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Home , Parathyroid gland

Human Physiology Course Parathyroid

Assoc. Prof. Mária Pallayová, MD, PhD [email protected]

Department of Human Physiology, UPJŠ LF April 13, 2020 (10th week – Summer Semester 2019/2020) and Functions

Thyroid gland Parathyroids Adrenal glands Endocrine pancreas , Testes Pineal Pituitary -Pituitary Axis GIT, , brain, heart, , ... Hormones and Functions

Thyroid gland Parathyroids Thymus Adrenal glands Endocrine pancreas Ovaries, Testes Pineal Pituitary Hypothalamus-Pituitary Axis GIT, adipose tissue, brain, heart, kidney, ... Lecture Outline

Functional of the thyroid gland

Synthesis, secretion, and metabolism of the

The mechanism of thyroid action

Role of the thyroid hormones in development, growth, and metabolism

Thyroid deficiency and excess in adults

Physiology of the parathyroids Functional Anatomy of the Thyroid Gland

two lobes + isthmus (just below the cricoid cartilage) attached to the by connective tissue A normal THGL in a healthy adult weighs about 15-20 g. Functional Anatomy of the Thyroid Gland

arterial blood supply: from a superior and an inferior thyroid a., which arise from the external carotid and subclavian a., respectively.

venous blood supply: a series of thyroid drain into the ext. jugular and innominate vv. ( a rich blood supply to the thyroid gland w/ a higher rate of blood flow per gram than even that of the kidneys).

innervation: adrenergic innervation from the cervical ganglia; cholinergic innervation from the n. vagus (regulation of vasomotor function to increase the delivery of TSH, iodide, and metabolic substrates to the THGL). Functional Anatomy of the Thyroid Gland

The colloid (a thick, gel-like substance) is a solution composed primarily of thyroglobulin (10-25%  the high viscosity), a large protein that is a storage form of the thyroid hormones. A cross-sectional view through a • The thyroid gland is portion of the THGL: T3 and T4 composed, of large numbers are synthesized and secreted by of closed follicles (100 to 300 the thyroid follicle um in diameter) filled with a secretory substance (colloid) and lined with cuboidal epithelial cells that secrete into the interior of the follicles. • The major constituent of colloid is the thyroglobulin w/the thyroid hormones. • Once the secretion has entered the follicles, it must be absorbed back through the follicular into the blood before it can function in the body. Thyroid Hormones thyroxine T4 (93%) and T3 (7%)  play key roles in the regulation of body development and govern the rate at which metabolism occurs in individual cells.

Without adequate levels of thyroid hormones, the body fails to develop on time. Cellular housekeeping moves at a slower pace, eventually influencing the ability of individual cells to carry out their physiological ff. The thyroid hormones exert their regulatory functions by influencing expression, affecting the developmental program and the amount of cellular constituents needed for the normal rate of metabolism. Thyroid Hormones

Thyroxine (T4) and triiodothyronine (T3) are iodinated derivatives of the amino acid tyrosine. They are formed by the coupling of the phenyl rings of two iodinated tyrosine molecules in an ether linkage. The resulting structure is called an iodothyronine. T4 contains four iodine atoms on the 3, 5, 3’, and 5’ positions of the thyronine ring structure. T3 has only three iodine atoms, at ring positions 3, 5, and 3’. Because T4 and T3 contain the element iodine, their synthesis by the thyroid follicle depends on an adequate supply of iodine in the diet. The molecular structure of the thyroid hormones

The numbering of the iodine atoms on the iodothyronine ring structure is shown in red. Iodine Is Required for Formation of Thyroxine

To form normal quantities of thyroxine, about 50 mg of ingested iodine in the form of iodides are required each year, or about 1 mg/week.

To prevent iodine deficiency, common table salt is iodized with about 1 part sodium iodide to every 100,000 parts sodium chloride. Simple Goiter: characterized by an enlargement of the entire gland, or of one of its two lobes, caused by a deficiency of iodine in the diet. The disease is especially apt to appear in adolescence. The administration of iodine, or of the iodine-containing hormone thyroxine, effectively prevents the disease. Prevention requires taking small doses of iodine for long periods. Ingestion of iodine during pregnancy prevents development of the disease in the infant as well as in the mother. Public health measures, including the addition of iodine to water supplies and to table salt, have helped to reduce the incidence of simple goiter in certain areas.

