Thyroid Hormones Flashcards
Thyroid hormones (T4 and T3)
are produced by the follicular cells of the thyroid gland and are regulated by TSH made by the thyrotropes of the anterior pituitary gland.
Thyrotropes are endocrine cells in the anterior pituitary which produce thyroid stimulating hormone (TSH) in response to thyrotropin releasing hormone (TRH). TRH is secreted by the hypothalamus.
The effects of T4 in vivo are mediated via T3 (T4 is converted to T3 in target tissues). T3 is the active form of the thyroid hormone.
Thyroxine
is produced by follicular cells of the thyroid gland. It is produced as the precursor thyroglobulin (thyroglobulin is a big molecule with lots of peptide chains with lots of thyrosine); which is cleaved by enzymes to produce active T4.
is produced by attaching iodine atoms to the ring structures of tyrosine molecules. Thyroxine (T4) contains four iodine atoms. Triiodothyronine (T3) is identical to T4, but it has one less iodine atom per molecule.
Iodide
- is actively absorbed from the bloodstream by a process called iodide trapping.
- In this process, sodium is cotransported with iodide from the basolateral side of the membrane into the cell and then concentrated in the thyroid follicles to about thirty times its concentration in the blood.
- Via a reaction with the enzyme thyroperoxidase, iodine is bound to tyrosine residues in the thyroglobulin molecules, Iodine can attach to one spot -> monoiodotyrosine (MIT) and Iodine can attach to 2 spots-> diiodotyrosine (DIT).
- Tyrosine molecules can be joined together and lead to the formation of MIT + DIT-> T3
- DIT + DIT -> T4
The 7 steps of biosynthesis of thyroid hormones
- Iodide uptake (increase in iodide uptake)
The Na+/I- symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodine ion via ATP. This process is activated by TSH; which is initiated by a decrease in iodide stores. - Oxidation of iodide and iodination of thyroglobulin ( organification). Oxidation of idodide via Thyroperoxidase (special enzyme in the colloid which oxidzes iodide to iodine). The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesised in the endoplasmic reticulum of the follicular cell and secreted into the colloid. MIT and DIT are formed and stored in the lumen of the thyroid follicle. Is inhibited by antithyroid drugs propylthiouracil (PTU) and Methimazole (MMI)
- Coupling of iodotyrosine residues to generate iodothyronines. Formation of T4 (DIT + DIT) and T3 (MIT + DIT). Activity: TSH and iodine availability. Inhibition of PTU and MMI
- Resorption of the TRG colloid into the cell. Thyroid-stimulating hormone (TSH) released from the pituitary gland binds the TSH receptor on the basolateral membrane of the cell and stimulates the endocytosis of TRG via megalin recptor in the colloid. Inhibition of Colchicine (medication that treats gout), Lithium, and Cytochalasin B (a cell-permeable mycotoxin)
- Proteolysis (the breakdown of proteins into smaller polypeptides or amino acids) of TRG. Colloid droplets fuse with lysosomes and enhanced by TSH.
- Endopeptidases: intermediates TRG
(Endopeptidase are proteolytic peptidases that break peptide bonds of nonterminal amino acids i.e. within the molecule)
-Exopeptidates: intermediates MIT + DIT
(Exopeptidates can break down proteins into monomers)
- 90% T4 and 10% T3
6. Recycling of Iodine into TRG. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T4 from the iodinated thyroglobulin.
7. conversion T4 into T3 by 5’ deiodinase. These vesicles are then exocytosed, releasing the thyroid hormones.
TSH effect growth by:
Increased: DNA RNA Proteins Cell size Cell number Follicle formation
TSH RECEPTOR IS LOCATED ON THE PLASMA MEMBRANE
TSH effect hormone synthesis by:
Increased: Increased trapping of iodide Iodination Endocytosis of colloid Thyroglobulin degradation Glucose oxidation NADPH generation
Control of the hypothalamic-pituitary-thyroid axis
The hypothalamus senses low circulating levels of thyroid hormone (T3 and T4) and responds by releasing thyrotropin-releasing hormone (TRH).
The TRH stimulates the pituitary to produce thyroid-stimulating hormone (TSH). The TSH, in turn, stimulates the thyroid to produce thyroid hormone until levels in the blood return to normal.
Thyroid hormone exerts negative feedback control over the hypothalamus as well as anterior pituitary, thus controlling the release of both TRH from hypothalamus and TSH from anterior pituitary gland.
Long loop targets organ feeding back to brain
Short loop is the brain feeding back to the brain; it involves TSH inhibition of TRH
Hormone pairs and thyroid disorders
Difference in the levels of hormones:
- target hormones: T4 and T3
- Pituiary hormone: TSH
Primary hypothyroidism: Hashimoto’s
- High TSH and low T3 and T4
Secondary Hypothyroidism: Pituitary Failure
-low TSH and low T3 and T4
Primary Hyperthyroidism: Autonomous Secretion of Target Gland Hormone; aka Grave’s disease
-low TSH and high T3 and T4
Secondary hyperthyroidism: Pituitary tumor
-High TSH and High T3 and T4
Conditions and factors that inhibit type I 5’ deiodinase activity
5’deiodinase makes T3 out of T4 in the follicular glands and different forms exist in different tissues
3 different types of deiodinase:
D1:turns T4 into T3; circulating T3
D2: Autoregulates T3 supply
D3: the inactivation pathway, reverse oxidinase, regulates and transforms T4 into inactive form, T3 transforms T4
Inhibiting factors:
- acute and chronic illness
- caloric deprivation (esp carbohydrate) and malnutrition
- glucocorticoids (stress hormones)
- adrenergic receptor antagonist (propranolol in high doses)
- oral cholecystographic agents (iopanoic acid, sodium ipodate)
- propylthiuracil (PTU)
T4 and T3 receptor
The thyroid hormones (T4 and T3) have a nurclear receptor that is located in the nucleaus of the cell; these hormones bind to DNA
Binding is recognized on DNA and activate the expression of the gene. Binding to DNA receptor activates mRNA formation transcription for proteins.
