THE ENDOCRINE SYSTEM
Endocrine System
• The endocrine system is a series of glands that release a hormone into the plasma,
where it is dissolved and transported throughout entire body within 60 seconds.
Every cell is exposed to the hormone, but not every cell responds to it. The cell must
have a functional hormone receptor. A cell that responds will do so in various ways. The
cells in the heart, pancreas, and brain respond to epinephrine differently. One thing that
always happens is that a cell will change its physiology in response to a hormone.
Hormones
• Hormones can be synergistic; aldosterone and antidiuretic hormone (ADH) both help
increase volume of fluid in body. Some hormones are antagonists; Atrial natriuretic
peptide (ANP, produced by heart cells) is the opposite of ADH, and makes you urinate
more. Some hormones are permissive; you need one around in order for a second to do
its job well. Thyroid hormone is permissive for growth hormone. Not enough thyroid
hormone can cause stunted growth, even if enough growth hormone is present.
• Basic hormone action
• Made by the gland’s cells, possibly stored, then released
• Circulate throughout the body vasculature, fluids
• Influences only specific tissues: target cells that have a receptor for that particular
hormone
• A hormone can have different effects on different target cells: depends on the
receptor
• Some hormones are “permissive” for the actions of another (T3 for GH)
Ultimate goal: alter cell activity by altering protein activity in the target cell.
Target Cell
• A target cell is only a target cell if it is has a functional receptor (a protein) for the
hormone. At home, you may watch TV with either a cable or satellite dish. Satellite
waves are exposed to those homes with cable, but only those with dishes receive the
signal. The target cell’s receptor serves to convert the signal into a response.
• Receptors are proteins, which can be inside the cell or on its membrane. What would
happen if there were a gene defect in the DNA code for a receptor? The receptor becomes
faulty. The receptor will also not function properly if the cell is exposed to excess salt,
heat, or pH.
What is a “receptor”?
• It is a protein made by the target cell (protein synthesis after gene expression)
• The protein is made, then inserted into plasma membrane, or found in cytoplasm or
nucleoplasm
• The active site on the protein “fits” the hormone
• Acts to convert the signal into a response
• What would happen if there were a gene defect in the DNA code for a receptor?
• What would happen if the receptor protein was denatured?
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What happens to hormones?
• Endocrine glands secrete hormones into the plasma. Then, several different events could
occur.
• It could bind to its receptor on the target cell, causing a change.
• Or, it could be destroyed by enzymes in the plasma.
• It could land in the kidneys and be filtered out before reaching its target.
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Neuronal Trigger
• The hormone is made in a neuron, is transported down the axon and stored in the synaptic
knob.
• It is released from there into the bloodstream, where it is carried to the target cell.
• Examples are oxytocin, ADH, Epinephrine.
Humoral Trigger
• Something in the blood is being monitored. When the level of that substance is too high
or low, it stimulates the release of the hormone.
• Examples are insulin, glucagon, parathyroid hormone.
• When you eat, glucose gets high, releases insulin, which tells cells to take in the sugar.
Excess sugar is then converted to glucagon, which is the storage form.
• When glucose is low, glucagon is broken back down to glucose and released into the
blood.
• When blood calcium is low, parathyroid gland hormone tells the intestinal cells to absorb
more calcium, and kidneys to reabsorb more ca, and stimulates osteoclasts to degrade
bone matrix so calcium goes into blood.
Hormonal Trigger
• A hormonal trigger is when one endocrine gland releases a hormone that stimulates
another endocrine gland to release its hormone.
Role of Hypothalamus
• The hypothalamus is like a mom, her small child is like the pituitary gland, her older
child doing homework is like the thyroid gland. None can move, only their messengers
can take their message from one to the other. Mom sends the young child to tell the older
one to get his homework done. She hears the young child passing the message, but after a
while, the homework is not presented to her, so tension builds up in her, and she sends
the messages more loudly until she is presented with the finished homework.
• This is what happens in the body.
• Hypothalamus makes TSH-RH (thyroid stimulating hormone releasing hormone)
• Pituitary makes TSH (thyroid stimulating hormone)
• Thyroid gland makes TH (thyroid hormone)
Thyroid Hormone
• The hypothalamus releases its hormone (TSH-RH) to the pituitary, telling the pituitary to
release its hormone (TSH), which tells the thyroid gland to release thyroid hormone
(TH).
