A BRIEF OVERVIEW OF THE THYROID GLAND By April Stoll

Anatomy of the Thyroid Gland The thyroid gland is located anterior and caudal to the cartilages of the larynx1 and is the largest endocrine gland in adults.2 It is a small, butterfly-shaped bilateral organ with 2 lobes joined by an isthmus.1,3 Each lobe is about 4 cm long.3 The normal weight of a nongoitrous adult thyroid is about 20 g,2 depending on body size and iodine supply.3 The thyroid is highly vascularized and receives blood from the superior thyroid arteries and branches of the external carotid artery.3 It is drained by corresponding veins into the internal jugular vein.3 Thyroid glandular tissue is comprised of spherical follicles that vary in size.3 Each follicle is lined with cuboidal epithelial cells1 (follicular epithelium) that encircle the inner colloid space (colloid lumen).4 References Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill;1998:2012. 2. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:20. 3. DeGroot LJ, Larson PR, Hennemann G. The Thyroid and Its Diseases. Chapter 1: Phylogeny, ontogeny, anatomy, and metabolic regulation of the thyroid, revised 01 August 2002 by Dumont JE, Corvilain B, and Maenhaut C. (Presented online at http://www.thyroidmanager.org). Accessed June 6, 2003. 4. De La Vieja D, et al. Physiol Rev. 2000;80:1083-1105.

Thyroid Basics: The main function of the thyroid is to control the body’s metabolism Its sole function is to make thyroid hormone This hormone has an effect on nearly all tissues of the body where it increases cellular activity

The Thyroid Produces and Secretes 2 Metabolic Hormones The two principal hormones are: Thyroxine (T4 ) and triiodothyronine (T3) Required for homeostasis of all cells Influence cell differentiation, growth, and metabolism Stimulate protein production in the body’s tissues T4 is the most abundantly secreted, but T3 is considerably more active Considered the major metabolic hormones because they target virtually every tissue The Thyroid Produces and Secretes 2 Metabolic Hormones. Triiodothyronine (T3) and tetraiodothyronine1 (or thyroxine, T4) are the 2 principal hormones of the thyroid gland.2 Chemically, they are iodothyronine hormones  iodine-containing amino acid derivatives of thyronine.2 They are the only known iodine-containing compounds with biological activity.1,2 Often referred to as the major metabolic hormones,3 the 2 thyroid hormones have profound effects on essential physiologic processes.1,3 References 1. De La Vieja D, et al. Physiol Rev. 2000;80:1083-1105. 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1383. 3. Kirsten D. Neonatal Netw. 2000;19:11-26

Thyroid Hormones Stimulate Metabolic Activities in Most Tissues Regulate the rate of overall body metabolism (specifically T3) T3 increases basal metabolic rate Increases body heat production Calorigenic effects T3 increases oxygen consumption by most peripheral tissues Thyroid Hormones Stimulate Metabolic Activities in Most Tissues. When the existence of specific nuclear binding sites in different T3-sensitive tissues was first demonstrated, T3 binding was also observed in almost all tissues.1 Thyroid hormone receptors are expressed in virtually all tissues.1 Heart, skeletal muscle, liver, and kidney are markedly stimulated by thyroid hormone. Brain, gonads, and spleen are heat sensitive and unresponsive to the calorigenic effect of thyroid hormone.1,2 References 1. Yen PM. Physiol Rev. 2001;81:1097-1142 2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1393.

The Chemistry of Thyroid Hormones: Thyroid hormones are derivatives of the amino acid Tyrosine bound covalently to iodine These hormones are basically two tyrosine's linked together with the critical addition of iodine at the three of four positions on the aromatic rings

T4/T3 Conversion Sites The liver is the major extrathyroidal T4 conversion site for production of T3 Some T4 to T3 conversion also occurs in the kidney and other tissues Sites of T4 Conversion. The major site of extrathyroidal conversion of T4 to T3 is the liver.1 In humans, D1, which is found in the liver, kidney, thyroid,1,2 and pituitary,2 generates circulating T3 for use by most peripheral target tissues.1 D2 was thought to be limited to the brain and pituitary,1 but has been found to be present in the human thyroid, heart, brain, spinal cord, skeletal muscle, and placenta.2 The distribution of D3 is mainly in the central nervous system, skin, and placenta.1,3 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1387-1388. 2. Bianco AC, et al. Endocr Rev. 2002;23:38-89. 3. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:125.

