Lecture 23 Flashcards
(22 cards)
Thyroid hormones T3 and T4 are able to inhibit the hypothalamus and the anterior pituitary from secreting further thyroid releasing hormone and thyroid stimulating hormone after T3 and T4 get released from the thyroid and elicit responses around the body. What else is responsible for inhibiting the production of thyroid stimulating hormone in the anterior pituitary?
On top of thyroid hormones T3 and T4 inhibiting the secretion of both TRH and TSH from the hypothalamus and that anterior pituitary. Somatostatin (somatotrophin release inhibiting factor) and dopamine will inhibit the production of TSH from the anterior pituitary from thyrotropes.
What pathway enables thyrotropes to be able to produce thyroid stimulating hormone in response to thyrotropin releasing hormone (TRH?)
When TRH is secreted from the hypothalamus, TRH will bind to TRH receptors (GPCR) present on thyrotropes present in the anterior pituitary, such that this leads to the activation of Galpha-q such that phospholipase C becomes activated.
As a result of phospholipase C becoming activated, this leads to the breakdown of phosphatidyl inositol 4, 5-bisphosphate (PIP2) into IP3 and DAG. IP3 is able to bind to IP3 gated calcium channels on the smooth ER, allowing for an increase in intracellular calcium.
DAG and Ca++ will bind to protein kinase C (PKC), activating it. This will allow PKC to be able to activate transcription factors which will go into the nucleus, bind to specific response elements, and increase transcription of specific precursors for TSH.
The mRNA for TSH will get translated into preTSH, and through multiple steps, it will be converted into mature TSH where it will get packed into vesicles, where it can remain in secretory vesicles, waiting to be secreted.
In response to increases in intracellular calcium, this will lead to secretion of the TSH such that the TSH will enter the blood to go to the thyroid to stimulate production of the thyroglobulin/thyroid hormones.
What pathway in the thyrotropes allows for regulation of thyroid stimulating hormone?
After TSH is produced, it will travel through the bloodstream and bind to receptors which are present on the thyroid follicular cells, leading to an increase in production of the thyroglobulin.
When T3 and T4 are sent into the blood, they go everywhere in the body, as well as to the thyrotropes of thyroid stimulating hormone.
T3 will arrive at the anterior pituitary and enter the thyrotropes. T4 is able to enter these thyrotropes as well but it must be deiodinated to T3.
Inside the cell, T3 will bind to the thyroid hormone receptor in the nucleus and act like an inhibitor for the synthesis of thyrotropin releasing hormone receptor (downregulation of transcription of mRNA.) This means that the amount of TRH receptors will decrease on the cell surface, thereby decreasing the TRH response.
The thyroid hormone receptor will also inhibit the mRNA of TSH from being synthesized.
Every aspect of thyroid gland metabolism is affected by what? What happens as a result of this immediately? What about intermediately? What about in cases of chronic stimulation?
It’s affected by thyroid stimulating hormone stimulation.
TSH stimulation immediately: increase in cAMP, colloid endocytosis and increase in T3 and T4 secretion
Intermediate TSH stimulation: increase in RNA synthesis, increase in iodide uptake and protein synthesis/translation
Chronic stimulation: increase in DNA content and mitotic activity. This will increase the size and cell amount in the thyroid. Chronic stimulation causes changes in the hormones and protein synthesis and it will physically cause the mitotic activity to increase and cause a growth in the thyroid.
Is the thyroid gland able to regulate output of thyroid hormone? How does this occur?
It can autoregulate thyroid hormone output.
The thyroid gland is able to regulate its output of thyroid hormone in cases when you consume large amounts of iodide. (leads to decrease in thyroid hormone secretion.)
When there is excess iodine present in the thyroid, this will downregulate the production of sodium/iodide symporters such that this will lead to a decrease in iodide uptake by the thyroid, helping to decrease the production and secretion of T3 and T4.
This is a protective mechanism to prevent the development of hyperthyroidism as a result of excess dietary iodine and allows for excess iodine that you do have in your body to be filtered out.
How does T3 exert its effects in target tissues?
T3 is responsible for transcription regulation.