• When thyroid hormone is released, it will circulate throughout the body, causing an
increase in metabolism in all of those cells. Some of the TH will bind to receptors in the
hypothalamus, and then the hypothalamus knows there is enough TH, and it will stop
releasing TSH-RH. Until the receptors in the hypothalamus are bound with the resulting
thyroid hormone, the hypothalamus is not satisfied that there is enough thyroid hormone
present.
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Hypothalamic Control of Hormone Secretion from the Adenohypophysis
• Hypothalamus regulates secretion of hormones
• Almost always controlled by negative feedback loops
– Blood concentration declines below a minimum
• More hormone is secreted
– Blood concentration exceeds maximum
• Hormone production is halted
• Secreted like neurotransmitters from axon terminals
– Secretes releasing factors to release hormones
– Can also secrete inhibiting hormones to turn off secretion of hormones
What if the hypothalamus released its signal and the thyroid released too much hormone?
• The hypothalamus will stop releasing its hormone. This is a negative feedback signal.
• When very few TH receptors are bound on the hypothalamus, it will keep releasing its
hormone. When its thyroid receptors are saturated, will stop.
Thyroid Hormone Effects
• All cells respond to thyroid hormone, increasing their metabolic rate (heart speeds up,
beats with greater force, more nutrients are used, etc). Too much thyroid hormone is
hyperthyroidism; these people are thin and active. When levels of TH are too low, it is
called hypothyroidism; these people are overweight, move slowly, have no energy.
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Thyroid Hormone
• How many controls are there over the thyroid? Three: TH, TSH, TRH.
• Thyroid hormone goes to all cells of the body, including the thyroid gland itself, as well
as the pituitary and the hypothalamus.
• As it does so, the receptors are bound, inhibiting the release of more hormones.
• The last hormone released is the one with the most significant role in feedback. In
this case, the last hormone released is thyroid hormone. Therefore, the presence of
thyroid hormone is what will stop the hypothalamus from wanting more.
• This is negative feedback, which is what most hormones have.
One Positive Feedback Hormone
• The one hormone that uses positive feedback is luteinizing hormone (LH).
• When LH is released, it stimulates the release of more LH, and more LH, until it reaches
a maximum level, then negative feedback kicks in.
What if a gland disobeys the negative feedback?
Example: Thyroid gland is impaired by a tumor.
• A thyroid tumor might cause it to over-secrete or under-secrete TH.
• Under-secreting thyroid tumor: what happens to the other hormone levels? Start with
the problem area (in this case, the thyroid is the place with the tumor), and then evaluate
the other glands. (Start with the problem area, the thyroid gland)
– TH will be low (hypothyroidism)
– TSH-RH will be high, since only a few hypothalamus receptors are bound
– TSH levels will be high.
• Over-secreting thyroid tumor:
– TH will be high (hyperthyroidism)
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–
–
TSH-RH will be low
TSH levels will be low. This combination tells you the source of the problem is
the thyroid.
Another Example: Pituitary tumor
• Under-secreting pituitary tumor (Start with the problem area, the pituitary)
– TSH is low
– TH is low (hypothyroidism)
– TSH-RH is high
• Over-secreting pituitary tumor
– TSH is high
– TH is high (hyperthyroidism)
– TSH-RH is low
•
NOTE: If the problem is the TSH, we don’t bother injecting TSH, we just give the
hormone that is lacking: Thyroid hormone.
Another Example: Hypothalamic Tumor
• Under-secreting hypothalmic tumor (Start with the problem area, the hypothalamus)
– TSH-RH is low
– TSH is low
– TH is low (hypothyroidism)
• Over-secreting hypothalamic tumor
– TSH-RH is high
– TSH is high
– TH is high (hyperthyroidism)
Other Hormone Cycles
• The adrenal cortex has the same cycle as thyroid hormone; it needs ACTH-RH
(adrenalcorticotropic releasing hormone), ACTH, CH.
• You always palpate the thyroid during a physical exam. If it is too large, it is called a
goiter. But you cannot just look at it and say its hyperthyroidism; it might be not be
hypothyroidism. You have to measure the hormone levels.
