Hypothyroidism Hyperthyroidism

cretinism goiter

What induces the above disease? Imbalance of thyroxine

Production, Regulation, and Action of Thyroid Hormones Early Studies on the Thyroid Gland Gross and Microscopic Anatomy of the Thyroid Gland Production of Thyroid Hormones Transport and Activities of T3 and T4 Regulation of Thyroid Hormone Production & Secretion Actions of Thyroid Hormones Hyper- and Hypothyroidism

Histology of the Thyroid Gland The thyroid gland contains numerous follicles, composed of epithelial follicle cells and colloid. Also, between follicles are clear parafollicular cells, which produce calcitonin (see coming lecture on calcium balance).

Thyroid Gland: Hormones and Iodine Metabolism The thyroid gland

Thyroid Hormones There are two biologically active thyroid hormones: - tetraiodothyronine (T4; usually called thyroxine) - triiodothyronine (T3) Derived from modification of an amino acid (tyrosine)

THYROID HORMONES Tyrosine Thyroxine (T4) 3,5,3’-Triiodothyronine (T3) OH I NH2 Thyroxine (T4) 3,5,3’-Triiodothyronine (T3) Tyrosine

Differences between T4 and T3 The thyroid secretes about 80 micrograms of T4, but only 5 micrograms of T3 per day. However, T3 has a much greater biological activity (about 10X) than T4. An additional 25 micrograms/day of T3 is produced by peripheral monodeiodination of T4. T4 thyroid I- T3

Why is Iodine Important in Thyroid Hormone Production? Thyroid hormones are unique biological molecules in that they incorporate iodine in their structure. Thus, adequate iodine intake (diet, water) is required for normal thyroid hormone production. Major sources of iodine: - iodized salt - iodated bread - dairy products Minimum requirement: 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). The transport of iodide into follicular cells is dependent upon a sodium/iodine cotransport 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 thyroid hormones.

The Next Step: Production of T3 or T4

The first Step: Production of thyroglobulin 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 monoiodotyrosine (MIT) or diiodotyrosine (DIT).

Initial Steps in Thyroid Hormone Synthesis follicle cell extracellular space colloid space I- thyroglobulin with monoiodotyrosines and diiodotyrosines iodination thyroglobulin gene I+ oxidation Na+ K+

Second step: Production of Thyroid Hormones from Iodinated Thyroglobulin The iodinated tyrosine residues on thyroglobulin are modified and joined to form T3 and T4, still attached to the thyroglobulin molecule.

Utilization of Thyroglobulin to Secrete Thyroid Hormones In order to secrete T3/T4, the thyroglobulin in the colloid space is internalized by endocytosis back into the follicle cell. This internalized vesicle joins with a lysosome, whose enzymes cause cleavage of T3 and T4 from thyroglobulin. Some T4 is converted to T3 at this point. T3 and T4 are then released into the extracellular space by diffusion. Only minute amounts of thyroglobulin are released into the circulation.

Utilization of Thyroglobulin to Secrete Thyroid Hormones follicle cell colloid space endocytosis thyroglobulin T3 T4 colloid droplet lysosome T3/T4 (deiodinated, recycled) extracellular space (T4 T3)

Transport of Thyroid Hormones Thyroid hormones are not very soluble in water (but are lipid soluble). Thus, they are found in the circulation associated with binding proteins: - Thyroid Hormone-Binding Globulin (~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.

Transthyretin (prealbumin, amyloidosis type I) Transthyretin (TTR) is a serum and CSF carrier of the thyroxine (T4) and retinol. This is how transthyretin gained its name, transports thyroxine and retinol. TTR was originally called prealbumin because it ran faster than albumins on electrophoresis gels. In CSF it is the primary carrier of T4, as albumin is not present. TTR also acts as a carrier of retinol (vitamin A) through an association with retinol-binding protein (RBP). Transthyretin (prealbumin, amyloidosis type I)

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.

THYROID HORMONE METABOLISM OH NH2 I T4 I OH O R T3 “Step up” I OH O R rT3 “Step down” I OH O R 3,3’-T2

THYROID HORMONE DEIODINASES Three deiodinases (D1, D2 & D3) catalyze the generation and/disposal of bioactive thyroid hormone. D1 & D2 “bioactivate” thyroid hormone by removing a single “outer-ring” iodine atom. D3 “inactivates” thyroid hormone by removing a single “inner-ring”iodine atom. All family members contain the novel amino acid selenocysteine (Se-Cys) in their catalytic center.

BASIC ORGANIZATION OF THE SELENODEIODINASES NH2 extracellular domain A C B E D intracellular domain COOH Se-Cys EXISTS AS A DIMER

Thyroid hormones are made from tyrosine and iodine Thyroxine and its precursors: Structure & Synthesis Thyroid hormones are made from tyrosine and iodine

Thyroid hormone synthesis Thyroxine and its precursors: Structure & Synthesis Thyroid hormone synthesis

One Major Advantage of this System The thyroid gland is capable of storing many weeks worth of thyroid hormone (coupled to thyroglobulin). If no iodine is available for this period, thyroid hormone secretion will be maintained.

Regulation of Thyroid Hormone Levels Thyroid hormone synthesis and secretion is regulated by two main mechanisms: - an “autoregulation” mechanism, which reflects the available levels of iodine - regulation by the hypothalamus and anterior pituitary

Autoregulation of Thyroid Hormone Production 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 Thus, there is negative feedback regulation of iodide transport by iodide.

