UAMS Biochemistry exam 3 endocrinology

Endocrine system

composed of glands that produce hormones that are secreted directly into the bloodstream for use through out the body

Hormone

Chemical substance that sends a message to another cell in the body.

These can either regulate or control another bodily function.

Endocrine

sent via the bloodstream

Exocrine

sent via the GI tract

neurocrine

sent neurologically

Paracrine

Sent in interstitial fluids

Hormone classification

based on:

• chemical structure

• mechanism of action

• stimulation of endocrine glands

• effect of hormone

What structural categories of hormones are hydrophilic?

Think proteins:

Amines.

peptides.

proteins.

This means they have shorter half-lives and are water-soluble.

What structural categories of hormones are hydrophobic?

Lipids.

They have longer half-lives and can have their effect on the body longer.

What amino acids make amine hormones?

Tryptophan (ex: melatonin).

Tyrosine (ex: epinephrine).

These get modified into amine hormones

What are the amine hormones?

Epinephrine.

Norepinephrine.

triiodothyronine.

Thyroxine.

Serotonin.

Urinary 5-hydroxyindoleacetic acid.

These have the shortest halflives

What are Peptide hormones made of and how do they work?

Chains of amino acids, generally <50.

They are hydrophilic, meaning they can’t cross cellular membranes easily.

They have to bind to a membrane bound receptor first. Once this is activated, they will initiate the cascade of intracellular signals to get the response.

What are the Protein hormones made of?

Chains of amino acids, primarily from residues in any length of more than 50 amino acids.

These will still have the primary, secondary and tertiary structures in them too.

What are Glycoprotein hormones made of?

Derived from a lipid, generally cholesterol.

They have similar half-life and solubility as Protein hormones.

What are Steroid hormones made of?

Derived from a lipid, generally cholesterol.

They are hydrophobic and must be transported in the blood bound to carrier proteins.

The difference in this and proteins, is that Steroids can cross the membrane easily because of the lipid content.

Where do Steroid hormones act in a cell?

The nucleus.

They bind to nuclear receptors in order to modify transcription and translation of genes.

This means it’s a little delayed due to genes needing to be produced to have the effect.

What are the Fatty acid hormones made of?

Made of small fatty acids from arachidonic acid.

They degrade rapidly and are only effective in the body for a few minutes.

What are trophic hormones?

they stimulate the target tissue to grow or increase in size or number.

What is the first Zonal layer and what does it do?

Zona glomerulosa (G-zone).

These cells make up the outer 10%.

Synthesize aldosterone.

What is the second zonal layer and what does it do?

Zona Fasciculata (F-zone), middle layer.

Synthesize glucocorticoids.

Cortisol, corticosterone, 11-deoxycorticosterone.

What is the third zonal layer and what does it do?

Zona reticularis (R-zone), inner layer.

Secrete sex steroids: Androgens

• Dehydroepiandrosterone (DHEA)

• Dehydroepiandrosterone-sulfate (DHEA-S).

• Androstenedione.

What is metabolism?

The sum of chemical processes that occur within a living organism to maintain life and includes catabolism and anabolism.

What does the speed that hormones are created or broken down determine?

The extent that they are capable of binding to receptors and doing their job.

Ex: the concentrations of protein bound hormones will be affected by the number of proteins available.

How does alcohol decrease hormones (through increased protein catabolism or decreased production)?

Alcohol consumption will decrease testosterone levels.

But if cirrhosis is present, the liver is unable to produce any proteins and when there are less proteins, there are less hormones.

How does the Adrenal steroid hormone synthesis affect hormones?

Many hormones are made in the adrenal gland through a cascade of enzymatic reactions.

When these enzymes are off, so is the hormone production.

What are the 2 organs for hormone elimination?

Kidney and liver.

The liver inspects the blood as it passes through and “tags” certain ones for destruction.

How are Steroid hormones removed?

By inactivating the metabolic pathways and excreted in bile or urine.

How are Thyroid hormones removed?

Inactivated by intracellular deiodinases.

How are Catecholamines removed?

They are rapidly degraded within circulation.

How are fatty acid hormones removed?