This increases NA, K, ATP, Mitochondria, respiratory enzymes, other enzymes, and proteins
PERMISSIVENESS an important property of the thyroid hormones.
Thyroid hormones bind DNA and promote the transcription of genes (the gene encoding adrenergic receptors) and increase expression of adrenergic receptors
A decrease in thyroid hormones would create a decrease in adrenergic receptors which would make NE useless
Effects of thyroid hormones
Nervous system:
T3 is absolutely required for perinatal brain development (lack=cretinism)
- growth of cerebral and cerebellar corex, myelinization (action potential on nerve)
- axon proliferation (ECM protein: laminin)
- synaptogenesis (connections on neurons)
In Adults, enhances:
- wakefulness and responsiveness
- emotional tone
- memory
Sympathetic nervous system:
synergizes with sympathetic nervous system (permissiveness)
- promotes increases in beta adrenergic receptor and Gs proteins
- important for metabolic and cardiac effects of thyroid hormone
Primary Hyperthyroidism:
high T4 and T3 and low TSH
Autoimmune thyroiditis: GRAVE’S DISEASE
- AUTOANTIBODIES BIND AND ACTIVATES TSH RECEPTORS; decreasing TSH is useless in these patients
- tumor of thyroid gland
Symptoms:
Large increases in BMR (basal metabolic rate)
* leads to weight loss despite increased food intake
Increase heat production: heat intolerance and excessive sweating
Increased SNS activity
* Tachycardia, tremor, nervousness, wide-eyed stare
Enlarged thyroid gland (goiter)
Exopthalmos: protusion of eyeballs; occurs when antbodies bind to TSH receptors and bind muscles around the eye that control the eye movement and contract the muscles.
Treatments for hyperthyroidism:
- Block active transport of iodide :
- with complex anions such as monovalent, hydrated ions similar in size to iodide
- Thyiocyanate: found in certain foods and in cigarette smoke (in large doses, thiocyanate can also inhibit organification).
- problems: the Jim Jones effect (poison)
- Perchlorate (ClO4): 10X more active as thiocyanate.
- Low doses (750 mg per day) have been used in the treatment of Grave’s disease.
- Excessive doses (2-3g per day) causes increased incidence of fatal aplastic anemia.
- Found in crop fertilizers and used as compoets for booster rockets in the space shuttle
- Iodination of thyroglobulin and coupling reaction (thyroperoxidase)
Thionamides or thioureylenes:
-propylthiouracil (crosses placenta, but ok to give to pregnant women if used with caution)
methimazole (Tapazole) (crosses placenta; DO NOT GIVE TO PREGO WOMEN)
carbimazole
Class D drug
Side Effects:
- (low) HA, drowsiness, or dizziness.
- immunosuppression
Drug-drug interactions:
- warfarin
- digoxin
- beta blockers
- Iodide:
- high doses cause paradoxical decrease in thyroxin biosynthesis, at the ORGANIFICATION STEP
- striking and rapid (changes in basal metabolic rate within hours)
- Radioactive Iodide (IODOTOPE THERAPEUTIC)- lower doses may limit rebound hypothyroidism
- this leads to partial destruction of the gland
- used when prolonged tx with anti-thyroid drugs or surgery has not led to remission. More commonly used in older pts.
- major disadvantage is long period of time required before hyperthyroidsm is controlled
Drugs that block Type I deiodinases: Propylthiouracil (PTU)
Drugs that block both Type I and Type II deiodinases: sodium ipodate, iopanoic acid.
*in additon, metabolism of these drugs lead to the release of 75-150mgs of iodide, which can further inhibit T4/T3 secretion. These drugs are commonly used as radiology contrast dyes
Thyroid storm
- Is a crisis or life-threatening condtion characterized by an exaggeration of the usual physiologic response seen in hyperthyroidism:
- high fever
- tachycardia
- nausea/vomiting
- irregular heart beat
- acute heart failure
- confusion/disorientation - Usually precipitated by concurrent medical problems; such as infections, stress, surgery, trauma, heart disease, diabetic ketoacidosis
- Treatment:
- antipyretics
- large dose (200-400 mg) propylthiuracil because of addtional action of blocking peripheral T4 conversion
- Beta blockers (propranalol) to counter effects on SNS and heart
Primary Hypothyroidism
- low T4/T3 and high TSH
- Autoimmune disease of thyroid: HASHIMOTO’S DISEASE
- blocks hormone synthesis and glandular growth
- Other causes:
- Genetic defect or autoantibodies vs. enzymes necessary for thyroid hormone synthesis or the conversion of T4 to T3 - Symptoms:
- Myxedema: accumulation of mucopolysaccharides with fluid accumulation (goiter)
- decreased thermogensis: cold intolerance
- lethergy, sleepiness, decreased mentation
- bradycardia
- LOWERING OF UPPER EYELID (PTOSIS)
- in utero or infancy and childhood:- marked retardation in growth
- severe mental retardation due to poorly developed nervous system
- Known as “cretins”
