THYROID HORMONE:• Gross and Microscopic Anatomy of the Thyroid Gland.• Production of Thyroid Hormones.• Transport of T3 and T4• Actions of Thyroid Hormones.• Regulation of Thyroid Hormones.• Hyper- and Hypothyroidism PREPARED BY: Dr.Abdul Wahab Aslam
HIsTOlOgY Of THE THYROID glaND• The thyroid gland contains numerous follicles, composed of epithelial follicle cells and colloid. Also, between follicles are Para-follicular cells, which produce Calcitonin.
THE THYROID glaND – HIsTOlOgY: Squamous epithelial cells, cuboidal cells (follicle cells). Gland is composed of hollow spheres, called colloid follicles. Colloid fills the follicle cavities. Follicle cells produce thyroglobulin. I
THE THYROID glaND:
THYROID HORMONEs: There are two biologically active thyroid hormones: - Tetraiodothyronine(T4; usually called thyroxine) - Triiodothyronine (T3) Derived from modification of tyrosine(amino acid).
DIffERENcEs bETwEEN T4 aND T3:• The thyroid secretes about 80mg of T4, but only 5mg of T3 per day.• However, T3 has a much greater biological activity about 10 folds than T4.• An additional 25mg/day of T3 is produced by peripheral monodeiodination of T4 by enzyme called 5’ Monodeiodenase. thyroid T4 T3 I-
MajOR sOuRcEs Of IODINE:• Thyroid hormones are unique biological molecules in that they incorporate iodine in their structure.• Thus, adequate iodine intake either through diet or water is required for normal thyroid hormone production.• Major sources of iodine are: - iodized salt - iodated bread - dairy products - shellfish• Minimum requirement(RDA): 75 micrograms/day• US intake: 200 - 500 micrograms/day
IODINE METabOlIsM• Dietary iodine is absorbed in the GI tract, then taken up by the thyroid gland (or removed from the body by the kidneys).• About 80% of the iodine is lost in urine where as only 20 % is taken up by the Thyroid follicular cells.• The transport of iodide into follicular cells is dependent upon a Na+/I- co-transport system.• Iodide taken up by the thyroid gland is oxidized by peroxide in the lumen of the follicle: Peroxidase I - I+• Oxidized iodine can then be used in production of thyroidhormones.
THE NExT sTEp: pRODucTION Of THYROglObulIN: Pituitary produces TSH, which binds to follicle cell receptors. The follicle cells of the thyroid produce thyroglobulin. Thyroglobulin is a very large glycoprotein. Thyroglobulin is released into the colloid space, where it’s tyrosine residues are iodinated by I+. This results in formation of monoiodotyrosine or diiodotyrosine.
THYROID fOllIclEs wITH acTIvITIEs:
ThyROId hORmONE SyNThESIS
TRANSpORT Of ThyROId hORmONES • Thyroid hormones are lipid-soluble. • Thus, they are found in the circulation associated with binding proteins: - Thyroid Hormone-Binding Globulin(TBG) (~70% of hormone) - Pre-albumin(Transthyretin) (~15%) - Albumin (~15%) • Less than 1% of thyroid hormone is found free in the circulation. • Only free and albumin-bound thyroid hormone is biologically available to tissues. • Among the amount of thyroid hormone production and release T4 is approximately 95% and T3 is 5%. But biological active is T3 so T4 is converted to T3 in peripheral tissues by the enzyme 5’monodeiodinase and become active.
CONvERSION Of T4 TO T3 T3 has much greater biological activity than T4. A large amount of T4 (25%) is converted to T3 in peripheral tissues. This conversion takes place mainly in the liver and kidneys. The T3 formed is then released to the blood stream. In addition to T3, an equal amount of “Reverse T3” may also be formed. This has no biological activity. T3 MIT + DIT Reverse T3 DIT + MIT
REGULATION Of ThyROId hORmONE LEvELS: • Thyroid hormone synthesis and secretion is regulated by two main mechanisms: - An “auto regulation” mechanism, which reflects the available levels of iodine. - Regulation by the hypothalamus and anterior pituitary.
