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Hormones of the thyroid and parathyroid gland Romana Šlamberová, M.D. Ph.D. Department of Normal, Pathological and Clinical Physiology Thyroid and Parathyroid glands Thyroid gland Produces hormones: Thyroxine (T4) Triiodothyronine (T3) Calcitonin other thyroid hormones, such as rT3, T2, and T1. - build T4 and T3, but it is possible that thay have function of their own Controlled by The hypothalamus [Thyreotropinreleasing hormone - TRH] and pituitary [Thyroid-stimulating hormone - TSH] Level of calcium Histology Follicles - The thyroid is composed of spherical follicles that selectively absorb iodide ions (I-) from the blood for production of thyroid hormones. 25% I- in the thyroid gland Inside the follicles = colloid (reservoir of materials for thyroid hormone production) Colloid is rich in a protein called thyroglobulin. Follicular cells - single layer of thyroid epithelial cells (secretes T3 and T4). Inactive gland = cuboidal cells Active gland = columnar cells Parafolicular cells (C-cells) Location - scattered among follicular cells and in spaces between the spherical follicles secrete calcitonin Synthesis and secretion Once the iodide is in the cell, it must be transformed into thyroid hormones and stored until it is needed. To create the hormones, the iodide must be attached to the tyrosine molecule (the tyrosine must be "iodinated“). The iodination requires four separate components in close proximity: iodide hydrogen peroxide (H2O2) thyroid peroxidase (TPO, an enzyme) thyroglobulin (Tg) When TSH activates the secretion, the hormones are separated from the thyroglobulin and secreted into the blood stream, where 99% combine with transport proteins. Synthesis and secretion Thyroglobulin - synthesized in the rough endoplasmic reticulum and then enter the colloid in the lumen of the thyroid follicle by exocytosis. Sodium-iodide (Na/I) symporter pumps iodide (I-) into the cell This iodide enters the follicular lumen from the cytoplasm by the transporter pendrin In the colloid, iodide (I-) is oxidized to iodine (I0) by an enzyme called thyroid peroxidase. Iodine (I0) is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain In conjugation, adjacent tyrosyl residues are paired together. The entire complex re-enters the follicular cell by endocytosis. Proteolysis by various proteases liberates thyroxine and triiodothyronine molecules, which enters the blood Synthesis and secretion Thyroxine (T4) It consists of four atoms of iodine attached to a molecule of tyrosine. secreted by the follicular cells of the thyroid gland Thyroxine (T4) is 65% iodine by weight. transported in blood T4 accounts for up to 90% of the protein-bound iodine in the blood. T4 seems to function primarily as a storage form, being transformed into T3 as needed to maintain proper body function. 99.95% bound to thyroxine-binding globulin (TBG) 0.05% bound to transthyretin and serum albumin. Up to 80% of the T4 is converted to T3 by peripheral organs such as the liver, kidney and spleen. T3 is about ten times more active than T4. Deiodination process by which an iodide atom is removed in transforming T4 to T3. It occurs throughout the body, including the thyroid, liver, pituitary, brain, and other organs. It is performed by enzymes containing selenium (important selenium in diet). T3, T4 - mechanism of action Most body cells have receptors for thyroid hormones on the cell membrane. the specific nuclear receptors, where they then regulate gene expression. Function: Regulation of oxygen use Regulation of basal metabolism rate Regulation of cellular metabolism Regulation of growth and development Stimulate the use of cellular oxygen to produce ATP Stimulate the synthesis of Na-K pumps As the cells produce and use more ATP, more heat is given off, and the body temperature rises. Functions of T4 and T3 stimulate protein synthesis increase the use of glucose and fatty acids for ATP production increase the decomposition of fats and enhance cholesterol excretion (thus reducing blood cholesterol levels) affect the regulation of body fluids, vascular resistance and blood pressure accelerate body