Thyroid Hormones, The Thyroid Gland PDF

Thyroid Hormones, The Thyroid Gland Dr Solomon Genet MUHAS  Objectives Importance of iodine in thyroid metabolism Mechanisms of iodination of tyrosine and their regulation Physiological control of thyroid growth and hormone secretion Physiological roles of t...

Thyroid Hormones, The Thyroid Gland Dr Solomon Genet MUHAS  Objectives Importance of iodine in thyroid metabolism Mechanisms of iodination of tyrosine and their regulation Physiological control of thyroid growth and hormone secretion Physiological roles of thyroxine (T4) and tri- iodothyronine (T3), their transport and metabolism Topics covered in this lecture Structure and synthesis of thyroid hormones Anatomy of the thyroid gland Ultra structure of the thyroid Mechanism of thyroid hormone production Regulation of hormone secretion Plasma transport of thyroid hormones Metabolism of thyroid hormones by deiodinase enzymes Thyroid hormone action Disorders of the thyroid gland  Thyroid hormones The thyroid produces two unique hormones: tri-iodothyronine (T3) and thyroxine (T4) T3 and T4 are the only iodine containing hormones in vertebrates The only source of iodide is dietary (vegetables, fish, salt). Optimal daily Iodine intake (taken up by the thyroid gland and used for hormone synthesis): Adults: 150 μg Iodide is scarce and Pregnancy, lactation: 200μg insufficient supply is a 0-1yr: 50μg major health problem in many parts of the world 1-6yr: 90μg 7-12 μg Iodine deficiency goitre Deficiency of iodine in diet causes increased secretion of TSH because of lack of T4 feedback Iodine deficiency is common in desert and mountain regions Salt iodinization is simple and inexpensive Structure of thyroid hormones Iodothyronines made from tyrosines in thyroglobulin T4 T3 (active) rT3 (inactive) Regulation of thyroid hormone secretion stimuli e.g.cold Hypothalamus hyperglycaemia TRH Inhibitory Anterior feedback pituitary TSH Thyroid T3 and T4 metabolism  Iodine deficiency goitre Hypothalamus TRH Inhibitory Anterior feedback pituitary TSH Thyroid Iodine T3 and T4 deficiency  Mechanism of Action of TSH on Thyroid follicles TSH TSHR Gs Gq Adenylate cyclase Phospholipase C ATP cAMP PIP2 DAG activates PKA PIP2 activates / protein PKC activation Stimulation of Ca 2+ thyroid hormone synthesis and release Endocrine glands *  Anatomy of the thyroid The thyroid gland consists of two lobes lying on either side of the ventral aspect of the trachea Each lobe is about 4 cm in length and 2 cm thickness connected together by a thin band of connective tissue called the isthmus. Weighing approximately 20 g profuse blood supply and venous drainage: superior thyroid arteries (arising from the external carotids) inferior thyroid arteries (arising from the subclavian arteries) Anatomy of the thyroid Ultrastructure of the thyroid The functional unit of the thyroid gland is the follicle  Cell arrangements in the thyroid epithelial cells form follicles the lumen is filled with ‘colloid’ - hormone precursor colloid follicular cells capillaries  Follicular cell activity small large follicles are follicles are active storing columnar cuboidal epithelia epithelia  Features of Thyroid Follicles Contain Colloid, which is a store of thyroglobulin A sodium/iodide symporter on the basal membrane of follicular cells traps and pumps in iodide from the plasma A thyroperoxidase enzyme TPO on the apical plasmalemma -oxidises the iodide to iodine -iodinates tyrosyl residues in the thyroglobulin, -couples tyrosyl residues to produce the thyroid hormones T3 (tri-iodothyronine) and T4 (thyroxine) still bound in the thyroglobulin and hence inactive.  Thyroid hormone production Iodine Trapping  Synthesis of Thyroid Hormone Uptake of iodide (I-) by the follicular cells involves an energy-requiring (ATPase-dependent) transport mechanism “Iodine trapping” Iodide is oxidized to active iodine by hydrogen peroxide. catalyzed by the heme-containing enzyme thyroid peroxidase (TPO) Iodine is then actively transported across the apical surface of the follicular cell, where it is immediately incorporated into the tyrosine residues of the large glycoprotein thyroglobulin molecules, catalyzed by TPO  Synthesis of Thyroid Hormone Thyroglobulin is taken up into the colloid of the follicle where, coupling reaction between pairs of iodinated tyrosine molecules occurs, catalyzed by TPO I I di-iodotyrosine mon-iodotyrosine MIT DIT I MIT + DIT = T3 DIT + DIT = T4 Thyroid hormones are stored in this state in colloid. Upon stimulated by TSH, thyroglobulin droplets are captured by the follicular cells by micropinocytosis Fusion of the droplets with lysosomes results in proteolyis of the thyroglobulin molecules and secretion of T4 and T3.  