These are rapidly inactivated by metabolism, though they are only active for a few seconds when they are active.

Why is it important to categorize hormones as water soluble or not?

When a hormone is water soluble, it travels easier through the body.

When they are free floating, this means they can be metabolized by any enzymes/substances that can do permanent damage to it.

Why are carrier proteins important in the body?

They help the hydrophobic hormones (fatty acids, fat soluble) get around the body.

With the carrier protein attached, it is guided to where it needs to be safely and no enzymes can act on it or chemical reactions happen.

The protein also increases the solubility and allows them to travel better.

Ex:

• albumin

• coticosteroid-binding globulin

• sex hormone-binding globulin

• thyroid binding

Binding globulin is kinda telltale of the action.

What is a Micelle/micelles?

A little aggregate made of amphipathic and lipid particles.

The hydrophobic parts will be on the inside, while the hydrophilic parts are on the outside.

These are formed when hormones and other lipid soluble thing travel in the blood/aqueous environments.

What is the most common feedback loop in the body?

The negative feedback loop

What is a negative feedback loop?

A loop that will turn itself off essentially. The product made will stop the call for it.

Kinda like how when you’re hungry, you eat. And when you’re full, you stop. The food fulfilled the hunger.

Ex:

The hypothalamus is monitoring the blood and sees that more thyroid hormone is needed. So, it will release thyrotropin-releasing hormone (TRH).

This will stimulate the Anterior pituitary gland to secrete Thyroid stimulating hormone (TSH).

The TSH will then stimulate the Thyroid to make more T3 and T4.

The T3/T4 will the inhibit the Anterior pituitary to not make any more TSH, and the Hypothalamus from making TRH. Thus, shutting itself off.

What is a positive feedback loop?

The more that’s made, the more it makes until something outside of it stops it.

2 types in the body: blood coagulation is one example, and giving birth is another.

When there is pressure on the cervix from a baby, the nerves stimulate the hypothalamus to produce oxytocin.

When the oxytocin reaches the nerve cells in the cervix, they strengthen the contractions and pushes against the cervix.

Thos pushes in turn will stimulate the hypothalamus more and more and the oxytocin strengthens the contractions more and more.

This continues until the baby is born and the pressure stops stimulating the hypothalamus.

Why do positive feedback loops need an outside stopper?

An outside stopper is a counter regulatory mechanism to be ready in case the cycle gets out of control.

This happens pretty easily since the more made stimulates more to be made, and can easily make too much by itself.

How are endocrine gland disorders categorized?

By the organ of function.

What is a disorder that affects the regulating gland called?

The secondary or tertiary

What is a disorder that affects the final endocrine gland called?

Primary.

What does primary, secondary, and tertiary Hypothyroidism look like in T4, TSH. TRH?

Primary: T4 decreased, TSH increased, TRH increased.

Secondary: T4 decreased, TSH decreased, TRH increased.

Tertiary: T4 decreased, TSH decreased, TRH decreased.

This is kind of backwards in a way: Primary is actually the last organ that sends out the hormone (thyroid). Secondary is the second still, it’s in the middle (anterior pituitary). And the third is actually the first organ that sends out a hormone (Hypothalamus).

Since the primary is where the final gland is messed up, the previous two are still okay and send out TRH and TSH to try and make the primary one work.

Same with Secondary, the second organ doesn’t work, so the third one is trying to send out TRH to get the cycle moving.

And then with tertiary, the third organ isn’t working, so none of them know to send out anything.

What does primary, secondary, and tertiary hyperthyroidism look like in the T4, TSH, TRH?

Primary: T4 increased, TSH decreased, TRH decreased.

Secondary: T4 increased, TSH increased, TRH decreased.

Tertiary: T4 increased, TSH increased, TRH increased.

Think of Hypothyroidism. but reverse to Increased Hormones because they can’t get the signals to turn it off.

What is the whole conversation between the hypothalamus, anterior pituitary gland, and the thyroid called?

Hypothalamus-pituitary-thyroid (HPT) axis

What factors can influence Hormone levels?

