thyroid hormone regulation Flashcards
What are the names of the thyroid hormones
3, 5, 3’, 5’ tetraiodothyronine is the hormone T4, also known as thyroxine. 3, 5, 3’ triiodothyronine is the hormone T3
blood supply to thyroid
superior thyroid artery (from the external carotid) and the inferior thyroid artery (from the thyrocervical trunk of the subclavian artery)
Structure of thyroid
Functional unit is the follicle, consisting of a layer of cells surrounding a lumen filled with a substance known as colloid. Thyroglobulin (TG) is the primary constituent of colloid. Blood vessels flow between the follicles. The parafollicular cells (C cells) are also found in between the follicles; these secrete calcitonin
Describe the uptake of iodide from plasma by the thyroid gland.
Iodide in the blood is transported into the thyroid by the iodide trap mechanism. A pump on the basal side of the follicular cell promotes accumulation of iodide 30-40 times that in the serum. This is against its electrical and chemical gradient.
Competitive inhibitor of iodide uptake by thyroid
Anions such as perchlorate (CLO4) are transported in the same mechanism as iodide so they inhibit iodide uptake
What happens to iodide after uptake by thyroid
Once inside the follicular cell, iodide diffuses from the basolateral (closest to the blood) to the apical (closest to follicular lumen) side then exits the follicular cell into the colloid, moving with its electrical and chemical gradient. Iodide must then be oxidized
Where does organification of iodide occur
(incorporation of iodide into tyrosyl residues on thyroglobulin) occurs at the follicular cell-colloid interface
Explain the synthesis and release of thyroglobulin into the lumen of the thyroid follicle.
TG is synthesized on the rough endoplasmic reticulum within the follicular cell and transported to the Golgi apparatus, where it is glycosylated and packaged into secretory vesicles. The secretory vesicles are released from the apical side of the follicular cell into the lumen and thus TG enters the colloid.
Identify the steps in thyroid hormone synthesis
Thyroperoxidase catalyzes iodination of tyrosyl moieties on TG forming mono- and diiodotyrosine > 2DITs or 1 DIT + 1 MIT couple to form iodothyronines (catalyzed by thyroperoxidase) >
compounds that inhibit iodination
thiourea drugs (e.g., propylthiouracil-PTU, and methimazole) aka goitrogens. decrease TH synthesis and secretion, ultimately leading to elevated levels of TSH and hypertrophy of the gland (goiter)
Identify the steps in thyroid hormone secretion
Endocytosis of TG from colloid lumen into follicular cells > lysosomal enzymes cleave T4 an T3 from TG > Release of T4 and T3 from thyroid.
Which thyroid hormone is produced in excess relative to the other one
Under normal conditions, the amount of T4 removed from TG is in excess (~20X) of the amount of T3 removed and thus released.
Thyroid hormone transport
Most TH in blood is protein bound (99.97%)
Thyroid binding proteins
thyroid binding globulin (TBG), thyroid binding pre-albumin (TBPA) and albumin
Half lives of T3 and T4
The half-lives of T4 and T3 are 7 days and 1 day, respectively b/c 10X more T4 is protein bound. TBG has a higher affinity for T4, thus T3 has a more rapid onset of action and shorter half life.
Which TH is the active form and how does it work on cells
T3, b/c the affinity of the TH receptor is 10 fold greater for T3 than for T4. T3 and T4 enter cells by active transport, then T4 is converted to T3 by 5-deiodinase. T3 enters nucleus, interacts with nuclear receptors and directs trxn of mRNA
List the actions of thyroid hormone
- Regulator of metablic rate. 2. fetal/neonatal brain development. 3. normal growth. 4. Enhance response to catecholamines. 5. metabolism
How does TH regulate metabolic rate
In absence of TH, basal metabolic rate decreases dramatically. This action of TH is calorigenic/ heat producing. The calorigenic effect is due to Na pumping and increased O2 consumption.
Which tissues are NOT affected by TH calorigenic effect
spleen, brain, testis
How does TH regulate fetal/neonatal brain development
They regulate proliferation, differentiation, myelinogenesis, neurite outgrowth, and synapse formation. Thus congenital hypothyroidism can lead to severe and irreversible mental retardation
TH and growth
Children with low TH levels can show severely stunted growth. This is due to the many developmental effects of TH. In addition when TH levels are low, growth hormone levels also decline
TH and catecholamine response
Thyroid hormones enhance the response to catecholamines and thus mimic the effects of sympathetic nervous system activation. There is evidence suggesting that the number of b-adrenergic receptors increases in response to a hyperthyroid status
TH and metabolism
low to moderate doses of TH tend to be anabolic, while high doses are catabolic. High TH lead to increased fuel consumption, protein breakdown and muscle wasting. Also lipolysis. Low to moderate TH promotes conversion of glucose to glycogen, and high doses enhance glycogenolysis
How does TSH regulate TH release
TSH is released from thyrotrophs in the anterior pituitary, then carried to thyroid gland where it stimulates the iodide pump, thyroperoxidase and endocytosis of colloid. TSH also increases iodide organification, coupling of iodotyrosines, TG synthesis and proteolysis. TSH causes proliferation of follicular cells and compensatory changes in colloid.
Iodide regulation of TH release
Iodide deficiency leads to decreased TH synthesis. High iodide in short term also causes decreased TH release (Wolff-Chaikoff effect) due to decreased incorporation of iodide into TG and diminished response to TSH.
Drugs/compounds that can inhibit TH synthesis/release
perchlorate and thiocyanate (found in cabbages and cassava) can inhibit iodide uptake from the blood. Additionally drugs like thioureas, propylthiouracil and methimazole can block the activity of TPO and thus the incorporation of iodide to form TH
Regulation of the hypothalamic-pituitary-thyroid axis
High T3 and T4 reduce the response of the anterior pituitary to TRH.