Toxic Goiter: exophthalmic goiter/ / thyrotoxicosis/Graves' disease (for the Irish physician Robert James Graves) is caused by an excess of thyroxine secretion. The excessive secretion may result from excessive stimulation by the . Thiouracil and iodine are sometimes used in the treatment of toxic goiter, as is irradiation of the gland by radioactive iodine. Synthesis and secretion of the thyroid hormones

T4 and T3 are not directly synthesized by the thyroid follicle in their final form. Instead, they are formed by the chemical modification of tyrosine residues in the structure of thyroglobulin as it is secreted by the follicular cells into the lumen of the follicle. The high concentration of thyroglobulin in the colloid provides a large reservoir of stored thyroid hormones for later processing and secretion by the follicle. The synthesis of T4 and T3 is completed when thyroglobulin is retrieved through pinocytosis of the colloid by the follicular cells. Thyroglobulin is then hydrolyzed by lysosomal enzymes to its constituent amino acids, releasing T4 and T3 molecules from their peptide linkage. T4 and T3 are then secreted into the blood. Thyroid Hormone - Synthesis Iodide Pump—the Sodium-Iodide Symporter (Iodide Trapping)

transport of iodides from the blood into the thyroid glandular cells and follicles (1st stage in the formation of thyr. horm.) The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell. This is achieved by the action of a sodium-iodide symporter (NIS), which co-transports one iodide ion along with two sodium ions across the plasma membrane into the cell. The energy for transporting iodide against a concentration gradient comes from the Na-K ATPase pump, which pumps Na out of the cell, thereby establishing a low IC Na concentr. and a gradient for facilitated diffusion of Na into the cell. Iodide Pump—the Sodium-Iodide Symporter (Iodide Trapping)

The process of concentrating the iodide in the cell is called iodide trapping. In a normal gland, the iodide pump concentrates the iodide to about 30 times its concentration in the blood. When the thyroid gland becomes maximally active, this concentration ratio can rise to as high as 250 times. The rate of iodide trapping by the thyroid is influenced by several factors, the most important the TSH. Thyroid cellular mechanisms for iodine transport, T4 and T3 formation, and T4 and T3 release into the blood. DIT, diiodotyrosine; MIT, monoiodotyrosine; NIS, sodium-iodide symporter; RT3, reverse triiodothyronine; T3, triiodothyronine; T4, thyroxine; TG, thyroglobulin. Iodide is transported out of the thyroid cells across the apical membrane into the follicle by a chloride- iodide ion counter- transporter molecule called pendrin. The thyroid epithelial cells also secrete into the follicle thyroglobulin that contains tyrosine amino acids to which the iodide ions will bind. Thyroglobulin and Chemistry of T4 and T3 Formation

1) Formation and Secretion of Thyroglobulin by the Thyroid Cells. 2) Oxidation of the Iodide Ion. 3) Iodination of Tyrosine and Formation of the Thyroid Hormones—“Organification” of Thyroglobulin. 4) Storage of Thyroglobulin. Chemistry of T4 and T3 formation

• the successive stages of iodination of tyrosine and final formation of T4 and T3 • Tyrosine is first iodized to monoiodotyrosine and then to diiodotyrosine. • Then, during the next few minutes, hours, and even days, more and more of the iodotyrosine residues become coupled with one another. Chemistry of T4 and T3 formation

• The T4 is formed when two molecules of diiodotyrosine are joined together; the thy- roxine then remains part of the thyroglobulin molecule. • One molecule of monoiodotyrosine couples with one molecule of diiodotyrosine to form T3, which represents about one fifteenth of the final hormones. Thyroid hormone synthesis and secretion DIT, diiodotyrosine; MIT, monoiodotyrosine.

