T or F. Almost all hormonal output of the thyroid gland is T3
F. It is T4, although T3 is much more active at target tissues
Describe the polarity of thyroid epithelial cells
These cells have a basal membrane facing the blood and an apical membrane facing the follicular lumen, which is composed mostly of colloid
What is colloid?
mostly newly synthesized thyroid hormones attached to thyroglobulin
How is thyroglobulin synthesized?
This is a glycoprotein, composed mostly of tyrosine, that is synthesized on the rough ER and the Golgi of the follicular cells and is then packaged into secretory vesicles (with thyroid peroxidase lining the inside) to be extruded across the apical membrane in the colloid-filled lumen to later have its tyrosine resides iodinated to form the precursors of thyroid hormones
How does iodide enter thyroid follicular cells?
the "I-trap" or 2Na+/I- cotransporter actively transports iodine from the basolateral side of the follicular cells against both electrical and chemical gradients and a 3Na/2K+ ATPase on the basolateral side maintains the gradient
NOTE: Iodide is passively taken up in the gut (about 80% of what we ingest)
What are some competitive inhibitors of the Na+/I- cotransporter?
thiocyanate (byproduct of tobacco smoke)
perchlorate (an industrial chemical)
What happens to I- once it enters the follicular cell?
It traverses to the apical membrane where it is oxidized to I2 by thyroid peroxidase
What can inhibit thyroid peroxidase?
propylthiouracial (PTU) (inhibits 5'-deionidase also)
Methimazole (inhibits thyroid peroxidase only)
What happens to I2?
It is ejected into colloid using a Cl- dependent channel called pendrin. At the apical membrane, just inside the follicular lumen, I2 combines with the tyrosine moieties of thyroglobulin (catalyzed by thyroid peroxidase) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)
What happens to MIT and DIT?
They remain attached to thyroglobulin in the follicular lumen until the thyroid gland is stimulated to secrete its hormones
What is the Wolff-Chaikoff effect?
High levels of serum I- inhibit organification (ie. formation of MIT and DIT)
What is the 'coupling' effect?
While still part of thyroglobulin, two seperate coupling rxns occur between MIT and DIT, again catalyzed by thyroid peroxidase. In one rxn, two molecules of DIT combine to form T4 or one molecule of MIT can combine with DIT to form T3
Why is more T4 produced than T3?
Because the DIT-DIT coupling rxn is much faster
What happens to the iodinated thyroglobulin with T4, T3, and leftover DIT and MIT?
It is stored in the follicular luman as colloid until the thyroid gland is stimulated to secrete its hormones
What happens when the thyroid gland is stimulated by TSH?
iodinated thyroglobulin is endocytosed into the follicular epithelial cells and transported to the basal membrane by microtubular action where T4 and T3 (and leftover DIT/MIT) are hydrolyzed from thyroglobulin by lysosomal enzymes and then transported across the basal membrane into nearby capillaries
What happens to the DIT and MIT that is left behind in the cell?
They are deionated by the enzyme thyroid deiodinase and the liberated I- is added to the intracellular pool to be used in the next cycle of hormone production.
What happens to T4 and T3 once they enter the bloodstream?
They circulate mostly bound to thyroxine-binding globulin (TBG), with smaller amounts bound to T4-binding prealbumin and albumin, and very little in free form.
NOTE: Because only the unbound thyroid hormones are physiologically active, the role of TBG is to provide a large reservoir of ciculating thyroid hormones, which can be released and added to the pool
What are the half-lives of the thyroid hormones? Why are they different?
T4- up to 8 days
T3- 24 hrs
The difference is due to the fact that T4 binds more avidly to TBG, and thus is protected
What conditions might produce an increase in TBG? What is the effect?
Situations like pregnancy tend to increase TBG (due to high levels of estrogen preventing hepatic breakdown) which has the effect of decreasing the amount of free (and active) thyroid hormones
NOTE: The transiently low free levels of thyroid hormones stimulates increased synthesis and secretion of additional thyroid hormones, so during pregnancy the overall picture is one of increased total T4 and T3 but decreased levels of free, physiologically active, thyroid hormone
What conditions might produce an decrease in TBG? What is the effect?
hepatic failure prevents TBG production and thus there are increased levels of free thyroid hormones
While T4 is the major secretory product from the thyroid, it is typically converted to T3, the more active form. How?
5' deiodinase catalyzes this conversion by removing one atom of I2 at the target tissue (the I2 is removed from the outer ring here)
NOTE: T4 can also be converted to reverse T3 (which is inactive) (the I2 is removed from the inner ring here) using 5-deiodinase
How is 5' iodinase involved during fasting states?
starvation inhibits 5' iodinase in tissues such as skeletal muscle, thus lowering O2 consumption (via less thyroid hormone production). Thus, T4 is mostly converted to rT3 instead of active T3.