Time of day

Emotional stress

Menstrual cycle

Menopause

Food intake/Diet

Drugs

How does stress affect Hormone levels?

The purpose of the endocrine system is to help us survive the stressors placed on us.

Hormones like glucocorticoids, catecholamines, GH, prolactin, Cortisol can increase when stressed.

They might even be able to form a positive feedback loop in chronically stressed individuals.

How does the time of day affect Hormone levels?

Our circadian rhythms or diurnal variations are due to Hormones being pumped out at certain times of day, depending on the light and darkness.

How does the menstrual cycle affect Hormone levels?

Lots of hormones are made at this time.

And each phase has different hormones pumped out for different purposes.

Follicular phase: Decrease in estrogen leads to increase in FSH for blood vessels and the thickness of the endometrium.

Luteal phase: progesterone is secreted for the ovulation until 14 days after.

Ovulation: the LH starts to decline and the FSH, then the estrogen and progesterone as well.

How does menopause affect Hormone levels?

When Estrogen levels fully drop, The FSH becomes unregulated.

There is also Hormone replacement therapy for this. It’s been found that estrogen by itself is beneficial for those in menopause, and the earlier it’s started, the more effective.

For men there is testosterone therapy for hypogonadism, but still debated due to colon cancer or CHD.

How does Food intake or diet affect Hormones?

Different hormones will help us know when to eat or stop eating, others help us keep glucose levels steady, and others help make sure we’re hydrated and steady.

How do drugs affect Hormones?

Drugs either inhibit or enhance things.

If you have something that needs to be inhibited, those levels will be low.

Same with enhancing things.

Ex:

• ACE inhibitors, lower Angiotensin in kidneys for hypertension by decreasing sodium and water reabsorption.

• Methimazole cessation of Thyroid hormones by inhibiting an enzyme that deals with iodination for T3/T4.

• Psychotropic drugs, these can lead to water retention and hyponatremia.

Where is the Thyroid gland located?

At the lower anterior neck and shaped like a butterfly.

It’s made of 2 lobes resting on each side of the trachea and bridged by the isthmus and a band of tissue running anterior to the trachea.

Right behind this lies the parathyroid glands.

These become important in surgery because you can cause hypocalcemia and permanent hoarse voice.

What does the parathyroid glands control?

Serum calcium levels

Recurrent laryngeal nerves innervating the vocal cords.

How does the fetus develop the thyroid and what is the most important part of the development?

The fetal thyroid develops from an outpouching of the foregut at the base of the tongue that moves to the adult location in the first 4-8wks.

By wk 11, there’s already thyroid hormone being produced.

The most important part of a developing thyroid is having Iodine. it is essential for the growth and the thyroid in general. The mom needs to have iodine in the diet, or it can lead to hypothyroidism. And for the baby, it can lead to mental impairment and cretinism.

What is another defect that can happen to a baby?

Congenital hypothyroidism.

Happens 1 out of every 1-4k births.

While in the mother, the baby is fine because he gets the hormones from the mom. But immediately after birth, the baby needs thyroid hormone treatment or the neurological development will be significantly impaired.

What is the thyroid gland mostly made up of?

Thyroid follicles.

What is a Thyroid follicle made of?

It’s made of an outer layer of follicular endothelial cells that surround the thyroid lumen filled with colloid.

(the follicular endo cells are also called thyrocytes).

What is the colloid mostly made up of?

Thyroglobulin, it’s made by the thyrocytes and is rich in tyrosine.

A protein used to produce thyroid hormones.

What is in-between the follicular endo cells and secrete calcitonin?

parafollicular cells.

aka C cells, this secretes calcitonin for calcium regulation.

What is the primary ingredient for Thyroid hormone?

Iodine.

This a very important piece of the thyroid pizzle.

Where can you find Iodine?

Seafood

Dairy

Vitamins

Contrast media for CT scans

Amiodarone (Heart med)

Recommended amount is 150ug daily. Developed countries get a lot more than the needed amount.

At what level of iodine intake does Hypothyroidism occur?

If it dips below 50ug a day, the thyroid can no longer make adequate amounts of thyroid hormone.

How is Thyroid Hormone made?