The steps involved in the synthesis of iodinated thyroglobulin involve  the synthesis of a thyroglobulin precursor,  the uptake of iodide,  the formation of iodothyronine residues. Thyroid Hormones – Transport in the Blood

Approximately 99.98% of T4 is bound to 3 serum proteins: – Thyroxine binding globulin (TBG) ~75%; – Thyroxin binding prealbumin (TBPA or transthyretin) 15-20%; – albumin ~5-10%

Only ~0.02% of the total T4 in blood is unbound or free.

Only ~0.4% of total T3 in blood is free. The protein-bound T4 and T3 molecules are protected from metabolic inactivation and excretion in the urine. Thyroid Hormones - Transport

The thyroid hormones have long half-lives in the bloodstream T4 onset and duration of action

slow onset and long duration of action no effect on the metabolic rate can be discerned for 2 to 3 days = there is a long latent period before T4 activity begins Once activity begins, it increases progressively and reaches a maximum in 10 to 12 days. Thereafter, it decreases with a half-life of about 15 days. Some of the activity persists for as long as 6 weeks to 2 months. T3 onset and duration of action

The actions of T3 occur about four times as rapidly as those of T4, with a latent period as short as 6 to 12 hours and maximal cellular activity occurring within 2 to 3 days. Most of the latency and prolonged period of action of TH are probably caused: – by their binding with proteins both in the plasma and in the tissue cells, followed by their slow release; – part of the latent period also results from the manner in which TH perform their functions in the cells themselves. Thyroid Hormones - Metabolism

Thyroid hormones are both activated and inactivated by deiodination reactions in the peripheral tissues. About 40% of the T4 secreted by the THGL is converted to T3 by enzymatic removal of the iodine atom at position 5 of the thyronine ring structure - catalyzed by a 5-deiodinase (type 1) located in the liver, kidneys, and THGL. CAVE: 5-deiodination is inhibited during fasting, trauma, most acute and chronic illnesses

T4 is the major secretory product of the THGL and is the predominant thyroid hormone in the blood. T3 is the physiologically active form of the thyroid hormones. Thyroid Hormone – Regulation of Secretion

When the concentrations of fT4 and fT3 fall in the blood, the gland is stimulated to secrete TSH, raising the concentration of TSH in the blood. This action results in increased interactions between TSH and its receptors on thyroid follicular cells. TSH Receptors and Second Messengers

The receptor for TSH is a transmembrane glycoprotein on the basal plasma membrane of the follicular cell. These receptors are coupled by Gs proteins, mainly to the adenylyl cyclase-cAMP-protein kinase A pathway. There is also evidence for effects via phospholipase C (PLC), inositol trisphosphate, and diacylglycerol.

The physiological importance of TSH-stimulated phospholipid metabolism in human follicular cells is unclear (very high concentrations of TSH are needed to activate PLC) The Mechanism of Thyroid Hormone Action

Most cells of the body are targets for the action of thyroid hormones. The sensitivity of a particular cell to thyroid hormones correlates to some degree with the number of receptors for these hormones. The cells of the CNS appear to be an exception. The thyroid hormones play an important role in CNS development during fetal and neonatal life, and developing cells in the brain are important targets for thyroid hormones. In the adult, brain cells show little responsiveness to the metabolic regulatory action of thyroid hormones, although they have numerous receptors for these hormones. The Mechanism of Thyroid Hormone Action

Thyroid hormone receptors (TR) are located in the nuclei of target cells bound to thyroid hormone response elements (TRE) in the DNA. TRs are protein molecules of about 50 kDa that are structurally similar to the nuclear receptors for steroid hormones and . Thyroid receptors bound to the TRE in the absence of T3 generally act to repress gene expression. The Mechanism of Thyroid Hormone Action

The fT3 and fT4 are taken up by target cells from the blood through a carrier-mediated process that requires ATP. Once inside the cell, T4 is deiodinated to T3, which enters the nucleus of the cell and binds to its receptor in the chromatin. The TR with bound T3 forms a complex with other nuclear receptors (a heterodimer or homodimer) to activate transcription. As a result, the production of mRNA for certain proteins is either increased or decreased, changing the cell’s capacity to make these proteins. T3 can influence differentiation by regulating the kinds of proteins produced by its target cells and can influence growth and metabolism by changing the amounts of structural and enzymatic proteins present in the cells. The Mechanism of Thyroid Hormone Action

