07-11-23 - The thyroid gland: control of secretion, effects of the thyroid hormones Flashcards
Learning outcomes
- Describe the role of the hypothalamus/pituitary axis in the control of release of T3 and T4 from the thyroid gland
- Describe the synthesis and storage of the thyroid hormones as part of the protein thyroglobulin and explain the mechanisms operating to control T3 and T4 release
- List the major physiological functions of the thyroid hormones
- List the main clinical causes and features of hyperthyroidism and hypothyroidism
- Describe the mechanisms of action of the thyroid hormones
What is the thyroid gland (TG)? What does it consist of?
Where is it located?
What major hormone does the TG secrete?
What is thyroid secretion controlled by?
Where is thyrobulin secretes into?
What is the role of the TG?
- The thyroid gland (TG) is one of the largest endocrine glands (normally 15 to 20 g in adults)
- The TG is bilobular
- It is located immediately below the larynx on each side of and anterior to the trachea
- The TG secretes two major metabolic hormones: thyroxine (T4) and triiodothyronine (T3)
- The thyroid gland also secretes calcitonin, a hormone involved in calcium metabolism
- Thyroid secretion is controlled primarily by thyroid- stimulating hormone (TSH) secreted by the anterior pituitary gland
- Thyroglobulin is secreted into the follicular sacs within the gland
- Unusually, TG both produces and stores hormones
How many closed follicles does the TG have?
What is the role of Cuboidal epithelial cells?
What is the main component of thyroglobulin?
What needs to happen before thyroid hormones can function in the body?
What is the role of C-cells?
- TG has many closed follicles (100-300 microns in diameter)
- Cuboidal epithelial cells secrete colloid into follicles
- Main component of colloid is thyroglobulin, which contains the thyroid hormones
- Secretions must be reabsorbed through epithelial cells and enter into bloodstream before it can function in body (blood flow 5xweight of the gland/minute)
- C cells secrete calcitonin (role in calcium regulation – especially in other mammals)
What % of TG hormones are T3 and T4?
What happens to almost all T4 in issues?
How potent is T3 compared to T4?
How does this affect its quantity and length of activity?
What is the role of T4 and T3?
How does lack of thyroid secretion / excess thyroids secretion affect metabolic rate?
- Approximately 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 the tissues
- T3 is approximately four 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
- Lack of thyroid secretion usually causes basal metabolic rate to fall 40% to 50% below normal,
- Excesses of thyroid secretion can increase the basal metabolic rate to 60% to 100% above normal
What is needed to form thyroxine?
How much iodine is needed a year?
What is done to prevent iodine deficiencies?
Where is iodide sequestered?
Where is excess excreted from?
- Iodine is required to form thyroxine
- Require approximately 50mg/year (about 1mg/week)
- Table salt is iodised to prevent deficiencies
- Iodine is sequestered by TG, excess usually excreted by kidneys
Iodide trapping (in the TG).
Where is iodine concentrated?
What is the first stage of thyroid hormone formation?
How does this occur?
What is the iodide concentration in a TG cell compared to the plasma?
What controls the rate of the movement of iodide in TG cells?
- Iodide trapping (in the TG)
- Iodine is concentrated within the TG cells
- First stage of thyroid hormone formation – transport of iodine from blood to thyroid gland cells and follicles
- Basolateral membrane of thyroid cell actively pumps iodide into the cells via sodium-iodide symporter (NIS) (2Na+:1 iodide) (using energy from the sodium pump)
- Iodide is then transported through apical membrane into follicle by “pendrin” – chloride-iodide antiporter, and becomes Iodine in the process
- Iodide is concentrated in TG cells (30x higher than plasma)
- Concentration can increase to 250x plasma
- Rate of this process controlled mostly by TSH (thyroid stimulating hormone)
What is thyroglobulin?
What is its MW?
Where is it synthesised and secreted?
What is it made from?
What forms T3 and 74?
Where does this occur?
Where is T3 and T4 stored?
- Thyroglobulin is a large glycoprotein molecule
- It has a MW of 335,000
- It is synthesised and secreted into follicles by ER and Golgi apparatus
- Thyroglobulin contains approximately 70 tyrosine amino acids
- Tyrosine + iodine forms T3 and T4 in the thyroglobulin
- T3 and T4 also stored as part of thyroglobulin
How is iodine formed?
What can iodine then combine with?
What does blockage of this system lead to?
- Enzyme peroxidase, located in or attached to apical membrane, is used to produce peroxide and this oxidises the iodide ions to iodine
- Iodine can then combine with tyrosine to form T3 and T4
- Blockage or absence of peroxidase system stops formation of thyroid hormones
Organification of thyroglobulin.
When does the binding of the oxidised iodine to thyroglobulin?
What is oxidised iodine associated with in thyroid cells?
What is the role of thyroid peroxidase in this process?
- Organification of thyroglobulin
- The binding of the oxidised iodine to thyroglobulin will occur spontaneously but slowly
- In thyroid cells, oxidised iodine is associated with thyroid peroxidase
- Thyroid peroxidase speeds up this reaction and iodine binds to tyrosine almost as soon as they come into contact with the thyroglobulin
Formation of T3 and T4 continued – iodination and coupling.
