Thyroid Hormones: Synthesis & Function

Thyroid Hormones Overview

• Thyroid hormones are crucial for various bodily functions
• These include development, metabolism regulation, normal growth, and brain development
• They also maintain metabolism and ensure functional activity of many organs
• The goal is to understand their synthesis, effects, and imbalances

Hypothalamic-Pituitary-Thyroid (HPT) Axis

• This axis involves the interplay between the hypothalamus, pituitary gland, and thyroid gland

Thyrotropin-Releasing Hormone (TRH)

• Hypothalamus produces TRH, a tripeptide hormone
• It is a key component of the HPT axis

Thyroid Gland Hormones

• The thyroid gland makes two major hormones: thyroxine (T4) and triiodothyronine (T3)
• A small amount of calcitonin is produced, important for calcium metabolism
• Predominantly thyroxine is produced (93%), and only 7% is triiodothyronine
• Thyroxine converts into triiodothyronine in tissues
• Both T4 & T3 are essential for function

Thyroid Gland Anatomy

• The thyroid consists of follicles (100-300 micrometers in diameter) filled with colloid
• Follicles are surrounded by a cuboidal epithelium layer
• Inactive gland: follicles are large, colloid abundant, and cells are flat
• Active gland: follicles are small, and cells are cuboidal or columnar
• Individual thyroid cells are on a basal lamina, next to fenestrated capillaries
• Thyroglobulin (a glycoprotein) is a major colloid component, containing thyroid hormones

Thyroid Cell Functions

• Transport iodide
• Synthesize thyroglobulin and secrete it into the colloid
• Produce and store thyroid hormones
• Remove hormones from thyroglobulin

Iodide Importance

• 1 mg/week of ingested iodine is needed for normal thyroid hormone production
• Synthesis is necessary
• Iodine converts to iodide and is absorbed via the GI tract
• 1/5 of absorbed iodide goes to the thyroid

Iodide Pump

• Iodide transport is critical for thyroid hormone formation
• Basal membrane pumps iodide against a concentration gradient through iodide trapping
• Normal gland concentration is 30x the blood concentration
• Maximally active gland concentrations can be 250x the blood concentration
• Sodium/iodide (Na+/I-) symporter assists the iodide pump

Thyroglobulin

• These cells secrete thyroglobulin into the follicles
• Thyroglobulin has 120-130 tyrosine amino acids
• Tyrosine is what binds with iodine to form the thyroid hormones formed from tyrosine

Processes

• Iodide ions are converted to an oxidized form to bind to tyrosine
• Thyroid peroxidase promotes iodine oxidation
• Hydrogen peroxide is the by-product of chemical reactions

Iodination and "Organification"

• This is the binding of iodine to thyroglobulin
• Tyrosine iodinase enzyme causes the process to occur within seconds or minutes

Endocytosis: Storing Hormones

• Each thyroglobulin molecule can contain 30 thyroxine molecules
• Normal human thyroid produces 23% MIT, 33% DIT, 35% T4, and 7% T3
• Hormones are stored in follicles and are enough to supply the body with normal thyroid hormone requirements for 2-3 months
• Symptoms of deficiency usually take months

Secretion of Hormones

• Thyroid cells send pseudopods to engulf colloid to form pinocytic vesicles
• Lysosomes fuse with vesicles and release digestive enzymes that digest/release: thyroxine and triiodothyronine
• These hormones diffuse through the cell base into the blood

Peripheral Conversion

• Released hormones transported to tissues
• Hormones bind with intracellular proteins
• The hormones are again stored, but are used slowly, over weeks

Thyroid Hormone Receptor (TR)

• TR is a nuclear receptor activated by thyroid hormone binding
• TR-α1 is found in skeletal and cardiac muscles
• TR-β1 is in the brain, liver, and kidney
• TR-β2 primary location is in the pituitary and hypothalamus

Thyroid Hormones Metabolic Increase

• Metabolic activities are increased in most of the body's tissues
• When large hormone quantities are secreted BMR can increase 60 to 100% above normal
• Rate of utilization of energy foods is accelerated
• Both protein synthesis and catabolism are increased
• Growth and mental processes are accelerated
• Endocrine glands activities are increased

Cellular Metabolic Activity

• Depends on the number and activity in the mitochondria of most cells by increasing the number and activity of mitochondria
• Thyroid hormones also increase movement of ions through cell membranes thanks to Na+-K+-ATPase
• Both the movement of sodium and potassium ions is increased, increasing heat in the body

Hormone impact on energy substrates

• Hormones don't only alter metabolism rate, but affect energy substrates
• T3 and T4 aid glycogen breakdown/glycogenolysis
• Also increase glucose formation/gluconeogenesis

Effects on Lipid Metabolism

• Includes lipolysis
• Also includes FFA release/oxidation from adipose
• LDL receptors in liver increase
• Cholesterol, phospholipid, and triglycerides decrease: oxidation increases more than synthesis
• The hormones increase the rate lost in feces

Effect of hormones on plasma and liver fats

• The hormone causes cholesterol excretion in bile
• Hormone increase low-density lipoproteins in liver cells, leading to rapid removal of low-density lipoproteins/plasma

Effects on Protein Metabolism

• For proper function, amino acids are increased
• Hepatic gluconeogenesis is stimulated by hormones and proteolysis also rises
• There's an overall synthesis rise, but sometimes it leads to muscle/protein loss
• T3 catabolic effects exacerbate symptoms in those with hyperthyroidism

Cardiovascular System

• Blood flow/cardiac output is increased
• Heart rate and strength are increased
• It increases arterial pressure

Hormone impact on Respiration

• Respiration and carbon dioxide production/mechanisms are activated as metabolism increases

Hormone impact on Gastrointestinal Motility

• Hormone secretion increases
• Thyroid hormones increases motility of GI tract as well.

Influence on nervous system

• These hormones influence the Central Nervous System
• Catecholamines have increased impact
• A hyperthyroid individual may experience nervousness and paranoia
• Reaction time is shortened through reflexes if the stimulus is enough

Impact on growth

• Thyroid hormone is important for growing kids
• Growth factors, like brain growth, benefit from the hormones
• Without thyroid hormones, the brain never fully matures
• If there's never treatment, patient could die or be mentally damaged by thyroid issues.

Other systems of the body

• Excitability is increased
• Intolerance to heat will become likely, along with increases in sweating
• Mild to extreme weight loss could occur, as well as varying degrees of diarrhea and muscle weakness
• Extreme fatigue, nervousness and inability to sleep may also occur

Thyroid Gland: TSH control

• TSH's is increased through cAMP pathways
• Proteolysis is increased because of stored hormones
• Activity that increases Iodide is activated as a result
• As a result, the pituitary gland's role is to increase hormone activation

TRH/TSH Secretion

• One of the best ways to increase TSH from anterior pituitary is to expose patient to coldness
• Basal metabolic rate rises depending on how long a person is exposed

Diseases of the Thyroid Gland

• Hyperthyroidism can arise if the levels of toxins are too high

Diseases: Hypothyroidism

• Happens, generally, when something impacts the process of autoimmunity
• Immunity actively destroys hormone rather than assist it, ultimately meaning more thyroid hormones will need to be released
• Can happen from general enlargement/swelling of goiter
• Or from not injecting enough iodide, either in the diet or elsewhere
• Overall, there'll be a decrease in hormones that ultimately result in lack of energy, and overall damage