The gene expression response to T3 is slow to appear. When T4 is administered, its course of action is usually slower than that of T3 because of the additional time required for the body to convert T4 to T3. Thyroid hormones also have effects on cells that occur much faster and do not appear to be mediated by nuclear TR receptors, including effects on signal transduction pathways that alter cellular respiration, cell morphology, vascular tone, and ion . T4 is taken up by the cell and deiodinated to T3, which then binds to the TR. The activated TR heterodimerizes with a second , 9-cis retinoic acid receptor (RXR), and binds to the thyroid hormone response element (TRE). The binding of TR/RXR to the TRE displaces repressors of transcription and recruits additional coactivators. The final result is the activation of RNA polymerase II and the transcription of the target gene. The activation of transcription by thyroid hormone Thyroid hormone activation of target cells

T4 and T3 readily diffuse through the cell membrane.

Much of the T4 is deiodinated to form T3, which interacts with the thyroid hormone receptor, bound as a heterodimer with a retinoid X receptor, of the thyroid hormone response element of the gene.

This causes either increases or decreases in transcription of that lead to formation of proteins, thus producing the thyroid hormone response of the cell. Physiological Functions of the Thyroid Hormones

A) Thyroid Hormones Increase the Transcription of Large Numbers of Genes Most of the Thyroxine Secreted by the Thyroid Is Converted to Triiodothyronine. Thyroid Hormones Activate Nuclear Receptors. Physiological Functions of the Thyroid Hormones

B) Thyroid Hormones Increase Cellular Metabolic Activity Thyroid Hormones Increase the Number and Activity of Mitochondria. Thyroid Hormones Increase Active Transport of Ions through Cell Membranes. Physiological Functions of the Thyroid Hormones

C) Effect of Thyroid Hormone on Growth General effects on growth manifest mainly in growing children. Specific effects - to promote growth and development of the brain during fetal life and for the first few years of postnatal life. Physiological Functions of the Thyroid Hormones

D) Effects of Thyroid Hormone on Specific Bodily Mechanisms Stimulation of Carbohydrate Metabolism Stimulation of Fat Metabolism Effect on Plasma and Liver Fats. Increased Requirement for Vitamins. Increased Basal Metabolic Rate. Decreased Body Weight. Physiological Functions of the Thyroid Hormones

E) Effect of Thyroid Hormones on the Cardiovascular System Increased Blood Flow and Cardiac Output. Increased Heart Rate. Increased Heart Strength. Normal Arterial Pressure (increased PP). Physiological Functions of the Thyroid Hormones

F) Other effects Increased Respiration. Increased Gastrointestinal Motility. Excitatory Effects on the Central . Effect on the Function of the Muscles. Muscle Tremor. Effect on Sleep. Effect on Other Endocrine Glands. Effect of Thyroid Hormone on Sexual Function. The Physiological Actions of Thyroid Hormones skeletal muscle, the heart, the liver, the kidneys the liver, the heart, the muscle, skeletal Thyroid Hormones - Functions Effect of Hypo- and Hypersecretion of Thyroid hormone Hypohyroidism Hyperthyroidism EXAMPLES OF THYROID DISEASES

1° Hypothyroidism Hyperthyroidism

www.hsc.missouri.edu/~daveg/thyroid/thy_dis.html EXAMPLES OF THYROID DISEASES

Juvenile Hypothyroidism Congenital Hypothyroidism

www.hsc.missouri.edu/~daveg/thyroid/thy_dis.html The Thyroid Gland – Parafollicular/C Cells ( )

Calcitonin, a polypeptide hormone produced by the THGL, tends to lower the plasma concentration, but its physiological importance in humans has been questioned. Calcitonin

In contrast to PTH, CT secretion is stimulated by an increase in plasma calcium.

Hormones of the GI tract, especially , also promote CT secretion.