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Thyroid Gland
• The functional unit of the thyroid gland is the thyroid follicle. The cells making up
the perimeter of the follicle are called follicular cells. They make and secrete the light
purple liquid within the follicle, called colloid. Colloid is water, filled with a lot of
protein called thyroglobulin, which is made by the follicular cells. Since thyroglobulin is
a protein, there is a gene that codes for it. TSH is what stimulates the follicular cells to
make thyroglobulin. TSH also increases the size of the follicular cells to accommodate
all this protein.
Thyroglobin
• When thyroglobulin is made, it is exocytosed from the follicular cell and stored outside
of the cell, in the follicle. As it moves across the cell membrane, a peroxidase enzyme
attaches iodine to the tyrosine (amino acid) portion of the thyroglobulin. This process is
iodination. After TSH stimulation, the follicular cells drink it back into the cell, and
another enzyme comes along and chops up the long thyroglobulin protein into smaller
pieces, each with some iodine on them.
• If a segment has two iodines, it is called T2. If there are 3 iodines attached, it is called T3
(Triiodothyronine). If it has 4 iodines it is T4 (thyroxine). The T3 and T4 are then
released into the bloodstream. Those thyroglobulin segments that have only 1-2 iodines
are recycled for parts and are not released.
• T4 is the most abundant form, but it is inert (inactive). T3 has robust activity in the
cell. So, T3 gets used first by the body cells. T4 takes longer to be ready; one iodine has
to drop off. As T3 is used up, T4 is being converted to more T3.
• To make thyroid hormone, you need iodine in your body. Iodized salt has enough to meet
this need. Iodine is brought into the follicular cells, gene expression occurs, thyroglobulin
is made. Without enough iodine in the diet, thyroid hormone cannot be made, no matter
how much TSH is present.
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Thyroid Gland
• Thyroid follicles- hollow structures surrounded by follicular and parafollicular cells
• Follicular cells produce Thyroglobulin (TG)
• Building block of TH, chemically attaching I- to tyrosine.
• In plasma, TH needs a “carrier molecule” or it will be cleared from body
Thyroid Hormone Synthesis & Secretion
• Link two tyrosine aa’s together and add iodine
• Thyroid hormone (TH) controls metabolic rate and protein synthesis
– Thyroxine – T4 : (93%)
– T3: triiodothyronine (7%); 4x as potent
• Active form
•
•
•
TG is booted out of the cell (exocytosis) and stored inside the hollow chamber of the
follicle. “Colloid”
When follicular cells receive signal to secrete (TSH), they take up TG (endocytosis),
cleave off the TH from TG, and secrete it into blood (exocytosis.)
PTU blocks the peroxidase process.
What are the “actions” of TH?
• Increases GI motility
• Increases mental activity
• Increases endocrine activity
• Promotes growth and brain development in fetal life, and early postnatal life.
• Stimulates fat metabolism, lipid mobilization from fat stores
• Excites CNS
• Causes sleep difficulty
Hormone Levels
• Know what would happen to the three hormone levels (TSH, TSH-RH, TH) in the
following conditions:
• Antibodies attacking thyroid gland, destroying the gland
• Antibodies binding to the TSH receptor, stimulating it
• Graves’ Disease
• Hashimoto’s Thyroiditis
TS Ratio
• The TS ratio is the amount of iodine in thyroid /iodine in serum.
• There are 30x more iodine ions in the thyroid gland than in the plasma.
• ATP is used to bring iodine into cells against its electrical gradient.
Goiter
• If someone has excess TSH, thyroid will get larger, called a goiter.
• You can have a goiter with decreased TH also. The cause of this is PTU (propyltriouracil), which inhibits TH production by blocking the peroxidase enzyme that joins the
iodine to the tyrosine. It results in low thyroid hormone levels, and a goiter develops.
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Release of TSH
• What happens when TSH is released? Every step in the process of making TH is
increased: Follicular cells become larger, more columnar. Metabolism increases: increase
in O2 use (especially in mitochondria), a large sodium gradient is outside, and a large K
gradient is inside, requires ATP to keep them from diffusing across their concentration
gradients; this process generates heat. The gene is activated for the NA-K pump. There
are sympathetic (beta) receptors in the heart that become stimulated. The heart increases
in force of contraction and rate.