growth, particularly the growth of nervous tissue Thyroid hormone diseases Iodine deficiency Decrease in serum T4 Increase in serum TSH Thyroid enlargement (goitre) Decrease in the degree of iodination of Tg Increase in T3/T4 ratio Iodine excess Inhibits iodide transport and hormone synthesis Inhibits thyroid growth Inhibits the function of thyroid hormones and growth Goitre (struma) term that refers to an enlargement of the thyroid (thyromegaly) Signs and symptoms associated with hypothyroidism or hyperthyroidism, can be inactive Growth pattern Uninodular, Multinodular, Diffuse Size Class I - palpation struma Class II - easily seen Class III - very large and is retrosternal (pressure results in compression marks) Causes Iodine deficiency Congenital hypothyroidism Hashimoto's thyroiditis or other thyroiditis Pituitary disease Graves' disease Thyroid cancer Thyroid hormone insensitivity Hypothyroidism Primary – deficiency of thyroid hormones Hashimoto's thyroiditis Cretinism Secondary – deficiency of TSH from pituitary gland Tertiary – deficiency of TRH from hypothalamus Main symptoms Slowed speech and breaking voice Dry puffy skin, especially on the face Thinning of the outer third of the eyebrows (sign of Hertoghe) Abnormal menstrual cycles Low basal body temperature Hashimoto's thyroiditis an autoimmune disease where the body's own T-cells attack the cells of the thyroid antibodies against thyroid peroxidase and/or thyroglobulin cause gradual destruction of follicles in the thyroid gland Symptoms – Myxedema, weight gain, depression, mania, fatigue, panic attacks, bradycardia, high cholesterol, reactive hypoglycemia, constipation, migraines, memory loss, infertility and hair loss. Treatment - thyroid hormone replacement Myxedema specific form of cutaneous and dermal edema increased deposition of connective tissue components (like glycosaminoglycans, hyaluronic acid, and other mucopolysaccharides) in subcutaneous tissue Symptoms: fatigue, weight gain, depression, dry skin, and brittle hair intolerance to cold, low blood pressure, shortness of breath, lethargy and seizures Cretinism A condition of severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormones. Reasons can be: endemic (deficiency of iodine) genetic sporadic (abnormal development of thyroid gland) Symptoms: reduced muscle tone and coordination cognitive impairment thickened skin and a protruding abdomen Hyperthyroidism Overactive tissue within the thyroid gland, resulting in overproduction of T4 and T3. Symptoms: Fast heart beat results in palpitations a fast nervous system in tremor and anxiety symptoms a fast digestive system in weight loss and diarrhea Diseases: Graves-Basedow disease Toxic thyroid adenoma – „hot“ adenoma Thyroiditis – inflammation Graves-Basedow disease caused by an antibody-mediated auto-immune reaction Symptoms: Goiter Exophthalmos (swelling behind the eyeball) "orange-peel" skin Fatigue weight loss with increased appetite rapid heart beats muscular weakness CALCITONIN Parafollicular cells of thyroid gland (C-cells) peptide of 32 amino acids stimulus for secretion – high plasma calcium (food intake – gastrin, cholecystokinin, glucagon) Function – to DECREASE plasma calcium and phosphates inhibits osteolysis – decreases absorption of Ca2+, P from bones stimulates incorporation of Ca2+, P to bones decreases absorption of Ca2+, P in kidneys decreases the effect of PTH on bones – PTH antagonist Parathyroid glands Parathyroid hormone (PTH) polypeptide of 84 amino acids stimulus for secretion – low plasma calcium function – to INCREASE plasma calcium activation of osteoclasts – stimulates absorption of Ca2+, P from bones decreases excretion of Ca2+ by kidneys increases excretion of P by kidneys stimulates conversion of vitamin D to calcitriol (vitamin D hormon) in kidneys Changes in PTH plasma level Hypoparathyroidism Muscle tetany (spasms) Convulsions Pain in the face, legs, and feet, abdominal pain Dry hair, dry skin Cataracts Hyperparathyroidism Decalcification of bones Multiple fractures (Osteitis fibrosa cystica) Kidney stones Lack of energy, memory problems, depression Relation - plasma Ca2+ concentration x hormones