You have the follicular cells that take iodine and tyrosine residues and then use Thyroid peroxidase (TPO) and make monoiodothyronine (MIT) and Diiodothyronine (DIT).

This is then used to make T3 and T4, which are bound together into a Thyroglobulin and stored in the thyroid lumen.

Once the thyroid gets TSH, it will take a thyroglobulin and bring it into the cells again. It is then processed by lysosomes and then released and freed into the body as T3 and T4.

What is T3?

Triiiodothyronine.

1 MIT residue and 1 DIT residue

What is T4?

Tetra-iodothyronine. aka Thyroxine.

2 DIT residues.

What does the activity of the thyroid hormone depend on?

The location and number of Iodine molecules.

How much T4 gets turned into T3?

80%.

35% is T3.

45% is reverse T3 (rT3).

How does T4 get turned into T3?

Through Outer ring deiodination.

This is 3-8x more metabolically active than T4 and is considered to be the biologically active form of thyroid hormone.

Since T3 is considered the biologically active form of Thyroid hormone, what are T4 and Thyroglobulin called?

T4 = pre-hormone

Thyroglobulin = prohormone.

What is a Prohormone?

A precursor with minimal hormone effect.

Which type of Iodothyronine 5’-deiodinase is the most abundant and found in liver and kidneys?

Type 1 Iodothyronine 5’-d.

This makes up the majority of T3.

Certain drugs used for hyperthyroidism are known to slow the ability of this.

Which type of Iodothyronine 5’-d is found in brain and pituitary and maintains steady T3 in the central nervous system?

Type 2.

It’s activity is decreased when T4 is high and increased when they are low.

What does Iodothyronine 5’-deiodinase do?

Turns T4 into T3.

This is another level of control outside of just TRH and TSH.

What is another name for TSH?

Thyrotropin.

TRH is thyrotropin releasing hormone.

How much T3 and T4 are actually unbound and usable for the body in circulation?

0.04% of T4

0.4% of T3

What are the 3 major bidning proteins?

Thyroxine binding globulin (TBG)

Thyroxine binding prealbumin (TBPA)

Albumin

What happens when these proteins are decreased or increased?

The free thyroid levels are out of whack.

Though for the most part, they’re fine.

What is the Hypothalamic-pituitary-thyroid axis?

It is the negative feedback loop to control Thyroid hormone levels.

When the hypothalamus senses low TH, it makes TRH in the neurons.

This stimulates cells of the Anterior pituitary to make TSH.

This TSH will then stimulate the thyroid to make Thyroid hormones (T3/T4).

Once the levels are corrected, the cycle stops with the hypothalamus.

This whole cylce requires each organ to work perfectly and have no interfering substances or agents that mimic TSH action.

How do T3/T4 get into cellls and what does it do there?

By being unbound and bind to cellular transporters and move across the membrane.

Once inside the cytoplasm, T4 is deiodinated into T3.

T3 will then use it’s nuclear receptor to produce RNA that will lead to production of proteins to influence metabolism and developement.

What are the available tests for Thyroid function?

Thyroid Stimulating hormone (TSH)

Thyroxine (T4)

Tri-iodothyronine (T3)

Free Thyroxine (FT4)

Free Tri-iodothyronine (FT3)

What is the most useful test for assaying thyroid function?

TSH.

It’s currently on the 3rd generation as an ultra-sensitive assay. It can detect down to 0.01 mU/L.

It’s used for moitoring/adjusting Thyroid hormone replacement therapy and screening for abnormal thyroid production.

It is also able to diagnose primary hypothyroidism

What specific lesser known disorder can the 3rd gen TSH assay detect due to it’s ultrasensitiveness?

(this isn’t in the powerpoint but is in the text book and i thought it was interesting, but do know that the 3rd gen TSH is more known for detecting Primary Hypothyroidism)

A Subclinical disease, a mild form of thyroid dsyfunction seen in the small changes of T4 that are large for the T3. (ex: A little decrease in T4 can be a big decrease in T3).

Subclinical hypothyroidism can have slightly increased TSH and normal FT4 levels.

And subclinical Hyperthyroidism has slighlty decreased TSH with normal T4.