Thyroid hormone receptor is dimerized to retinoic X receptor (RXR) in the nucleus and will be bound to some DNA region known as thyroid hormone response elements. When thyroid hormone is not bound, thyroid hormone receptor will be bound to a corepressor, thus preventing transcription from occurring. Only when T3 binds to these thyroid hormone receptors is the corepressor able to be removed from the receptor/DNA complex, such that this will lead to an increase in transcriptional activity of the thyroid hormone response element. Inhibition can also occur in the case that corepressors bind to the thyroid hormone receptor when T3 binds, inhibiting transcription.
When T3 binds to the thyroid hormone receptor and allows for activation of transcription of specific genes, what biological responses occur?
The increase in heat will lead to an increase in BMR, the increase in ATP will allow for more ATP to be present such that it can be broken down by the ATPases which have been increased in production and more heat can be produced. This is why people with an overactive thyroid will have overactive catabolic pathways and have excess energy burned.
What is hypothyroidism? What is hyperthyroidism? How does hyperthyroidism affect oxygen consumption? What about hypothyroidism?
Hypothyroidism: lower than normal levels of thyroxine (T4). Increased levels in oxygen consumption in the heart, kidneys, liver, diaphragm, pancreas. The pituitary will try to work harder to produce more TSH.
Hyperthyroidism: heightened levels of T4. Decrease in oxygen consumption & the pituitary will stop producing TSH.
On top of increasing heat production, what other biological actions does T3 mediate?
1) Protein synthesis: leads to changes in expression of specific proteins. There will be an increase in general protein synthesis and catabolism. (the effects of catabolism are more sustained) There will be a slight increase in specific protein synthesis, but the increase in protein degradation can put you at a negative nitrogen balance.
2) Nervous system/brain: leads to the growth and development of the nervous system and causes increased sensitivity to neurotransmitters which can cause pretty profound behavioral effects
3) General metabolism: leads to general metabolic effects through interactions with other hormones like insulin and glucagon. T3 affects all aspects of intermediary metabolism.
When T4 enters in fetal circulation from the mothers circulation, it will end up being converted into T3 to be used for specific processes in neurodevelopment. What T3 dependent processes in neurodevelopment occur throughout pregnancy, and when does the fetus/child begin relying on its own supply of T4?
- neuron proliferation and migration
- development of the cochlea
- formation of the neocortex and striatum
- formation and development of the cerebellum
- axon and dendrite growth with myelination
- synapse formation
After the child is born, they will begin relying on their own bodies production of T4 to aid in neurodevelopment.
Why is it that much younger children have much higher levels of thyroid hormone than adults do? What would deficiencies of T4/T3 do with regards to neurodevelopment during pregnancy?
Young children are still growing and T4/T3 is super important for growth and development so they need much higher levels.
If there are deficiencies in thyroid hormones during pregnancy, this could lead to serious neural defects. (Having deficiencies towards the early stages of pregnancy would result in more neuronal defects than towards birth.
What are the clinical features of hyperthyroidism?
- Skin: warm, moist/sweaty bc of higher metabolic rate
- cardiovascular system: high heart rate
- GI system/appetite and weight: increase in appetite, decrease in weight and increase in GI motility
- Nervous system: increased muscle twitching, irritability, insomnia, and easily altered mood
- muscles: weakness
What are the clinical features of hypothyroidism?
- skin: colder and dry, edema/myxedema (swelling)
- cardiovascular system: lower heart rate
- GI system/appetite and weight: decrease in appetite and increase in weight gain
- nervous system: intellectual disabilities, slower reflexes, memory loss, and lethargy
- muscles: weakness
What diseases can lead to the formation of hyperthyroidism? How does it begin?
1) Tumors: if they occur in the thyroid, they can lead to excess T3 and T4 release. If these tumors occur in the anterior pituitary, they can lead to excess thyroid stimulating hormone production. If it’s an ectopic tumor, this can lead to an increase in TSH or T3/T4 production.
2) Graves Disease: autoimmune disorder that leads to the release of thyroid stimulating immunoglobulins. Antibodies against the thyroid stimulating hormone receptor which will stimulate the thyroid. These will end up mimicking thyroid stimulating hormone but not have the same feedback inhibition of the hypothalamus and the anterior pituitary that TSH has. These thyroid stimulating antibodies will end up stimulating the TSH receptor in your thyroid, causing the increase in release of thyroid hormones T3 and T4. Overstimulation of the thyroid can lead to increase in growth of the thyroid (formation of a goiter)
Explain the characteristics of Graves’ Disease and how does it occur?