Effects of Thyroid Hormone
• TH also stimulates neurons; the person feels more alert, observing their environment with
more interest. With not enough TH, they lose interest, become sluggish. When there is
too much TH, they get muscles tremors, liver cleaves stored glycogen to increase blood
glucose levels, gluconeogenesis increases in the liver (generation of glucose from storage
forms, which keeps blood glucose levels from dropping too low, called hypoglycemia),
and body cells grow. Remember, you need TH present for GH to work. TH is also
important for brain development in fetal life.
•
We can measure hormones in the blood by radioimmunoassay (RIA) or ELISA (enzymelinked immunosorbent assay).
Diagnosing the etiology (cause) of hypo/hyperthyroidism
• Methods of measuring plasma concentration of hormones:
– RIA (radioimmunoassay)
– ELISA (enzyme-linked immunosorbent assay)
• Sample a small amount of patient’s blood; sent to lab
• Concentration is determined, recorded as picomolar concentration
RIA
•
In a dish are antibodies against a hormone we want to measure. Before adding blood, add
the hormone with a radioactive tag that can be recognized by those antibodies. It forms a
complex; wash away the unreacted hormone. Then measure the radioactivity that is given
off, this is the saturation point (the starting point). Now add the patient’s blood sample. If
it has a lot of the hormone that is already attached, it will compete to push off the
radioactive hormone, and the radioactive signal will drop proportionally. If the patient
does not have much hormone, there is not much decrease in radioactivity. This is an
inverse relationship. The RIA test is expensive and dangerous, so ELISA is preferred.
ELISA
• Pregnancy test is an example of an ELISA test.
• On the strip are antibodies. If pregnant, a hormone binds to the receptor. When the strip
gets wet, a second set of antibodies move over the pregnancy hormone. The substrate,
when cleaved, precipitates out of solution; it gives you a color, and a new line appears,
turning the negative into a plus sign. If no hormone is present, there is no second set of
antibodies, the enzyme is not cleaved, no color change.
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•
Is she a little or a lot pregnant? Well, there is no in-between, so is this test not considered
quantitative? Actually, it can be quantitative: Suppose she had sex only a few hours ago.
The test would be negative, since it takes 7 days for zygote to implant into uterus, which
is when hormone levels are high enough for detection. If she is 6 months pregnant, the
response time is faster. Since the response time is faster in the presence of higher
hormone levels, we can quantify the pregnancy also. The parasite chomping into uterine
artery can cause bleeding, seems like a period. She may be shocked to find out she’s
pregnant.
Hyperthyroidism (Most commonly caused by Graves Disease)
• Signs include thinness, eyes that stick out like a bug (exophthalmoses).
• Graves Disease is a person who has antibodies against TSI. These antibodies bind to
thyroid gland, tricks it into making excess TH, while TSH-RH and TSH levels are
decreased. You can also get hyperthyroidism from over-secreting tumors.
There are two ways to treat this disease
• You can have the thyroid oblated (killed off) by drinking radioactive iodine; it kills just
thyroid tissue. As metabolic rate slows, gains weight again. They set off Geiger counters
for months afterwards. Then start on artificial thyroxin, need to figure out what their set
point is for normal.
•
The other way (not so good) is to have the thyroid gland surgically removed. However,
the parathyroid glands are often damaged or removed during this surgery. They often
intentionally leave some thyroid tissue behind, in hopes of leaving enough parathyroid
glands there. If too many of the parathyroid glands are removed, calcium levels go down,
can go into cardiac arrest. Now the patient has to have two hormones replaced.
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Hypothyroidism
This can be caused by
• Hashimoto’s thyroiditis
• Iodide deficiency
• Tumor
• Defective enzyme in thyroid.
Know the difference between cretinism and congenital hypothyroidism.
Disorders of Thyroid
• Hypothyroidism
– Hashimoto’s thyroiditis
– Iodide deficiency
– Tumor (undersecreting)
– Defective thyroid (enzyme problem)
• Draw the disrupted pathway!
• Goiter?
• Thyromegaly-TSH stimulation leads to increased number and size of thyroid cells
• Cretinism- mental defects due to maternal deficiency
• Myxedema
• Hashimoto’s and idiopathic hypothyroidism are similar in symptoms
Cretinism (diminished mental ability)
• This term describes babies whose MOTHER had the lack of iodine. Baby now cannot get
iodine, and the baby will have reduced growth and intellectual ability. Once it is born and
gets a healthy diet, it still won’t go back to normal because TH is necessary for proper
myelination and synaptic formation.