What does Thyroid hormone control?

Tissue growth

Brain maturation

Increased energy production

Increased oxygen consumption

Increased expression of Beta-adrenergic receptors

Specific effects to organs

How are total Thyroxine (T4) levels measured?

Bychemiluminometric assay or other immunometric techniques.

Since 99% of Thyroid hormone is bound up, it’s more accurate to measure free T4.

This assay can be affected by binding protein abnormalities. If one is suspected, use dialysis to perform.

What is the reference range of TSH?

0.3-4.2 mIU/L

What is the reference range of total T4?

0.4-4.0 mIU/L

How much free T3 comes from the thyroid?

only 20%, the rest is from T4 being deiodinated into T3.

This means theres more T4 than T3 present.

While T3 is also more biologically active, it does have a shorter half-life.

What is the T3 difference between hyper/hypothyroidism and Thyrotoxicosis?

With hyper/hypothyroidism, both the T3 and T4 are affected (increased or decreased depending on which).

Thyrotoxicosis is only a decreased T3.

What is the reference range of total T3?

80-200 ng/dL.

This assay can be affected by autoantibodies to thyroid hormones and abnormal carrier protein levels.

Why is free T4 a better test than total T4?

While FT4 makes up a smaller fraction of TT4, it is the active form of T4 and can enter tissues. it also isn’t hindered by abnormal levels of carrier proteins.

it is the 2nd line test for thyroid disorders and can help nsrrow down the diagnosis with TSH.

Increased values can be hyperthyroidism or from excess TH replacement.

What is the range of FT4?

0.9-1.7 ng/dL

Why is FT3 less used than FT4?

Due to it’s low concentrations.

It’s mostly used to confirm hyperthyroidism.

Though sometimes it is used to evaluate clinically euthyroid pts who have an altered distribution of thyroid binding proteins, such as in pregnancy or dysalbuminemia.

What is the reference range for FT3?

2.8-4.4 pg/mL

Why is Thyroglobulin measured?

It is a great tumor marker and post-treatment thyroid cancer surveillance test.

this is because of how it is exclusively made in the thyroid follicular cells. When it’s in circulation, it’s proof of thyroid tissue.

Pts who have had thyroid cancer succesfully treated should have undetectable levels of Thyroglobulin.

How is Thyroglobulin measured?

By immunoenzymatic assays, ELISA and more.

The accuracy of this test depends on the specificy and no antithyroglobulin antibodies.

And since 25% of pts with thyroid cancer have antithyroglobulin antibodies, it is very important to screen for these.

Though once succesfully treated, these antibodies should disappear over time.

What is graves disease?

A autoimmune disorder that has Antibodies directed to the TSH recpetor in the thyroid. This leads to growth of the thyroid gland (aka goiter) and overproduction of thyroid hormone.

It’s the most common cause of thyrotoxicosis.

It’s measured by detecting the antibodies (TSH recpetor antibodies). It’s about 70-100% with graves.

15% are related to someone with graves, and is 5x more likely in women.

The labs will have high FT4 and no TSH.

What is the treatment for Graves disease?

Beta-blockers, proylthiouracil, methimazole.

Radioactive iodine (this might require lifelong THR).

And surgery

What are the characteristic features of Graves disease?

Goiter

Ophthalmopathy: orbital tissues swell, can cause conjuctivitis, double vision, corneal disease.

Dermopathy

What is Hashimotos thyroiditis?

aka Chronic lymphocytic thyroiditis.

Antibodies lead to destruction of the thyroid gland and lead to decreased thyroid hormone.

This is the most common cause of hypothyroidism.

The TPO antibody is measured for this, being in 80-99% of pts.

Treat with thyroid replacement therapy.

What is the Thyroglobulin (Tg) antibody?

Because thyroglogulin isn’t secreted into the blood, whenever destruction of the thyroid happens, it can cause leakage into the blood. This is were antibodies can form towards it (anti-Tg).

Mostly associated with Hashimotos (35-60%).

While in Graves, it’s 12-30%

What is the reference range for antithyroglobulin?

<4.0 IU/mL