What is tyrosine iodised to?
What reactions occur over the next few minutes/hours/days?
What are the major products from these reactions?
- Formation of T3 and T4 continued – iodination and coupling
- Tyrosine is iodized to monoiodotyrosine and then to diiodotyrosine
- Over the next few minutes/hours/days, mono and/or diiodotyrosine residues become coupled with one another
- Products from these reactions:
1) Major product is thyroxine (T4) = 2x diiodotyrosine
2) Approx 1/15th of product is trioiodothyranine (T3) = mono+diodo tyrosine
3) Small amount of reverse T3 = diodo +monoiodo tyrosine (not important physiologically?)
Iodination and coupling diagram (in picture)
How many T3 and T4 molecules are stored in thyroglobulin after synthesis/coupling has finished?
Where is thyroglobulin stored?
How long does this supply last?
How can this be problematic in terms of pathophysiology/deficiency?
- When synthesis/coupling has finished, each thyroglobulin molecule contains up to 30 T4s and a few T3s
- Thyroglobulin stored in follicles until needed
- Supply lasts for 2-3 months
- Deficiency/pathophysiology of process may be undetected for a few months
How are T3 and T4 released?
How is colloid brough into TG cells?
What happens to these vesicles?
- T3 and T4 cleaved from thyroglobulin
- T3 and T4 then released as free hormones
- Colloid (containing thyroglobulin with its T3 and T4) brought into cell at the apex by pincocytosis
- Pinocytotic vesicles in the thyroid cell fuse with lysosomes which contain digestive enzymes –e.g., proteases
What is the action of proteases in TG cells?
Where do free T3 and T4 go?
What proportion of T4 and T3 is there?
How is this different from hormones delivered to tissues?
- Proteases digest thyroglobulin and release T3 and T4
- T3 and T4 diffuse through basolateral membrane into capillaries and bloodstream
- Approximately 93% thyroxine (T4), 7% T3 initially
- Approximately half of T4 is de-iodinated to T3 over next few days
- Most of the hormone delivered to the tissues is T3
Release diagram (in picture)
Describe the onset and duration of action of T4 and T3.
What is the latency period of these hormones due to?
- Onset and duration of action of T4 and T3
1) T4
* 2- or 3-day latent period
* Increase in activity over about 10-12 days
* Diminishes over several weeks/months (half life approx. 15 days
2) T3
* T3 more rapid response – latent period of 6 to 12 hours, max activity in 2-3 day
- The latency period of these hormones is due to binding to proteins but also due to how T3 and T4 mediate reactions downstream
Transcription of genes due to thyroid hormones.
How do T4 and T3 enter cells?
What happens to most of the T4?
How do these hormones affect transcription?
What does this generated?
What do thyroid hormones act on?
- Transcription of genes due to thyroid hormones
- T4 and T3 enter the cell membrane by carrier-mediated active transport
- Most T4 is deiodinated to form T3
- T3 interacts with the thyroid hormone receptor
- This leads to increases or decreases in transcription of genes that lead to the formation of proteins
- These proteins lead to a thyroid hormone response of the cell being generated
- Thyroid hormones act on many cells/systems
Major physiological effects of the thyroid hormones.
What do thyroid hormones cause the mobilisation of?
- Major physiological effects of the thyroid hormones
- Thyroid hormones cause the mobilisation of carbohydrates, fat, and protein stores via direct and indirect actions (in picture)
How do thyroid hormones affect metabolic processes?
How are these affected in increased and decreased secretion?
- Thyroid hormones lead to a general increase in metabolic processes – increased Basal Metabolic Rate (BMR)
- Increased secretion – weight loss,
- Decreased secretion – weight gain
Major effects of thyroid hormones, and effects of hypo and hypersecretion (in picture):
1) BMR/temp regulation
2) Carb/lipid/protein metabolism
3) Nervous system
4) CVS
5) Muscular system
6) Skeletal system
7) GI
8) Reproductive system
9) Integumentary system (body’s outer layer – skin, hair, nails, glands)
Why is precise physiological regulation of T3 and T4 secretion required? What is TSH?
What is the role of TSH?
What is the stimulatory effect of TSH mediated by?
What controls anterior pituitary secretion of TSH?
Describe the mechanism behind TRH binding and release of TSH?
How does cold affect TRH and TSH levels?
How is T3 and T4 secretion regulated?
- Precise physiological regulation of T3 and T4 secretion is required as there is narrow homeostatic range required to maintain appropriate metabolism
- TSH (thyrotropin) an anterior pituitary hormone increases T3 and T4 secretion (and all known secretions from TG)
- The stimulatory effect of TSH is mediated by cAMP as a second messenger
- Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, thyrotropin releasing hormone (TRH)
- Mechanism of TSH binding and TSH release:
1) TRH binds TRH receptors in the pituitary cell membrane.
2) This binding activates the phospholipase second messenger system inside the pituitary cells to produce large amounts of phospholipase C then secondary messenger cascade leading to TRH release
- Cold causes excitation of the hypothalamic centres for body temperature increasing TRH and TSH
- Regulation of T3 and T4 secretion is by negative feedback from T3 and T4
