Thyroid Gland and Hormones

• The thyroid gland is located below the larynx, on each side of the trachea.
• The hormones it produces include triiodothyronine (T3), thyroxine (T4), and calcitonin.
• Calcitonin regulates calcium metabolism.

Thyroid Hormones

• T3 is more effective but less secreted, leading to a decreased concentration in plasma and a shorter half-life.
• T4 has greater than 90% secretion, increasing concentration in plasma, and is converted to T3 in tissues.

Follicles

• The thyroid gland contains follicles filled with colloid.
• Follicles are lined with cuboidal epithelial cells, also called follicular cells, which secrete hormones into the interior of the follicles.
• Thyroglobulin, a glycoprotein containing T-hormones, is a major constituent of colloid.
• Hormones are secreted into follicles, then the colloid is absorbed through epithelial cells and into the blood.

T-Hormone Synthesis

• The process starts with iodine (I) ingested from iodized salt, with 1/5 used for T-hormone synthesis.
• Iodide (I-) trapping uses an iodide pump, specifically the Na+/I- cotransport.
• Thyroid peroxidase oxidizes iodide.
• Thyroglobulin, a protein with about 70 tyrosine amino acids, undergoes iodination of tyrosine, known as organification, facilitated by thyroid peroxidase.

T-Hormone Synthesis Steps

• Iodination of tyrosine forms monoiodotyrosine (MIT).
• Iodination of MIT forms diiodotyrosine (DIT).
• Conjugation of MIT and DIT yields triiodothyronine (T3), with a ratio of 1/15.
• Conjugation of two DIT molecules forms tetraiodothyronine (T4).
• Conjugation of MIT and DIT can also form reverse triiodothyronine (RT3).

T-Hormone Secretion

• The process begins with endocytosis of colloid which fuses with lysosomes inside the follicular cells.
• Thyroglobulin is digested by proteases in lysosomes, releasing free MIT, DIT, T3, T4, and RT3.
• T3 (7%) and T4 (93%) diffuse into the blood.
• Deiodination of MIT and DIT by deiodinase recycles iodine and contributes to the organification of thyroglobulin.

T-Hormone Transport

• T-hormones bind to plasma proteins, including thyroxin binding globulin (highest affinity), transthyretin (thyroxin binding prealbumin), and albumin (highest capacity).
• Because they have a high affinity to plasma proteins they are slowly released from proteins which results in a long half-life: 1 day for T3 and 6 days for T4.
• Metabolism involves conjugation in the liver, then excretion via the intestine and stool.

Mechanism of Action

• Slow release from the blood to tissues, leading to a slow onset and long duration of action.
• Most T4 is converted to T3 in plasma and cells by deiodinase and T3 has a faster and higher effect.
• Enters the target cell via diffusion, it's then stored inside the target cell (bound to proteins)
• Gradual release occurs from proteins
• Binding to nuclear receptors in heterodimer with RXR (retinoid X receptor) – bound to HRE
• Release of corepressor and binding of coactivator and RNA-polymerase on the complex
• Transcription process transpires
• Leads to formation of proteins (enzymes, structural and transport proteins...) - Generalized increase in body activity

Effects

• Increases metabolic activity of tissues, leading to an increase in basal metabolic rate (BMR).
• It raises the number and activity of mitochondria, which then increases the rate of ATP formation.
• Increases oxygen consumption and heat production.
• Increases the rate of nutrient utilization.
• Increasing carbohydrate metabolism means stimulation of glucose absorption from the GIT, uptake of glucose, glycolysis, gluconeogenesis, insulin secretion and degradation
• Mobilization of fats from adipose tissue which means there is an increase FFA in plasma
• Increases the rate of protein synthesis and breakdown.
• There is need for more vitamins for the increased production of enzymes which may cause hypovitaminosis.
• Decreases body weight due to higher BMR.
• Increases the number and affinity of beta-receptors for catecholamines.
• Increases metabolic rate, escalating oxygen needs and waste production, causing vasodilation, higher blood flow, and higher cardiac putout.
• Elevates heart rate and strengthens cardiac contraction by increasing the number and affinity of beta-adrenergic receptors.
• Influences the central nervous system leading to nervousness, psychoneurotic tendencies, anxiety, worry, and paranoia.
• Promotes vigor in muscles which may lead to weakness due to proteocatabolism, tremor.
• Causes insomnia, increases the rate of hormone secretion in endocrine glands, while also controlling normal sexual function

Regulation of Secretion

• The hypothalamus releases TRH (thyrotropin releasing hormone), which increases TSH production (thyroid stimulating hormone, thyrotropin) by the anterior pituitary.
• Somatostatin (SS) from the hypothalamus reduces TSH production.

Anterior Pituitary Regulation

• The secretion can be regulated by the anterior pituitary: TSH (cAMP)
• Glycoprotein, ↑ secretion of T3 and T4
• ↑ iodide trapping
• Iodination of tyrosine and conjugation of MIT and DIT
• ↑ endocytosis and proteolysis of thyroglobulin
• ↑ size, number and secretory activity of thyroid cells
• Trophic effects of TSH: development, growth, maturation, differentiation of follicular cells

Thyroid Disease: Hypothyroidism

• Caused by disorders of the thyroid gland or anterior pituitary (↓ TSH) or the hypothalamus (↓ TRH).
• Symptoms include fatigue, somnolence, mental slowness, constipation, decreased heart rate, cardiac output, and decreased BMR, increased body weight, depressed hair growth and dry skin, a husky voice, myxedema, eye bagginess, swelling of the face and cardiovascular complications, atherosclerosis.
• Cretinism includes hypothyroidism in fetal life or childhood, mental retardation, and dwarfism, with growth of bones inhibited more than soft tissues, leading to a big belly and tongue.

Thyroid Disease: Hyperthyroidism

• Graves disease, which is an autoimmune disorder (circulating antibodies against TSH receptor stimulate this receptor and causes hyperactivity of thyroid gland.
• Symptoms of this include excitability, heat intolerance, increased sweating, weight loss, diarrhea, muscle fatigue, hand tremors, insomnia, increased pulse pressure and BMR, and enlargement of the thyroid gland. -Exophthalmos (protrusion of eyeballs) is caused by swelling of retro-orbital tissues, plus degenerative changes in extraocular muscles (autoimmune process).
• Cardiovascular complications (atrial fibrillation, heart failure)

Struma

• Also known as a Goiter, is the enlargement of the thyroid gland
• It includes eu-, hypo-, hyperfunction of thyroid gland
• Endemic condition (struma)- the iodide deficiency has reduced the synthesis and the secretion of T hormones, so increased secretion of TSH increases the hypertrophy of thyroid gland.