The thyroid gland: control of secretion, effects of the thyroid hormones Flashcards
What is the Thyroid Gland (TG)?
- One of the largest endocrine glands, normally 15 to 20g in adults
- Bilobular, located immediately below the larynx of each side of and anterior to the trachea
- Secretes two major metabolic hormones; thyroxine (T4) and triiodothyronine (T3)
- Thyroid secretion is controlled primary by the thyroid-stimulating hormone (TSH) secreted by the anterior pituitary gland
- The thyroid gland also secretes calcitonin, a hormone involved in calcium metabolism
- Thyroglobulin is secreted into the follicular sacs within the gland
- Usually TG produces and stores hormones (unusual for a gland to both secrete and store!)
What are the important cells, compartments and secretions of the Thyroid Gland ?
- Thyroid Gland has many closed follies (100 - 300 microns in diameter)
- Cuboidal epithelial cells secrete colloid into follies
- Main component of colloid is thyroglobulin which contains the thyroid hormones
- Secretions must be reabsorbed through epithelial cells and enter into the blood stream before it can function in the body (blood flow 5x weight of the gland/minute)
- C cells secrete calcitonin (role in calcium regulation - especially in other mammals)
So what is T3 and T4?
- Approx 93% of metabolically active hormones secreted by the thyroid gland is Thyroxine (T4) and 7% is Triiodothyronine (T3)
- Almost all T4 is eventually converted to T3 in tissues (as T3 is more potent)
- T3 is approximately 4 times as potent as T4, but it is present in the blood in much smaller quantities and persists for a much shorter time compared with Thyroxine
- T4 and T3 increase metabolic rate
What does a lack of thyroid secretion cause?
- Lack of thyroid secretion usually causes basal metabolic rate to fall 40% to 50% below normal
What does an excess of thyroid secretion cause?
- Excesses of thyroid secretion can increase the basal metabolic rate to 60% to 100% above normal
Why do we need Iodine?
- Iodine is required to form Thyroxine (T4)
- Require approx. 50mg / year (about 1mg/week)
- Table salt is iodised to prevent deficiencies of this in our diet
- Iodide is sequestered by the Thyroid gland (Thyroid can concentrate iodide), excess usually excreted by kidneys
How do we trap Iodine in the Thyroid Gland?
- Concentrating iodine within thyroid gland cells
- First stage of thyroid hormone formation - transport of iodide from blood to thyroid gland cells and follicles
- Basolateral membrane of thyroid cell actively pumps iodide into the cells via the sodium-iodide symporter (NIS) (2Na+: 1 iodide) (using energy from the sodium pump)
- Iodide concentrated in the cell (30x more than plasma). Concentration can increase to 250x plasma concentration
- Rate is controlled mostly by TSH (thyroid stimulating hormone) - “The main controller”
- Iodide transported through apical membrane into follicle by “pendrin-chloride-iodide anti-porter”
What are the different steps involved in transporting and making T3 + T4?
1). Iodide trapping
2). Oxidising iodide = Iodine
3). Oragnification of Thyroglobulin
4). Coupling
5). Storage
6). Release
What is thyroglobulin and how does it help produce T3 and T4?
- Thyroglobulin - large glycoprotein molecule
- MW 335,000 synthesised and secreted into follicles by ER and Golgi apparatus
- Contains approx 70 tyrosine AAs
- Tyrosine + iodine = T3 + T4
- This happens within the thyroglobulin
- T3 and T4 also stored as part of thyroglobulin
What happens to the iodine inside the cell ?
- Iodide ions are converted to oxidised form of iodine - either I (0) or I (3-) which can combine with tyrosine
- Enzyme peroxidase, located in or attached to apical membrane, is used to produce peroxide and this oxidises the iodide ions to iodine
- Blockage or absence of peroxidase system stops formation of thyroid hormones
What happens in the Organification of Thyroglobulin step?
This is the binding of the oxidised iodine to thyroglobulin
- It will occur spontaneously but slowly
- In thyroid cells, oxidised iodine is associated with thyroid peroxidase (acts as a catalyst)
- It speeds the reaction up and iodide binds to tyrosine almost as soon as they come into contact with the thyroglobulin
How do we form T3 and T4?
Stages of iodination and coupling;
1). Tyrosine is iodised to monoiodotyrosine and then to diiodotyrosine
2). Next few minutes/hours/days, mono and/or diodo iodotyrosine residues become coupled with one another
- Major product is Thyroxine (T4) = 2x diiodotyrosine
- Approx 1/15th of product is trioiodothyranine (T3) = mono + diodo tyrosine
- Small amount of reverse T3 = diodo + monoiodotyrosine (not important physiologically?)
See image
How do we store T3 + T4?
Storage;
- When synthesis / coupling has finished, each thyroglobulin molecule contains up to 30 T4’s and a few T3’s
- thyroglobulin stores in follicles until needed
- Supply lasts for 2-3 months
- Deficiency / pathophysiology of process may be undetected for a few months
- Hence if something goes wrong find 2/3 month down line since stopped working
How is T3 an T4 cleaved + released ?