Congenital Hypothyroidism
• Congenital hypothyroidism is the term for a baby whose thyroid gland is not working
correctly, the problem is only with baby, not with the mom. Congenital hypothyroidism
and cretin babies have similar symptoms. Child will stay tiny because GH does not work
without TH.
Hashimoto’s thyroiditis
• Hashimoto’s thyroiditis is an autoimmune disorder, where antibodies attack and destroy
the thyroid gland, and TH goes down while TSH-RH and TSH are elevated. The
healthy remaining thyroid tissue will enlarge.
• Myxedema is non-pitting edema. Touch it, feels solid, and does not leave a fingerprint
when you push on it. People with Hashimoto’s thyroiditis have depressed mental and
emotional activity, may have psychosis, not in touch with reality, detached. They gain
weight easily, are tired and sleep a lot.
Iodine deficiency
• Iodine deficiency has decreased TH, other hormones increased.
Other things that cause hypothyroidism are defects in any parts of the gene expression of
thyroglobulin in follicular cells; TH not released in proper amounts.
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Adrenal glands
• They are neuronal and hormonal, like the pituitary.
• Both adrenal medulla glands together weigh only one gram! The adrenal medulla is an
extension of the nervous system. If the chromatin cells there are detached, they will
differentiate into a neuron! The adrenal cortex suppresses the full development of the
nervous system development of the adrenal medulla. The adrenal glands release
catecholamines, such as norepinephrine, and especially epinephrine. These
catecholamines are released when the sympathetic nervous system is activated (“fight or
flight”).
Epinephrine is antagonistic to insulin
• When you run from a predator, is that when you want insulin to take glucose from blood?
No, you want to keep it there so the brain can get the glucose. The brain needs to think of
a way to escape, and thinking burns glucose. Fatty acids are broken down as another
source of ATP. Heart rate and force increases. Digestion slows, respiratory passages
open, bronchiole dilation occurs. BP goes up from vasoconstriction in less needed organs.
Adrenal Cortex layers
• The bulk of the adrenal gland is the adrenal cortex. It has layers, from superficial to
deep: “GFR”
• G = Zona glomerulosa: makes aldosterone
• F = Zona fasciculate: makes androgens and glucocorticoids (cortisol and
corticosteroids)
• R = Zona reticularis: makes androgens and glucocorticoids (cortisol and
corticosteroids)
• (Don’t confuse this pneumonic with GFR in the kidney, which stands for glomerular
filtration rate)
The Adrenal Glands
• Located on the superior surface of the kidneys
• Two endocrine glands in one (different embryological origin)
– Adrenal medulla – a knot of sympathetic nervous tissue
• Chromaffin cells – modified postganglionic sympathetic neurons
• Secrete epinephrine (mostly).
• Active in “fight, flight, and fright” response
• Glycogen broken down to glucose for ATP production
• Fats broken down to fatty acids for ATP production
• Heart rate and force increases
– Adrenal cortex – bulk of the adrenal gland
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The Adrenal Cortex
• Secretes a variety of hormones- all are steroids made from cholesterol and are grouped
into two main classes, plus androgens:
– Glucocorticoids
• Cortisol – secreted in response to ACTH and stimulates fat and protein
catabolism and gluconeogenesis.
– Mineralocorticoids
• Aldosterone -Sodium/water reabsorbed and loss of potassium
• Androgens- small amount but still important
Adrenal Gland Hormones
• In the Z. glomerulosa, aldosterone (a mineral corticoid) is released. It targets the cells of
kidney, increases the amount of salt and water that is reabsorbed.
• The other two zonas make glucocorticoids and androgens. Glucocorticoids are cortisol
and corticosteroids.
Androgens
• Androgens (DHEA; Dehydroepiandrosterone), is a testosterone-like steroid hormone,
but is not the primary hormone responsible for the male characteristics; testosterone from
the testes does that. However, since females do not have testes, they are sensitive to
androgens present in their body, and the androgens in females cause them to have
pubic and axillary hair. If that part of the adrenal cortex hypersecretes androgens, it
won’t impact a male, because the testes makes more than that already. However, in
females, hypersecretion causes masculinization.