Neuroendocrine Regulation of Thyroid Hormones: 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) - TSH beta subunit, which gives specificity of receptor binding and biological activity a LHb FSHb TSHb  LH FSH TSH

the hypothalamic-pituitary-thyroid axis Feedback regulation the hypothalamic-pituitary-thyroid axis Hormones derived from the pituitary that regulate the synthesis and/or secretion of other hormones are known as trophic hormones. Key players for the thyroid include: TRH - Thyrotropin Releasing Hormone TSH - Thyroid Stimulating Hormone T4/T3 - Thyroid hormones

T3 & T4 Control Pathways & Diseases from Malfunction

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+ I- thyroglobulin follicle cell gene endocytosis T3 T4 colloid droplet I+ iodination K+ ATP 1 3 2

Mechanism of Action of TSH TSH binds to a plasma membrane-bound, G protein-coupled receptor on thyroid follicle cells. Specifically, it activates a Gs-coupled receptor, resulting in increased cyclic AMP production and PKA activation. TSH Gsa Adenylyl Cyclase ATP cyclic AMP Protein kinase A Follicle cell

Regulation of TSH Release from the 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 TSH synthesis pituitary T3/T4 + -

Regulation of TSH Release from the Anterior Pituitary 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 (calcium) and DAG (PKC) pathways to cause increased production and release of TSH. TRH phospholipase C G protein-coupled receptor IP3 calcium DAG PKC calmodulin Thyroid hormones also inhibit TRH synthesis.

- Negative Feedback Actions of Thyroid Hormones on TSH Synthesis & Release hypothalamus TRH TRH receptor TSH synthesis pituitary T3/T4 + - TRH synthesis

PITUITARY-THYROTROPE CELL

TSH regulation of thyroid function TSH binds to specific cell surface receptors that stimulate adenylate cyclase to produce cAMP. TSH increases metabolic activity that is required to synthesize Thyroglobulin (Tg) and generate peroxide. TSH stimulates both I- uptake and iodination of tyrosine resides on Tg.

Ion transport by the thyroid follicular cell organification Propylthiouracil (PTU) blocks iodination of thyroglobulin COLLOID BLOOD NaI symporter (NIS) Thyroid peroxidase (TPO) PTU, a thioamide drug used to treat hyperthyroidism

THYROGLOBULIN SYNTHESIS IN THE THYROID FOLLICULAR CELL Iodination of Tyr residues of Tg COLLOID TSH TSH receptor TPO

THYROID HORMONE SECRETION BY THE THYROID FOLLICULAR CELL COLLOID DIT MIT I- TSH TSH receptor

Other Factors Regulating Thyroid Hormone Levels 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.

Actions of Thyroid Hormones Required for GH and prolactin production & 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.

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 basal metabolic rate. What are the specific actions of thyroid hormone on body systems?

Cardiovascular system: Thyroid hormones increases heart rate, cardiac contractility and cardiac output. They also promote vasodilation, which leads to enhanced blood flow to many organs. Central nervous system: Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state. Too little thyroid hormone, and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness. Reproductive system: Normal reproductive behavior and physiology is dependent on having essentially normal levels of thyroid hormone. Hypothyroidism in particular is commonly associated with infertility.

Specific actions of thyroid hormone: development TH is critical for normal development of the skeletal system and musculature. TH is also essential for normal brain development and regulates synaptogenesis, neuronal integration, myelination and cell migration. Cretinism is a condition of severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormones (congenital hypothyroidism) due to maternal nutritional deficiency of iodine.

Effects of Thyroid Hormone on Nutrient Sources 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) Effects on Lipids: Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. They also enhance oxidation of fatty acids in many tissues. Finally, plasma concentrations of cholesterol and triglycerides are inversely correlated with TH levels.

Mechanism of Action of T3 T3/T4 acts through the thyroid hormone receptor - intracellular, in steroid receptor superfamily - acts as a transcription factor - receptor binds to TRE on 5’ flanking region of genes as homodimers and/or heterodimers. - multiple forms (alphas and betas) exist - one form (alpha-2) is an antagonist at the TRE

More on Receptor Coactivators and Corepressors When not bound to hormone, the thyroid hormone receptor binds to target DNA (TRE on 5’ flanking region). It is associated with corepressor proteins that cause DNA to be tightly wound and inhibit transcription. Binding of hormone causes a conformational change, resulting in loss of corepressor binding and association with coactivator proteins, which loosen DNA structure and stimulate transcription.

Expression and Regulation of Thyroid Hormone Receptors Thyroid hormone receptors are found in many tissues of the body. Thyroid hormone inhibits thyroid hormone receptor expression (TRE on THR genes).

One Major Target Gene of T3: The Sodium/Potassium 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. T3 also acts on mitochondria to increase ATP synthesis The resulting increased metabolic rate increases thermogenesis (heat production).

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. Many causes (insufficient iodine, lack of thyroid gland, lack of hormone receptors, lack of TBG….)

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.

Thyroid Hormone Excess: Hyperthyroidism Emotional symptoms (nervousness, irritability), fatigue, heat intolerance, elevated metabolic rate, weight loss, tachycardia, goiter, muscle wasting, apparent bulging of eyes, may develop congestive heart failure. Also due to many causes (excessive TSH release, autoimmune disorders,…)

Graves' disease:A condition usually caused by excessive production of thyroid hormone and characterized by an enlarged thyroid gland, protrusion of the eyeballs, a rapid heartbeat, and nervous excitability. Also called exophthalmic goiter.

a thioamide drug used to treat hyperthyroidism Regulates of Basal Metabolic Rate (BMR). Increases oxygen consumption in most target tissues. Permissive actions: TH increases sensitivity of target tissues to catecholamines, thereby elevating lipolysis, glycogenolysis, and gluconeogenesis.

EXAMPLES OF THYROID DISEASES Hypothyroidism Hyperthyroidism

cretinism goiter