AUTO REGULATION Of ThyROId hORmONEpROdUCTION • The rate of iodine uptake and incorporation into thyroglobulin is influenced by the amount of iodide available: - Low iodide levels increase iodine transport into follicular cells - High iodide levels decrease iodine transport into follicular cells Thus, there is negative feedback regulation of iodide transport by iodide.
NEUROENdOCRINE REGULATION Of ThyROIdhORmONES: ROLE Of TSh• Thyroid-stimulating hormone (TSH) is produced by thyrotroph cells of the anterior pituitary.• TSH is a glycoprotein hormone composed of two subunits: - alpha subunit (common to LH, FSH, TSH, hCG) - TSH beta subunit, which gives specificity of receptor binding and biological activity.
ACTION Of TSh ON ThE ThyROId TSH acts on follicular cells of the thyroid. - increases iodide transport into follicular cells - increases production and iodination of thyroglobulin - increases endocytosis of colloid from lumen into follicular cells Na+ K+ I- Na+ gene ATPfollicle colloid droplet thyroglobulin I-cell endocytosis thyroglobulin thyroglobulin iodination I+ I- T3 T4
mEChANISm Of ACTION Of TSh• TSH binds to G protein-coupled receptor on thyroid follicular cells.• Specifically, it activates a Gs-coupled receptor which leads to activation of Adenyl cyclase resulting in increased c-AMP production and PKA (Protein Kinase-A) activation. Adenylyl TSH Cyclase Gsa ATP cyclic AMP Follicle cell Protein kinase A
REGULATION Of TSh RELEASE fROmThE ANTERIOR pITUITARy• TSH release is influenced by hypothalamic TRH, and by thyroid hormones themselves.• Thyroid hormones exert negative feedback on TSH release at the level of the anterior pituitary. - inhibition of TSH synthesis - decrease in pituitary receptors for TRH hypothalamus + TRH TRH receptor - - pituitary TSH synthesis T3/T4
INfLUENCE Of TRh ON TSh RELEASE• Thyrotropin-releasing hormone (TRH) is a hypothalamic releasing factor which travels through the pituitary portal system to act on anterior pituitary Thyrotroph cells.• TRH acts through G protein-coupled receptors, activating the IP3 (Ca2+) and DAG (PKC) pathways to cause increased production and release of TSH. IP3 calcium G protein-coupled receptor TRH phospholipase C calmodulin DAG PKC• Thyroid hormones also inhibit TRH synthesis.
NEGATIvE fEEdbACk ACTIONS Of ThyROIdhORmONES ON TSh SyNThESIS ANd RELEASE TRH synthesis hypothalamus + TRH - TRH receptor - T3/T4 pituitary - TSH synthesis TSH binds Thyroid gland follicle cell receptors
Other FactOrs regulating thyrOid hOrmOnelevels• Diet: a high carbohydrate diet increases T3 levels, resulting in increased metabolic rate (diet-induced thermogenesis).• Low carbohydrate diets decrease T3 levels, resulting in decreased metabolic rate.• Cold Stress: increases T3 levels in other animals, but not in humans.• Any condition that increases body energy requirements (e.g., pregnancy, prolonged cold) stimulates hypothalamus TRH TSH.
actiOns OF thyrOid hOrmOnes: Thyroid hormones are essential for normal growth of tissues, including the nervous system. Lack of thyroid hormone during development results in short stature and mental deficits (cretinism). Thyroid hormone stimulates or increase Basal Metabolic Rate(BMR).