Aldosterone
• The Z. Glomerulosa makes aldosteone, but it does not follow a typical HPA axis; it is a
humeral release mechanism. A few things trigger it, especially high potassium plasma
levels. That signals the kidneys to reabsorb sodium, and water comes with it. But
potassium is secreted and then excreted. Potassium is secreted by the cells of nephron,
sodium and water are regained, and that increases blood volume. A2 is angiotensin 2
(studied more in unit 4); there is a blood plasma protein called angiotensinogen. Any
word that ends in –ogen means they are zymogens, the proteins are released in an
inactive form. When activated, cascade events occur. When the kidney detects BP is too
low, it releases rennin, which cuts angiotensinogen into its active form. Here is the
process:
•
Angiotensinogen  angiotensin 1, travels through blood and ends in pulmonary capillary
bed, where cells have angiotensin converting enzyme, cuts A1 into A2, stimulates adrenal
cortex to make more aldosterone, and hypothalamus to release ADH. If BP drops, this
cascades into events that lead to water and salt retention, blood volume and BP goes up.
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Prednisone,
cortisone, and
aldosterone are all
similar in structure.
One can be used to
make the others.
Mechanisms
• ACTH is released by pituitary.
• ACTH is required for adrenal to release CTH, corticotropic hormone. Need ACTH to get
the cholesterol to be processed into aldosterone. But if you raise ACTH, you do not get a
matching increase in aldosterone; it goes up, but not proportionally. Aldosterone is a
humeral mechanism.
• CRH is released by the hypothalamus, pituitary releases ACTH, adrenal cortex releases
corticoids, effects almost all cells in body.
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Glucocorticoids
• Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid
receptor (GR), which is present in almost every vertebrate animal cell. The name
glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the
metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure.
They suppress the immune system (they are anti-inflammatory).
• Cortisol (hydrocortisone) and aldosterone are two of the most important glucocorticoids.
• Others are prednisone, prednisoline, dexamethasone, and triamcinolone, which are also
commonly used medicines for anti-inflammation.
Increase in glucocorticoids causes things:
• Cortisol is called a stress hormone; it does several things:
• Cortisol stimulates protein and triglyceride catabolism
• Stimulates gluconeogenesis in the liver
• Inhibits glucose uptake by the body but not the brain
• It elevates blood glucose (diabetogenic effect)
• It inhibits non essential functions like reproduction and growth
• It suppresses the immune response, Inhibition of inflammation also
• It is prescribed to suppress inflammation and the immune system.
Metabolic Effects of Cortisol
• Stimulates protein and triglyceride catabolism
• Stimulates “gluconeogenesis” in liver
• Inhibition of glucose uptake by body (insulin antagonism) but not by brain. Elevates
blood glucose levels, “diabetogenic effect.” Nervous system becomes primary user of
glucose during stress.
• Inhibition of non-essential functions (reproduction; growth)
• Cortisol tames immune response
• Inhibition of inflammation and immune responses (pharmacologic doses used to suppress
immune system.)
Genetic Influence
• The gene code you got from parents is different from theirs, but not a lot. But the
expression of your genes can be very different because of how they lived their life. How
much activity, smoking, and weight gain has gone on before puberty will damage stem
cells, and can silence or activate a gene. The children of these people can have genetic
differences because of this.
Physical Abuse causes loss of adaptability to stress
• Children exposed to severe physical abuse are more likely to commit suicide later; their
DNA is methylated, causing a reduced number of glucocorticoid receptors. They cannot
bind cortisol, cannot deal with stress like other people. If you don’t eat a lot, your
children and grandchildren will live 30 years longer, and live healthier lives.
Cortisol
• Cortisol (also known as corticosterol and also known as hydrocortisone)
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•
•
•
The hypothalamus releases ACTH-RH, pituitary releases ACTH, adrenal gland releases
cortisol. The adrenal gland also can release androgens.
When there is an intense need to make cortisol in response to stress, and if the body
cannot keep up with the demand for cortisol, excess ACTH might be shunted into
the androgen production pathway, so that androgens are secreted instead of
cortisol. Excess androgens do not affect males, but females might develop more
masculine features.
What is “stress” that causes cortisol production? Stress can be emotional or physical.