Thyroid hormone production I2 I2 I- Iodinated thyroglobulin TPO T3 & T4 10 minute break  Plasma transport of T4 and T3 Only >0.5% of released thyroid hormones exist in a free form Thyronine-binding globulin (TBG) single binding site for T4 and T3 carries 70% of the circulating thyroid hormones Transthyretin or Thyroxine binding pre-albumin (TBPA) carries 10% of the circulating T4 affinity for T3 is 10x lower than for T4 rapid dissociation from hormones Albumin single strong binding site for T4 and T3 and a few weak ones carries 15% of the circulating thyroid hormones rapid dissociation from hormones  Peripheral metabolism of T4 100mg/day steroid 10% hormone secreted from the gland 90% 80% Iodothyronines are unusual in that the main thyroid product, T4, is not the metabolically active hormone, T3 T4 is converted to metabolically active T3 by Type 1 deiodinase in liver and kidney Peripheral conversion creates 80% circulating T3  Peripheral metabolism produces T3 from T4 Iodothyronines are unusual in that the main thyroid product (T4) is not the active hormone (T3) Metabolism of T4 to T3 occurs primarily in the liver and kidney T4 is converted to T3 by Type I deiodinase  Types of deiodinase Type 1 - provides T3 to plasma Location- liver, kidney Type 2 - provides intracellular T3 in central nervous system Location - brain, pituitary Type 3 - inactivates T3 and T4 Location - glial cells in central nervous system, placenta  Breakdown Iodothyronines are finally deiodinated to thyronine Iodide is salvaged by the kidney and reused  Thyroid Hormone action Two genes which code for T3-receptors: chromosome 17 coding for the α receptor chromosome 3 coding for the β receptor 4 major T3 receptors formed by alternative mRNA splicing  Thyroid Hormone action Binding of T3 to its receptor (TR) causes formation of homo- or heterodimers Homodimer Heterodimer, RXR, retinoic acid receptor DNA binding domain to hormone response elements (HRE) on the DNA helix. Along with other transcription factors (co- activators/repressors) to regulate gene expression. Thyroid Receptor action TR in the nucleus bind DNA and activate transcription Timescale - hours  Effects of T3 on basal metabolic rate Act on nearly every tissue Increases the basal metabolic rate and increases O2 use and heat production Increasing the number and size of mitochondria, stimulating the synthesis of enzymes in the respiratory chain Increases production of Na+/K+ ATPase (which uses 20-45% of all ATP) 2 K+ ATP 3 Na+ outside inside  Effects of T3 on metabolism Protein metabolism: stimulates protein breakdown Carbohydrate metabolism: potentiates glycogenolysis, gluconeogenesis Lipid metabolism: stimulates cholesterol breakdown and enhances lipolysis T3 - T3 T3 Effects of T3 in the cardiovascular system Increases cardiac output, rate and force Acts by increasing production of myosin, 1 receptors, Ca2+ ATPase these proteins increase contractility 'bounding pulse' in hyperthyroidism, weak pulse in hypothyroidism Effects of T3 on the Gastrointestinal tract and muscle Gastrointestinal tract: stimulates gut motility Increases skeletal muscle activity  Developmental effects of T3 Stimulates surfactant production lungs Essential for postnatal growth of CNS stimulates the production of myelin, neurotransmitters, axonal growth Stimulates linear growth of bone  Control of Thyroid function 1) The classical hypothalamic- pituitary-thyroid axis 2) Deiodinases 3) Autoregulation of hormone synthesis by the thyroid itself 4) Stimulation or inhibition of thyroid function by TSH receptor autoantibodies Disorders of the thyroid hormones  Hyperthyroidism Most common cause is Graves’ disease Due to autoimmune production of antibody to the TSH receptor which acts like a superactive TSH Hyperthyroidism – ‘thyrotoxicosis’ restless, anxiety exophthalmos - eyes protrude goitre tachycardia and rapid pulse lose weight diarrhoea intolerance of heat hot hands hand tremor Hyperthyroidism due to hormone secreting tumours Tumour tissue comprises functional follicles ‘Follicular thyroid cancer’ Solution: Thyroxine suppression therapy Thyroxine suppression therapy to reduce recurrence of thyroid cancer Hypothalamus TRH Inhibitory Anterior feedback pituitary T3 TSH thyroxine Thyroid treatment T3 and T4  Hypothyroidism Cretinism in young, myxoedema in adult failure of production by thyroid failure or pituitary or hypothalamus to produce TSH or TRH Hashimoto’s disease- autoimmune destruction of thyroid Goitre - lymphocytic infiltration thyroid hormone resistance – inactivating mutation of thyroid hormone receptor  Hypothyroidism apathy, tiredness goitre heart slowing and slow pulse muscle weakness weight gain constipation intolerance of cold cold hands  Drugs affecting the thyroid Thyroxine is given for hypothyroidism Thiocarbamides: reduce thyroid hormone synthesis by inhibiting TPO carbimazole, propylthiouacil Iodine: in large doses reduces the activity of the gland in hyperthyroidism Radioactive iodine :can be given to destroy thyroid tissue by local irradiation  Summary The thyroid hormones tri-iodothyronine (T3) and thyroxine (T4) are iodine containing hormones sntheised from Tyrosine Thyroid hormones are produced by follicular cells lining thyroid follicles (functional unit of the thyroid). The hormones are stored bound to thyroglobulin in colloid in the lumen of the follicles Stimulation by anterior pituitary TSH cause the stimulation of thyroid hormone synthesis and release Iodothyronines transported bound to the plasma proteins and T4 is peripherally metabolised to T3 by deiodinases Thyroid hormones mediate their actions by binding to nuclear thyroid hormone receptors which bind to HRE to activate gene transcription  Next time… Peptide hormones, as expemplified by insulin and glucagon  Suggested reading Basic and clinical endocrinology, Greespan and Gardner, 6th edition, Ch 7 Endocrinology, an integrated approach, Nussey and Whitehead, Ch 3 available online: http://www.ncbi.nlm.nih.gov/books/bv.fcg i?rid=endocrin.chapter.235