Human Physiology Course Thyroid Gland Parathyroid Glands Assoc. Prof. Mária Pallayová, MD, PhD [email protected] Department of Human Physiology, UPJŠ LF April 13, 2020 (10th week – Summer Semester 2019/2020) Hormones and Functions Thyroid gland Parathyroids Thymus Adrenal glands Endocrine pancreas Ovaries, Testes Pineal Pituitary Hypothalamus-Pituitary Axis GIT, adipose tissue, brain, heart, kidney, ... 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 anatomy of the thyroid gland Synthesis, secretion, and metabolism of the thyroid hormones The mechanism of thyroid action Role of the thyroid hormones in development, growth, and metabolism Thyroid hormone 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 trachea 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 veins 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 epithelium into the blood before it can function in the body. Thyroid Hormones thyroxine T4 (93%) and triiodothyronine 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 gene 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/hyperthyroidism / 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 pituitary gland. 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 peptide 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.