Examples of physical stress can range from fighting an infection to just a little paper cut
that needs to remodel tissue. Cortisol tells tissues to stop using glucose (except brain), but
will mobilize fatty acids to release energy for the other tissues. It tells the skeletal muscle
to start breaking down actin, myosin, and other proteins to release the free amino acids
into bloodstream. The liver takes in these free amino acids and fatty acids and converts
them into new glucose molecules that you did not acquire from your food. Since these are
new glucose molecules being formed, this process is called gluconeogenisis (“generation
of new glucose”). The new glucose molecules are released back into the blood (blood
glucose levels rise) so the other tissues can have some energy.
Prednisone
• If a person has a lot of cortisol or prednisone in their body, blood sugar levels rise too
much, and sugar spills out in the urine. They have symptoms of diabetes, although that is
not their disease. You have some cortisol in you now to help maintain normally
elevated blood glucose levels between meals, and glucocorticoids stimulate smooth
muscle in the vasculature to maintain BP.
• In high doses only, prednisone may be given for asthma because it suppresses
smooth muscle from constricting, and bronchioles cannot close up. What would you
predict their hormone levels to be?
• Makes you hungry to be on this med (prednisone), hard time sleeping because brain is
stimulated. If you abruptly stop taking prednisone, the person gets the same symptoms as
Addison’s disease. Can’t maintain BP, blood glucose drops, can go to hospital. A person
on high dose for 1 or more weeks must be tapered off.
• There are two ways to use prednisone: high dose, short duration (okay to stop cold
turkey)
• Lower dose, longer duration (need to wean off).
Adrenal Gland Deficiencies
• Primary Adrenal Insufficiency: Addison’s Disease
– primary hypoadrenalism; entire adrenal gland is destroyed due to atrophy or
autoimmune disorder
– Tuberculosis –disease attacks adrenal gland
– ACTH is increased (map the pathway!)
• Secondary adrenal insufficiency
– deficiency of ACTH
– Rapid withdrawal of pharmacologic doses of cortisol
• Signs/symptoms: Water/salt imbalance, plasma volume depletion, low blood glucose,
pigmentation, Addisonian crisis
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ADDISON’S DISEASE
• Also called Primary Adrenal Insufficiency and hypoadrenalism; mainly see effects in
the hands, fingers, and gums. Addison’s disease may be caused by anything that disturbs
the production of adrenal hormones (for some reason, Tuberculosis attacks the adrenal
glands as well as the lungs, and can cause hypoadrenalism). In Addison’s disease, the
adrenal cortex does not respond to HPA orders. Cortisol (CTH) levels are low, but
pituitary ACTH and hypothalamus ACTH-RH hormones are high.
ACTH
• ACTH is a peptide (protein) hormone, synthesized from a larger protein called POM-C
(Pro-opiomelanocortin). From the large POM-C protein, you cut out one segment, called
ACTH, and another segment called MSH (melanocyte simulating hormone). When the
ACTH levels increase but you still need more, PROM-C cleavage continues to occur, and
more MSH is generated at the same time. When MSH is in excess, you get darker skin
(hyperpigmentation).
Addison’s Disease
• Symptoms of Addison’s disease are decreased glucose levels, a drop in blood
pressure from water and salt imbalance, and darkening of the skin. Aldosterone is
also not being made, so kidneys cannot absorb salt and water as well, blood volume and
pressure decreases even more.
Secondary Adrenal Insufficiency
• In Secondary Adrenal Insufficiency, the problem is in pituitary; it is not secreting
enough ACTH, maybe because of a tumor. Cortisol levels drop, but hypothamus ACTHRH increases. A person can also get secondary hypoadrenalism from rapid withdrawal of
cortisol meds. Symptoms are the same as for primary adrenal insufficiency, except blood
tests show that pituitary ACTH levels are low, adrenal hormones are low, and
hypothalamus ACTH-RH is high.
CUSHING’S DISEASE
• Excess ACTH caused only by a pituitary tumor. Patient has excess cortisone, high
blood pressure, high blood glucose, and too much aldosterone is produced. More salt
and water is reabsorbed by the kidney, so the blood volume increases. In this disorder, the
hypothalamus (ACTH-RH) levels are low, the other hormone levels (ACTH,
cortisol, androgens, and aldosterone) are high.
CUSHING’S SYNDROME (Andrenogenital Syndrome)
• Excess cortisol secretion, but not caused by the pituitary gland. It could be caused by
primary hyperadrenalism, an adrenal tumor, or even by a tumor in the lungs that releases
ACTH (ectopic ACTH producing tumor). In this disease, all adrenal cortical hormones
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(cortisol, androgens, and aldosterone) are elevated, but ACTH-RH and ACTH levels
are low.
