated by a closed-loop negative feedback system ( T3, T4, TSH and T3, T4 TSH) which serves to keep TH output at, or close to, a steady level determined by the sensitivity of the pituitary to the negative feedback of TH. The system is analogous to a thermostat, and has in fact been called a thyrostat, which maintains a constant, or near-constant, temperature. This closed-loop can be opened in many ways; for example Removal of thyroid: T3 and T4, TSH Hypothyroid Goiter: 1. Administration of sodium thiocyanate (CNS - ) or potassium perchlorate (HClO 4 - ). T/S ratio 1:1 (preventing iodide access to thyroid gland by blocking the iodide pump). No TH is formed ( TH, TSH) and a goiter results. 2. Administration of propylthiouracil (inhibits conversion of Iodide to Iodine). No TH is formed ( TH, TSH), and goiter results with the notable exception that T/S ratio becomes very high (100:1 or 200:1). 3. I - deficiency - Little I - is trapped (due to iodide deficiency) so little TH is made and a goiter results ( TH, TSH).

11 Euthyroid goiter: This situation, which can develop in people who live in the so-called "goiter belts", regions remote from the ocean, where the soil and vegetation are poor in iodine, is transient. In the case of a low-iodide diet, the deficit is never as absolute as that produced by an enzymatic block. The gland gets some iodide and makes some TH (overall, TH, TSH). Hyperthyroid goiter: A hyperthyroid goiter is produced by autoimmune stimulation (production of Thyroid-Stimulating Immunoglobulins). Thyroid-Stimulating Immunoglobulins (TSI) is a antibody against the TSH receptor which binds to TSH receptor and mimic TSH actions on thyroid gland TH synthesis. ( TSI, T3 and T4, TSH) SUMMARY OF CONTROL ELEMENTS: 1. Euthyroid Goiter - Iodine deficiency, TSH to compensate for TH. 2. Hyperthyroid Goiter - Over secretion of TSI which mimics TSH, TSI, TH, 3. Hypothyroid Goiter - Administration of drugs such as propylthiouracil, SCN -, perchlorate, TH and TSH. H. Laboratory evaluation of thyroid functions: 1. Measurement of circulating thyroid hormones (T3 and T4) by radioimmunoassay (RIA). 2. RIA for human TSH (h TSH) Normal values = micro units/ ml of blood Elevation in serum TSH is the most sensitive measure for primary hypothyroidism. TSH above 5.0 (hypothyroidism), administration of Thyroxine (T4). Below 0.5 (hyperthyroidism), radiation treatment plus T4. 3. Other measurements influenced by thyroid function: a. BMR: Increased in hyperthyroidism and decreased in hypothyroidism. b. Cholesterol and LDL: Decreased in hyper and increased in hypothyroidism.

12 I. Thyroid abnormalities: 1. In deficiency states: Hypothyroidism. 2. In clinical states of over activity: Hyperthyroidism or Thyrotoxicosis. a. Disease characterized by hypothyroidism: i. Thyroid failure (surgical, immune or radio iodide destruction of the thyroid gland): Primary disease. ii. Pituitary or hypothalamus failure (TRH or TSH deficiency): Secondary disease iii. Absence or defective thyroid hormone receptors, mutations in thyroid receptor gene mostly single amino acid substitution in the ligand binding domain of the receptor. This mutation reduces the affinity of TH for receptors, reducing their function. iv. Myxedema: Mucoproteinous (mucopolysaccharide and hyaluronic acid) skin deposit. Bagginess under the eyes, swelling of the face, iodine deficiency. v. Cretinism: Extreme hypothyroidism during infancy or childhood. Failure of growth, especially bone and brain, idiotic look, protruding tongue, pot belly and mental retardation b. Symptoms of Hypothyroidism: i. Decreased BMR, decreased pulse rate, decreased vitality ii. Increased LDL and cholesterol iii. Growth failure, weight gain, constipation, cold intolerance, dry scaly thickened skin iv. Mucopolysaccharide deposition, hoarse voice, lethargic, sluggishness, dull, puffy eyelids, enlargement of tongue v. Depression and insomnia c. Disease characterized by hyperthyroidism: Graves' Disease (thyrotoxicosis): Emotional trigger such as loss or potential loss of person results in thyrotoxicosis in some individual. T3,T4, TSI, TSH (TSI is an immunoglobulin of MW 150,000 daltons). d. Symptoms of Hyperthyroidism: a. Increased BMR, catecholamine activity, rapid heart rate, cardiac output, cardiac beta receptors. congestive heart failure

13 b. Increased sweating, vasodilation, body heat (feeling too hot), moist skin. c. Increased gastrointestinal malfunction, diarrhea, weight loss, (despite an increase in appetite). d. Bone: negative calcium balance, osteoporosis, fractures. e. Eye discomfort, marked protrusion of eyes (exophthalmos). f. Neuromuscular fatigue, sweating, hyperactive reflexes, negative nitrogen balance g. Psychotic behavior, hyperkinetic behavior (shaking of the hands), muscular weakness (myopathy), irritability and anxiety Pregnancy: estrogen, TBG, total plasma T3 and T4.

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