AKA Toxic diffuse goiter. It likely begins as a result of genetic and environmental factors. This is the most common cause of hyperthyroidism and often results in an enlarged thyroid as a result of increased proliferation of the thyroid cells.
Characteristics: insomnia, hyperactivity, sweating, heat intolerance, weight loss, heart issues, exophthalmos, infrequent menstrual periods, and personality changes
What condition can occur with the eyes for individuals with Graves’ Disease? How does it occur?
Exophthalmos - bulging of the eyes from the eye socket.
The reason is that fibroblasts and adipocytes behind the eye express the thyroid stimulating hormone receptor. When the thyroid stimulating antibodies stimulate the TSH receptor, this can lead to excess inflammation in the tissue behind the eye, leading to excess fluid accumulation. This leads to excess pressure buildup behind the eyes, pushing the eyeballs out. Eventually, the muscles behind the eyes are going to become irreversibly fibrotic, which will cause damage and hardening of the muscles, making this bulging a permanent problem.
What treatment exist for hyperthyroidism?
1) Methimazole: prevents iodide oxidation to iodine radical, preventing iodotyrosine formation
2) Propylthiouracil: inhibitor of thyroid peroxidase function - prevents formation of the thyroid hormone from iodotyrosines
3) Thiocyanate and perchlorate: inhibitors of the iodide uptake and prevents iodine accumulation, preventing iodotyrosine and iodothyronine formation
4) ablation: done through surgery and the use of radioactive iodide. All of which lower production of thyroid hormone. If surgical means are taken and all of the thyroid is removed, then we have to supplement with thyroid hormone.
What are the causes of hypothyroidism?
1) Loss of thyroid tissue:
- iodiopathic (spontaneously): due to inflammation, an autoimmune response, or dysgenesis
- iatrogenic (caused by treatment): surgery or radioactive iodine
2) Hypothalamic/pituitary problems: issues with release of TRH and TSH from hypothalamus and anterior pituitary, causing issues with T3 and T4 release
3) Inherited defects: anything that causes issues with iodide uptake, iodination, or coupling of iodotyrosines to form the iodothyronines. can also be something that cause issues with deiodination of T4 to T3 or issues with T3 receptor
4) Dietary iodide insufficiency: not getting enough iodide can lead to formation of endemic goiters/cretinism
5) Hashimoto’s disease (chronic immune thyroiditis): autoimmune disorder that leads to the production of antibodies against specific proteins/antigens in the thyroid. Inflammation in the thyroid leads to lymphocyte infiltration into the thyroid, causing destruction of the thyroid. TSH concentrations in the body will increase, leading to a diffuse goiter.
What is cretinism? What are the characteristics? How does it occur?
It’s a condition of severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormone, usually due to maternal hypothyroidism. It can be a result of not enough iodine in the region, uptake issues, or spontaneous mutations.
Leads to short adult statue, neurological impairment, reduced muscle tone and coordination.
Where does the issue of cretinism occur most?
Cretinism occurs most in less developed countries (limited access to iodine)
This condition can be screened for after birth. If doctors find any issues with T3 or T4, babies will end up with thyroxine as a supplement for the rest of their lives.
What is myxedematous cretinism and how does it occur?
It’s a result from iodine deficiency and hypothyroidism in the fetus during late pregnancy or in the neonatal period. This ends up resulting in intellectual disability, short stature, goiter, swelling/edema, and hypothyroidism.
What causes Hashimoto’s disease (chronic immune thyroiditis) and how can it be treated?
It’s caused by an autoimmune disease which leads to the production of specific antibodies which target proteins in the thyroid. It leads to inflammatory response in the thyroid, leading to immune system response in the thyroid and leading to the destruction of the thyroid tissue.
As a result, this significantly decreases the amount of T3 and T4 to be produced, preventing T4/T3 from acting as a negative feedback inhibitor for the release of TRH and TSH from the hypothalamus and the anterior pituitary.
Because of this, TSH concentrations will increase, which will end up causing rapid proliferation of the thyroid tissue, leading to the formation of a diffuse goiter. (can be treated through thyroxin supplementation)