- T3 an T4 are cleaved from thyroglobulin
- T3 and T4 then released as free hormones
- Colloid (containing thyroglobulin with its T3 and T4) brought into the cell at the apex by pinococytosis
- Pinocytotic vesicles in the thyroid cell fuse with lysosomes which contain digestive enzymes (e.g proteases)
What are the actions of proteases (release phase?) ?
- Proteases digest thyroglobulin and release T3 and T4
- T3 and T4 diffuse through basolateral membrane into capillaries and bloodstream
- Approx 93% thyroxine (T4), 7% T3 initially
- Approx half of T4 is de-iodinated to T3 over the next few days
- Most of the hormone is delivered tissues is T3
Truncate larger structure and cleave off some amino acids making smaller so can be transported through basolateral membrane into blood stream so it can act where it needs to
How is T3 and T4 transported to cells?
- > 99% of T3 and T4 are in the blood bound to plasma proteins (synthesised by the liver)
- Proteins mainly thyroxine-binding globulin, thyroxine-binding prealbumin and albumin
- Proteins have high affinity for T3 and T4 so release them only slowly at the tissues (T3 released more quickly than T4)
How quickly would an injection of Thyroxine show up in the blood and why?
- 2 or 3 day latent period
- Increase in activity over about 10-12 days
- Diminishes over several weeks/months (Half life approx. 15 days)
- T3 more rapid response - latent period of 6-12 hours, max activity in 2-3 days
- Latency is due to binding to proteins but also due to how T3 and T4 mediate reactions downstream
How do T4 and T3 affect transcription genes?
- T4 and T3 enter the cell membrane by carrier-mediated active transport
- Most T4 deiodinated to form T3
- T3 interacts with the thyroid hormone receptor
- Leads to increase or decreases in transcription of genes that lead to the formation of proteins
- Thyroid hormone response of the cell is generated
Thyroid Hormones act on many cells/systems;
- Growth
- CNS development
- Cardiovascular
- Metabolism
Hence why wont see an instant response as this can take days to show up !
What are the Major Physiological effects of the Thyroid hormones?
1). Mobilisation of Carbohydrate, fat and protein stores (direct and indirection actions)
- Increase glucose uptake from GI tract
- Increase glucose utilisation (esp muscle and tissue)
- Increase liver glycogenolysis and gluconeogensis
- Increase Lipolysis in adipose tissue (increase plasma Free Fatty acids)
- Increase tissue oxidation of Free Fatty Acids
- General increase in protein turnover with net increase in anabolism
- Increase in specific enzymes / membrane proteins / hormone receptors
- Permissive actions for other hormones (GH, prolactin, gonadal and adrenal steroids)
- Essential for normal development and function of CNS and PNS
2). Increased Basal Metabolic Rate (BMR);
- Increase secretion = Weight loss
- Decreased secretion = Weight gain
3). Increases in almost every system;
- Blood flow and cardiac output
- Respiration
- GI motility
- Excitatory effects on CNS (Anxiety, worry, nervousness etc)
- Muscle vigour but will cause decrease at high hormone concentration due to excess protein catabolism, often muscle tremor
- Rates of secretion of other hormones
- Sexual disfunction - various effects, complex and not well understood
How is T3 and T4 regulated by Negative feedback?
- Increased T3 and T4 strongly inhibits the Anterior pituitary to stop producing Thyroid Stimulating Hormone (TSH)
- Increased T3 and T4 inhibits the hypothalamus to stop the production of Thyrotropin-releasing hormone (TRH)
- Iodine coming in affects it, increases total collection of iodine in thyroid, increase T3 + T4 and increase neg feedback
How does Thiocyanate regulate T3 and T4 ?
- Thiocyanate ions decrease iodide trapping
- The same active pump that transports iodide ions into the thyroid cells can also pump thocyanate ions
- Thiocyanate competitively inhibit iodide transport into the cell
- Thyroglobulin still formed but isn’t iodinated and therefore cannot form thyroid hormones
- Low Thyroid hormones increases the secretion of TSH
- Overgrowth of the thyroid gland caused even though no Thyroid hormones
- Enlarged thyroid gland = goitre
How does Propylthiroacil regulate T3 and T4 ?
- Propylthiroacil (e.g Carbimazole / Methimazole) prevents formation of thyroid hormones from iodides and tyrosine
- Block the peroxidase enzyme that is required for iodination of tyrosine and blocks the coupling that forms T3 and T4
- (Like Thiocyanate) does not prevent formation of thyroglobulin
- Absence of T3 and T4 leads to feedback enhancement of TSH secretion by the anterior pituitary gland = growth of glandular tissue = goitre
How does and increased Plasma Iodide affect the regulation of T3 and T4?
When plasma Iodide is x100 normal, most activity decreases
Short term - only lasts a few weeks;
- iodide trapping rate is reduced
- iodination of tyrosine to form T3 and T4 also decreased
- Endocytosis of colloid from follicles stops
- rapid shutdown of T3 and T4 secretion into the blood
- Gland size and blood supply decreases
- We administer iodides for 2-3 weeks before surgical removal of the thyroid gland to decrease the amount of surgery and bleeding
