Thyroid Hormones

1. Thyroid Hormones Eric Lazartigues, Ph.D. Department of Pharmacology elazar@lsuhsc.edu (504) 568-3210

2. H H H H H H H H C C C C C C C C COOH COOH COOH COOH H H H H NH2 NH2 NH2 NH2 I I HO O I I I I HO O I T3 (active) I I HO O I I H H HO C C COOH I HO + 2 H NH2 MIT Tyrosine I H H HO C C COOH H NH2 I DIT 90 % Thyroxine (T4) deiodinase Reverse T3 (inactive) Bound to plasma proteins: TBG

3. Biosynthesis of Thyroid Hormones: Steps 1 and 2 1 2 Step 1: Iodide uptake: Na/I Pump (symporter)- ATP dependent. Inhibited by ClO4- and SCN- Activated by TSH (↓stores iodine→↑ uptake) Step 2: Oxidation of iodide and iodination of thyroglobulin Thyroid peroxidase (TPO) (apical surface) Fomation of MIT and DIT Storage in the lumen of thyroid follicle Inhibited by PTU and MMI Follicular cell Blood

4. Biosynthesis of Thyroid Hormones: Steps 3 and 4 Step 3: Coupling of iodotyrosine residues to generate iodothyronines. Thyroid peroxidase. Formation T4 (DIT+DIT) and T3 (MIT+DIT) Activity: [TSH] and iodide availability Inhibition: PTU, MMI 1 2 3 4 Step 4: resorption of the TRG colloid into cell Endocytosis of TRG via receptor: megalin Inhibition: Colchicine, Li2+, I-, cytochalasine B Follicular cell Blood

5. Biosynthesis of Thyroid Hormones: Steps 5 to 7 Step 5: Proteolysis of TRG. Colloid droplets fuse with lysosomes Enhanced by TSH Endopeptidases: TRG→intermediates Exopeptidates: intermediates→MIT+DIT 90% T4 and 10% T3 1 2 3 4 5 6 7 Step 6: Recycling of Iodine I- →TRG Step 7: conversion T4→T3 5’deiodinase Blood

6. Trapping of I Iodination Endocytosis of colloid Thyroglobulin degradation TSH TSH a b AC g b G s (+) cAMP Protein Kinase A Increased Increased Increased Increased DNA Cell size Glucose oxidation RNA Cell number NADPH generation Protein Follicle formation Growth Hormone Synthesis Figure 4 : Effects of TSH on thyroid gland

7. Caloric Thermal Signals Hypothalamus T4 T3 TRH TRH release  synthesis Somatostatin Dopamine T4 T3 T3 TSH Long Loop TSH Tissue T4,T3 Thyroid T4 T 4 Figure 5. Axis for Thyroid Control

8. Hormone Pairs and Thyroid Disorders Primary Secondary Hyperthyroidism High hypothyroidism Pituitary tumor Hashimoto’s Pituitary Hormone Normal Primary Hyperthyroidism Pituitary Failure Autonomous Secretion of Target Gland Hormone Low Secondary Hypothyroidism Grave’s disease Low Normal High Target Hormone

9. Conditions and Factors That Inhibit Type I 5'-Deiodinase Activity Acute and chronic illness Caloric deprivation (especially carbohydrate) and Malnutrition Glucocorticoids Adrenergic receptor antagonists (e.g., propranolol in high doses) Oral cholecystographic agents (e.g., iopanoic acid, sodium ipodate) Propylthiouracil

10. T T Cytoplasm 3 4 Tissue deiodinase T 3 TR Nucleus mRNA Intracellular Effects Proteins for growth and maturation + + Mitochondria Other enzymes, proteins Na , K - ATPase Respiratory enzymes  ATP use O Consumption Metabolic rate 2 O 2 Substrates CO Thermogenesis 2 Cardiac Output Food Intake Urea Sweating Ventilation Mobilization of Ventilation Insensible water loss stored fat, Renal Function carbohydrates and Proteins Muscle Mass Whole Body Effects Adipose Tissue (permissive)

11. Effects of Thyroid Hormone Nervous System: 1. T3 is absolutely required for perinatal brain development. i). Growth of cerebral and cerebellar cortex. ii). Axon proliferation iii). Synaptogenesis. 2. In Adults, enhances: i). Wakefulness and responsiveness ii). Emotional tone iii). memory Sympathetic Nervous System. 1. Synergizes with sympathetic nervous system. i). Promotes increases in b-adrenergic receptor and Gs proteins. ii). Important for metabolic and cardiac effects of thyroid hormone.

12. Primary Hyperthyroidism: T4 and T3,  TSH 1. Autoimmune thyroiditis: Grave’s disease - Autoantibodies bind and activate TSH receptors - Other: Tumor of thyroid gland. 2. Symptoms: - Large increases in BMR • Leads to weight loss despite increased food intake. -  Heat production: heat intolerance and excessive sweating. -  SNS activity • Tachycardia, tremor, nervousness, wide-eyed stare - Enlarged thyroid gland – Goiter - Exophthalmos: Protrusion of eyeballs.