NOTE: brain 5'-iodinase is not affected by fasting
There are two types of 5'-iodinase. Where is Type I active?
liver, kidney, and thyroid
There are two types of 5'-iodinase. Where is Type II active?
Pituitary, CNS, and placenta
NOTE: 5-iodinase is active in all tissue
Normally conversion of T4 to T3 and rT3 are in a ratio of approximately 45:55% respectively. What situations can increase the amount of rT3 made?
pregnancy, fasting, stress, hepatic and renal failure, and BBs can all do this
Normally conversion of T4 to T3 and rT3 are in a ratio of approximately 45:55% respectively. What situations can decrease the amount of rT3 made?
Obesity increases the amount of T3 made
How does T3 act at the target tissue?
It enters the nucleus via a Na+-dependent transporter and binds to a nuclear receptor. The T3-receptor complex then binds to a thyroid-regualtory element (TRE) on DNA, where it stimulates DNA transcription
What are the effects of thyroid binding?
Increase in BMR (via increased O2 consumption/upregulation of NaKATPase),
lipid (resulting in lowered serum cholesterol) and protein metabolism (resulting in muscle wasting),
increased gluconeogenesis and glycogenolysis (energy sources)
How does thyroid hormone affect the heart?
Myosin, B1-adrenergic receptors, and Ca+ ATPase are produced leading to increases in heart rate AND contractility. This is because increased O2 consumption caused by thyroid action must be met with increased O2 delivery to organs
How does thryoid hormone induce increase oxygen consumption? Are any organs spared from this effect?
They increase Na/K ATPase production resulting in increased O2 consumption and thus increased BMR in all organs except the brain, gonads, and spleen
Ultimately increased oxygen consumption depends on increased availability of substrates for oxidative metabolism. How are substrates liberated in these states?
Thyroid hormone increases glucose absorption from the GI and increases the effects of other hormones that liberate fat and proteins
NOTE: While thyroid hormones both increase protein production AND increases degradation, their net effect is degradation, which results in muscle wasting
How do thyroid hormones affect growth?
They act synergistically with growth hormone and somatomedins to promote bone formation and ossification.
How does thyroid hormone affect perinatal development?
it is essential for normal CNS maturation. Hypothyroidism during this period can lead to severe, irreversible mental retardation and thus should be screened for
How is synthesis of TSH regulated?
Thyrotropin-releasing hormone (TRH) is secreted by the paraventricular nuclei of the hypothalamus and acts on the thyrotrophs of the anterior pituitary to cause synthesis AND secretion of TSH
NOTE: TRH also stimulates secretion of prolactin by the anterior pituitary
When does TSH (and thyroid hormones) begin to be produced during gestation?
What else influences secretion of TSH?
While TRH from the hypothalamus induces TSH secretion, TSH production is also influenced by the serum levels of thyroid hormones which work by negative feedback. Thus, high levels of T3 inhibits formation of more TSH
How does TSH act on the thyroid gland?
When TSH binds to a membrane receptor coupled to adenylyl cyclase via a Gs protein, cAMP is activated which increases hormone synthesis (basically all steps are amplified) and causes follicular cell hypertrophy
How else can the Gs-dependent TSH receptor on the thyroid gland be stimulated?
IgG class thyroid-stimulating immunoglobulins (Abs). This is the basis of Graves disease
NOTE: In graves disease, circulating TSH levels are actually lower than normal due to negative feedback on the abnormally high levels of thyroid hormone
How would levels of TRH, TSH, and T4/T3 be affected by primary hypothyroidism (i.e. a defect at the level of T4/T3 production?
TRH and TSH- High (due to low negative feedback from T4/T3)
How would levels of TRH, TSH, and T4/T3 be affected by primary hyperthyroidism (i.e. an overproduction at the level of T4/T3 production?
TSH and TRH- Low
How would levels of TRH, TSH, and T4/T3 be affected by secondary hypothyroidism (i.e. a defect at the level of TSH production)?
TSH and T4/T3- Low
How would levels of TRH, TSH, and T4/T3 be affected by secondary hyperthyroidism (i.e. an overproduction at the level of TSH production)?
TSH and T4/T3- High
What are the effects of reduced iodine intake during development?
cretinism/dwarfism are possible, characterized by profound mental retardation, short stature, and delayed motor development
NOTE: Tx with a few days of birth restores normal growth BUT if treated after this time cannot restore mental development