Because the net effect of CT is to promote calcium deposition in bone, the stimulation of CT secretion by GI hormones provides an additional mechanism for facilitating the uptake of calcium into bone after the ingestion of a meal. Effects of calcitonin (CT) on calcium and phosphate metabolism Summary - Key Concepts

The THGL consists of two lobes attached to either side of the trachea. Within the lobes of the THGL are spherical follicles surrounded by a single layer of epithelial cells. Parafollicular cells that secrete calcitonin are also present within the walls of the follicles. The major thyroid hormones are thyroxine (T4) and triiodothyronine (T3), both of which contain iodine. Thyroid hormones are synthesized by iodination and the coupling of tyrosines in reactions catalyzed by the enzyme thyroid peroxidase. Summary - Key Concepts (cont.)

Thyroid hormones are released from the THGL by the degradation of thyroglobulin within the follicular cells. The synthesis and release of thyroid hormones is regulated by thyroid-stimulating hormone (TSH), mainly via cAMP. TSH release from the anterior pituitary is regulated by the concentration of thyroid hormones in the circulation. In peripheral tissues, T4 is deiodinated to the physiologically active hormone T3 by 5-deiodinase. Summary - Key Concepts (cont.)

In target tissues, T3 binds to the thyroid hormone receptor (TR), which then associates with a second TR or other nuclear receptor to regulate transcription. TR regulates transcription by binding to specific thyroid hormone response elements (TRE) in target genes. Thyroid hormones are important regulators of CNS development. Thyroid hormones stimulate growth by regulating release from the pituitary and by direct actions on target tissues, such as bone. Summary - Key Concepts (cont.)

Thyroid hormones regulate the basal metabolic rate and intermediary metabolism through effects on mitochondrial ATP synthesis and the expression of genes encoding metabolic enzymes. An excess of thyroid hormone (hyperthyroidism) is characterized by nervousness and increased metabolic rate, resulting in weight loss. A deficiency of thyroid hormone (hypothyroidism) is characterized by decreased metabolic rate, resulting in weight gain. Endocrine Tissues: Hormones and Functions

Thyroid hormone Parathyroids Thymus Adrenal Endocrine Pancreas Ovaries Testes Pineal Pituitary Hypothalamus-Pituitary Axis The Parathyroid Glands

Normally there are 4 parathyroid glands located immediately behind the thyroid gland - one behind each of the upper and each of the lower poles of the thyroid.

Each parathyroid gland is about 6 mm long, 3 mm wide, and 2 mm thick and has a macroscopic appearance of dark brown fat. The Parathyroid Glands

Secretion of PTH is stimulated by a decrease in plasma-ionized Ca. PTH plays a vital role in Ca and P homeostasis, and acts on bones, kidneys, and intestine to raise the plasma Ca concentration and lower the plasma P concentration. In humans, the normal plasma calcium concentration is 9.0 to 10.5 mg/dL. Plasma Ca exists in three forms: ionized or free Ca (50% of the total), protein-bound Ca (40%), and Ca bound to small diffusible anions - citrate, phosphate, and bicarbonate (10%). The association of Ca with plasma proteins is pH-dependent. At an alkaline pH, more Ca is bound; the opposite is true at an acidic pH. Distribution of ionized Ca2+, diffusible but unionized Ca complexed to anions, and nondiffusible protein-bound Ca in blood plasma. Summary of effects of PTH in response to decreased EC fluid Ca ion concentration. CaSR, calcium sensing receptor.