Symptoms of Cushing’s Disease and Cushing’s Syndrome
• Fat deposition around waist, scapula (buffalo hump), and “moon” shaped face. There is
muscle loss and weakness (cortisol tells muscles to break down), thin skin with striae,
(High levels of cortisol leads to destruction of collagen, get thin and striae on skin),
hyperglycemia, immune suppression. Excessive amounts of adrenal stimulation causes
release of male steroids, causing male secondary characteristics, but only in females.
Adult onset disease in females causes masculinization, including facial hair, thicker
jaw and skull.
Excessive Adrenal Hormones
 Cushing’s Disease- pituitary tumor (excess ACTCH)
 Cushing’s Syndrome
• Ectopic ACTH producing tumor (lungs) Glucocorticoid therapy
• Iatrogenic
• Primary hyperadrenalism -Functioning adrenal tumor-, all adrenocortical
hormones elevated; adrenogenital syndrome
 Signs/symptoms: buffalo hump, moon face, muscle loss/weakness, thin skin with striae,
hyperglycemia, immune suppression
Congenital adrenal hyperplasia
• Congenital adrenal hyperplasia (CAH) in a female fetus causes the clitoris to enlarge
and the labia major fuse into a scrotal sac. These babies have a mutation in a gene, some
enzyme is not expressed which is required to convert cholesterol into corticosteroids, so
cholesterol is shunted to the pathway that is not compromised: androgen production.
Boys are not affected; girls need a surgery and cortisol for life, will be fine. The most
common gene mutation is 21 beta or 11 beta hydroxylase to covert progesterone to
corticosterone. If the presence of ACTH is driving the pathway, and it is blocked at this
enzyme, the ACTH can only be used to make androgens.
CAH- Excessive and Deficient?
• Congenital Adrenal Hyperplasia (CAH)
– Autosomal recessive trait (congenital)
– Deficiency of any of the five enzymes necessary for cortisol production.
– Increased ACTH (leads to adrenal hyperplasia) MAP IT!
– Leads to overstimulation of adrenal androgen pathways.
– Mineralcorticoids may be excessive or deficient (depends on enzyme affected).
– Males seldom diagnosed at birth, females have virilization (enlarged clitoris,
fused labia, etc).
– With treatment, surgery, sex characteristics and fertility is normal
STUDY TIP
• What hormones are antagonistic to insulin?
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–
–
–
GH
Cortisol
Epinephrine
GROWTH HORMONE (SOMATOTROPIN)
• GH needs TH to be present. GH stimulates all cells to increase protein synthesis, fat
utilization, and gluconeogenisis, but there is a decline in body usage of glucose as energy.
The person is diabetogenic, gigantism is the result of excess GH during pre-puberty and
acromegaly is the result of excess GH after growth plates closed. The genetic
determination of a person’s height has multiple genes involved, so parents might be tall
and have smaller children. There are no rules to predict it. A child may also be small due
to a defect in the placenta, blocking nutrients during development.
GROWTH HORMONE (SOMATOTROPIN)
• Increased protein synthesis
• Increased fat utilization
• Increased gluconeogenesis but decline in body usage of glucose as energy
• Diabetogenic
• Excess leads to gigantism during prepuberty and acromegaly after growth plates are
closed
PARATHYROID GLANDS
• There are several of these glands, embedded in the thyroid gland on the posterior surface.
The parathyroid glands are the ones that are the most responsible for maintaining blood
calcium levels. They accomplish this by releasing parathyroid hormone, which
stimulates osteoclasts to chew away bone, releasing the bone’s calcium into the
bloodstream. The antagonist of parathyroid hormone is calcitonin, which is produced
in the thyroid gland, and stimulates osteoblasts to take calcium from the blood and
deposit it in bone. Parathyroid levels are released by a humeral mechanism. If blood
calcium levels are low, parathyroid hormone is released. If blood calcium levels are
high, parathyroid levels are low.
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•
•
•
There are three ways that the parathyroid gland raises blood calcium levels
Stimulates osteoclasts to move bone calcium into the bloodstream
Stimulates the intestines to absorb more calcium from diet
Stimulates the kidneys to stop excreting calcium
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