• Required for GH and prolactin production and secretion• Required for GH action• Increases intestinal glucose reabsorption (glucose transporter)• Increases mitochondrial oxidative phosphorylation (ATP production)• Increases activity of adrenal medulla (sympathetic; glucose production)• Induces enzyme synthesis• Result: stimulation of growth of tissues and increased metabolic rate. Increased heat production (calorigenic effect)
eFFects OF thyrOid hOrmOne On nutrientsOurces:• Effects on protein synthesis and degradation: -increased protein synthesis at low thyroid hormone levels (low metabolic rate; growth) -increased protein degradation at high thyroid hormone levels (high metabolic rate; energy)• Effects on carbohydrates: -low doses of thyroid hormone increase glycogen synthesis (low metabolic rate; storage of energy) - high doses increase glycogen breakdown (high metabolic rate; glucose production)
One majOr target gene OF t3: the na+/K+atPase PumP: Pumps sodium and potassium across cell membranes to maintain resting membrane potential Activity of the Na+/K+ pump uses up energy, in the form of ATP About 1/3rd of all ATP in the body is used by the Na+/K+ ATPase T3 increases the synthesis of Na+/K+ pumps, markedly increasing ATP consumption(BMR increases). T3 also acts on mitochondria to increase ATP synthesis(size and number of mitochondria will increase). The resulting increased metabolic rate increases thermo genesis (heat production).
thyrOid hOrmOne actiOns which increaseOxygen cOnsumPtiOn • Increase mitochondrial size, number and key enzymes. • Increase plasma membrane Na-K ATPase activity. • Increase futile(ineffective) thermogenic energy cycles. • Decrease superoxide dismutase activity.
eFFects OF thyrOid hOrmOnes On thecardiOvascular system• Increase heart rate• Increase force of cardiac contractions• Increase stroke volume• Increase Cardiac output• Up-regulate catecholamine receptors
eFFects OF thyrOid hOrmOnes On theresPiratOry system• Increase resting respiratory rate• Increase minute ventilation• Increase ventilatory response to hypercapnia and hypoxia
eFFects OF thyrOid hOrmOnes On the renalsystem• Increase blood flow• Increase glomerular filtration rate(GFR)
eFFects OF thyrOid hOrmOnes On Oxygen-carrying caPacity • Increase RBC mass • Increase oxygen dissociation from hemoglobin
EffEcts of thyroid hormonEs on intErmEdiarymEtabolism • Increase glucose absorption from the GI tract • Increase carbohydrate, lipid and protein turnover • Down-regulate insulin receptors • Increase substrate availability
EffEcts thyroid hormonEs in Growth andtissuE dEvElopmEnt Increase growth and maturation of bone. Increase tooth development and eruption. Increase growth and maturation of epidermis, hair follicles and nails. Increase rate and force of skeletal muscle contraction. Inhibits synthesis and increases degradation of mucopolysaccharides in subcutaneous tissue.
EffEcts of thyroid hormonEs on thE nErvoussystEm • Critical for normal CNS neuronal development • Enhances wakefulness and alertness • Enhances memory and learning capacity • Required for normal emotional tone • Increase speed and amplitude of peripheral nerve reflexes
EffEcts of thyroid hormonEs on thErEproductivE systEm • Required for normal follicular development and ovulation in the female • Required for the normal maintenance of pregnancy • Required for normal spermatogenesis in the male
thyroid hormonE dEficiEncy: hypothyroidism Early onset: Delayed/incomplete physical and mental development. Later onset(Youth): Impaired physical growth Adult onset(Myxedema) : Gradual changes occur. Tiredness, lethargy, decreased metabolic rate, slowing of mental function and motor activity, cold intolerance, weight gain, goiter, hair loss, dry skin. Eventually may result in coma. Causes: (a) Insufficient iodine. (b) Lack of thyroid gland. (c) Lack of hormone receptors. (d) Lack of TH binding globulin.
how is hypothyroidism rElatEd to GoitEr? • During iodine deficiency, thyroid hormone production decreases. • This results in increased TSH release (less negative feedback). • TSH acts on thyroid, increasing blood flow, and stimulating follicular cells and increasing colloid production.
midwEst – thE GoitEr bElt • If goiter is due to decreased I, then thyroid gland enlarges – called endemic or colloidal goiter. • Pituitary gland TSH stimulate thyroid gland to produce TH, but the only result is that the follicles accumulate more and more unusable colloid. • Cells eventually die from over activity and the gland atrophies.