(1) PTH stimulates , causing release of Ca into the EC fluid; (2) PTH increases reabsorption of Ca and decreases PO4 reabsorption by the renal tubules, leading to decreased excretion of Ca and increased excretion of PO4; (3) PTH is necessary for conversion of 25(OH)- cholecalciferol to 1,25(OH)2- cholecalciferol, which, in turn, increases Ca absorption by the intestines. Parathyroid hormone

1. PTH acts directly on the kidney to increase reabsorption of calcium. 2. PTH increases resorption of bone. This increases blood calcium levels. 3. PTH promotes the final conversion of vitamin D to its active form, the , that increases uptake of calcium from the intestine. Parathyroid hormone

Ultimately calcium balance depends on absorption of calcium from the intestine. The rising blood calcium levels act as a negative feedback signal to decrease PTH secretion. Blood calcium levels control PTH levels. Parathyroid hormone (PTH) stimulates bone to release calcium (Ca+2) and the kidneys to conserve calcium. It indirectly stimulates the intestine to absorb calcium. The resulting increase in blood calcium concentration inhibits secretions of PTH Bone resorption by : PTH binds to receptors on , causing them to release osteoprotegerin ligand (OPGL), which binds to receptors on preosteoclast cells. that differentiate into mature osteoclasts. The osteoclasts then develop a ruffled border and release enzymes from lysosomes, as well as acids that promote bone resorption. Osteocytes are osteoblasts that have become encased in bone matrix during bone tissue production. Typical daily exchanges of calcium between different tissue compartments in a healthy adult

Fluxes of calcium (mg/day) are shown in color. Total calcium content in each compartment is shown in black. Note that the majority of ingested calcium is eliminated from the body via the feces. Effects of parathyroid hormone (PTH) on calcium and phosphate metabolism Regulation of blood calcium level. Top: When the blood calcium (Ca2 ) level is high, the thyroid gland secretes calcitonin. Calcitonin promotes the uptake of Ca2 by the bones, and therefore the blood Ca2 level returns to normal.

Bottom: When the blood Ca2 level is low, the parathyroid glands release parathyroid hormone (PTH). PTH causes the bones to release Ca2 . It also causes the kidneys to reabsorb Ca2 and activate vitamin D; thereafter, the intestines absorb Ca2 . Therefore, the blood Ca2 level returns to normal. Effect of changes in plasma calcium on PTH and calcitonin (CT) secretion

(Modified from Arnaud, CD, Littledike T, Tsao HS. Simultaneous measurements of calcitonin and parathyroid hormone in the pig. Effects of 1,25-dihydroxycholecalciferol [1,25-(OH)2 D3] on calcium and phosphate metabolism

Can be caused by a tumor Increases PTH secretion Bones are resorbed and soften, deform more easily. Fracture spontaneously Excess calcium and phosphate released into body fluids may be deposited in abnormal places. (kidney stones)

Can be caused by injury or surgical removal Decreased PTH Reduced activity. Bones are strong, but blood calcium concentration decreases. Abnormally excitable nervous system. Trigger spontaneous impulses. Tetanic contractions may cause respiratory failure and death. Hypocalcemic tetany in the hand, called carpopedal spasm. Physiology of the teeth to cut, grind, and mix the food eaten the enamel, dentin, cementum, pulp the crown, the root, the

20 deciduous teeth (milk teeth) - they erupt between the seventh month and the second year of life, they last until the sixth to the 13th year

32 permanent teeth Functional parts of a tooth Metabolic Factors Influence Development of the Teeth thyroid and growth hormones accelerate the rate of development and the speed of eruption of teeth the deposition of salts in the early-forming teeth (enamel, dentin, calcification) is affected by the availability of calcium and phosphate in the diet, the amount of vitamin D present, and the rate of PTH secretion

When they are deficient, the calcification of the teeth may be defective and the teeth will be abnormal throughout life. Caries caries result from the action of bacteria on the teeth, the most common of which is Streptococcus mutans. the deposit of plaque, a film of precipitated products of saliva and food, on the teeth. bacteria depend on carbohydrates - their metabolic systems are strongly activated and they multiply, they form acids (particularly lactic acid) and proteolytic enzymes the calcium salts of teeth are slowly dissolved in a highly acidic medium, the salts become absorbed, the remaining organic matrix is rapidly digested by the proteolytic enzymes. Role of Fluorine in Preventing Caries fluorine helps develop enamel more resistant to caries fluorine ions replace many of the hydroxyl ions in the hydroxyapatite crystals, which in turn makes the enamel several times less soluble fluorine may also be toxic to the bacteria fluorine promotes deposition of calcium phosphate to “heal” the enamel surface