Thyroid-Stimulating Hormone (TSH) Also known as Thyrotropin Is secreted from cells, called thyrotrophs, in the anterior pituitary, which in turn is controlled by the hypothalamus Is the major regulator of the thyroid gland It Regulates thyroid hormone production, secretion, and growth Is regulated by the negative feedback action of T4 and T3 Its synthesis and release is stimulated by thyroid-releasing hormone (TRH) Thyroid-Stimulating Hormone (TSH). Thyroid stimulating hormone (TSH; also called thyrotropin), a glycoprotein hormone with  and  subunits, is secreted by the anterior pituitary gland.1,2 Thyroid stimulating hormone is inhibited by thyroid hormone in a classic endocrine negative feedback loop.2 Its synthesis and release is stimulated by thyrotropin-releasing hormone (TRH), which is the major positive regulator of TSH secretion.3 TSH is the major regulator of the thyroid gland.4 Physiological roles of TSH include stimulation of various thyroid functions, eg, iodine uptake and organification, production and release of thyroid hormone from the gland, and promotion of thyroid growth.2,5 TSH-cyclic adenosine monophosphate (cAMP) is the prime regulator of iodide uptake and concentration and T3/T4 formation.6 TSH-cAMP induces the expression and activation of the 3 necessary genes encoding proteins involved in iodide uptake and thyroid hormone formation: the sodium-iodide symporter (NIS), thyroglobulin (Tg), and thyroperoxidase (TPO).6 References 1. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1390. 2. Grossman M, et al. Endocr Rev. 1997;18:476-501. 3. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:208. 4. Nillni EA, et al. Endocr Rev. 1999;20:599-648. 5. Grossman M, et al. Mol Endocrinol. 1995;9:948-958. 6. Kohn LD, et al. Trends Endocrinol Metab. 2001;12:10-16.

TSH-cAMP Thyroid-Stimulating Hormone-cyclic Adenosine Monophosphate (cAMP) Is the prime regulator of iodide uptake and concentration T3/T4 formation Induces the expression and activation of the 3 necessary genes that encode proteins involved in iodide uptake and thyroid hormone formation Sodium-iodide symporter (NIS) Thyroglobulin (Tg) Thyroperoxidase (TPO)

Thyroid-Releasing Hormone (TRH) Is secreted by hypothalamic neurons Is only a tripeptide, with the basic sequence of amino acids being glutamic acid-histidine-proline Is inhibited by high blood levels of thyroid hormones in the negative feedback loop Is the major positive regulator of TSH secretions

Hypothalamic-Pituitary-Thyroid Axis Negative Feedback Mechanism In this negative-feedback system, increasing levels of circulating thyroid hormone inhibit the synthesis of TSH directly at the pituitary level and indirectly at the level of the hypothalamus by reducing the secretion of TRH.1,2 TRH is the major regulator of the synthesis and secretion of TSH, and therefore it plays a central role in regulating the hypothalamic-pituitary-thyroid (HPT) axis.3 Thyroid hormone can negatively regulate TSH transcription by direct and indirect mechanisms, and can negatively regulate TRH at the transcriptional level,1,4 decreasing transcription of TSH mRNA.4 References Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:206-207. 2. Dahl GE, et al. Endocrinology. 1994;135:2392-2397. 3. Nillni EA, et al. Endocr Rev. 1999;20:599-648. 4. Yen PM. Physiol Rev. 2001;81:1097-1142.

Thyroid Disorders Hypothyroidism Two common examples are: Iodine deficiency Primary thyroid disease Symptoms include: Lethargy Fatigue Cold-intolerance Weakness Hair loss Reproductive failure Hyperthyroidism The most common form is Graves Disease Is less common than Hypothyroidism Symptoms include: Nervousness insomnia high heart rate eye disease anxiety

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