14. 1 Rx For Hyperthyroidism - 1 Block Active Transport of iodide Complex anions: monovalent, hydrated ions similar in size to Iodide. Thiocyanate: found in certain foods and in cigarette smoke (in large doses, thiocyanate can also inhibit organification) Problems- The Jim Jones effect Perchlorate (ClO4-) – 10x more active as thiocyanate. Low doses (750 mg per day) have been used in the treatment of Grave’s disease. Excessive doses (2-3 g per day ) causes increased incidence of fatal aplastic anemia. I- I- I- Na cap

15. Io I- Io TPX DIT DIT DIT DIT MIT T3 T3 T3 T4 MIT T4 T4 MIT MIT DIT MIT 4 3 Rx For Hyperthyroidism - 2 Treatments Iodination of Thyroglobulin and Coupling Reaction (thyroperoxidase) Thionamides or thioureylenes : propylthiouracil, methamizole, carbimazole Methimazole Other: Side effects headaches drowsiness or dizziness. immunosupression Drug-drug interactions: especially: warfarin, digoxin, beta-blockers

16. DIT DIT DIT DIT T3 T3 MIT T3 T4 MIT T4 T4 MIT MIT MIT DIT 4 3 Rx For Hyperthyroidism - 3 Treatments Io I- Iodide: High doses cause paradoxical decrease inthyroxin biosynthesis, at the organification step Striking and rapid (changes in basal metabolic rate within hours) Radioactive Iodide (131I), (IODOTOPE THERAPEUTIC) - 80 to 150 µCi/gram (lower doses may limit rebound hypothyroidism). This leads to partial destruction of the gland. - Used when prolonged treatment with anti-thyroid drugs or surgery has not led to remission. More commonly used in older patients- Major disadvantage is long period of time required before hyperthyroidism is controlled. Drugs that block Type I deiodinases: propylthiouracil Drugs that block both Type 1 and Type II deiodinases: sodium ipodate, iopanoic acid . In addition, metabolism of these drugs lead to the release of 75-150 mgs of iodide, which can further inhibit T4/T3 secretion. These drugs are commonly used as radiology contrast dyes. Io TPX

17. THYROID STORM 1. Thyroid storm is a crisis or life-threatening condition characterized by an exaggeration of the usual physiologic response seen in hyperthyroidism * High fever * Tachycardia * Nausea/vomiting * Irregular heart beat * Acute heart failure * Confusion/disorientation 2. Usually precipitated by concurrent medical problems (infections, stress, surgery, trauma, heart disease, diabetic ketoacidosis) 3. Treatment: - antipyretics, - large dose (200-400 mg) propylthiouracil because of additional action of blocking peripheral T4 conversion - -blockers (propranalol) to counteract effects on SNS and heart

18. á â T4 and T3 TSH Primary Hypothyroidism 1. Autoimmune disease of thyroid: Hashimoto’s disease • Blocks hormone synthesis and glandular growth 2. Other Causes: i). Genetic defect in or autoantibodies vs. enzymes necessary for thyroid hormone synthesis or the conversion of T4 to T3. Severe iodide deficiency Lithium 3. Symptoms: - Myxedema: Accumulation of mucopolysaccharides with resultant fluid accumulation . - Decreased thermogenesis: cold intolerance - Lethargy, sleepiness, decreased mentation - Bradycardia. - Lowering of upper eyelid (ptosis) - In utero or infancy and childhood: Marked retardation in growth. · Severe mental retardation due to poorly developed · nervous system. Known as "cretins". ·

19. Iodide replacement in small quantities (100-300 µg/day) if iodide deficiency is suspected. Hormone Replacement with T4 or T3 All can be given orally Synthetic Thyroxins: Levothyroxine sodium (SYNTHROID,) Synthetic T3: Lyothyronine sodium (L-T3) • - 80% absorption in the small intestine that is partially blocked by Ca2+ and iron supplements • Efficacy is monitored by serum TSH levels • Adverse Effects: Rare and most often associated with excessive doses • Looks like hyperthyroidism: heat intolerance, irritability,insomnia, nausea/vomiting, nervousness or anxiety, tremor, and weight loss. • In patients with underlying cardiac problems: angina, atrial fibrillation, heart failure, palpitations, peripheral edema.

20. CONTRAINDICATIONS: Patients with heart disease, diabetes, adrenal insufficiency and treatment for obesity DRUG INTERACTIONS Estrogen:  Thyroxine-binding globulin (TBg) thereby  free T4/T3 Barbiturates:  hepatic metabolism of both Levothyroxine (SYNTHROID) and Lyothyronine T4/T3 Enhances the response to: anticoagulant therapy, Tricyclic antidepressants (receptor responsiveness), vasopresors and symapthomimetics ( receptor expression)  Metabolism of Corticosteroids