First, it stimulates the
sodium/potassium ion pumps of the principal cells to work even harder. These
pumps drive potassium from the blood into the cells and from there it flows
down its concentration gradient into the tubule to be excreted as urine. At the
same time, the pumps drive sodium in the opposite direction from the cell into the
blood, which allows more sodium to flow from the tubule into the cell down its
concentration gradient. Since water often flows with sodium through osmosis, water also moves into the blood, increasing blood volume and
therefore blood pressure. The other function of aldosterone is to stimulate the
proton ATPase pumps in alpha-intercalated cells which cause more protons to get
excreted into the urine. Meanwhile, ion exchangers on the basal surface of the
cell move the negatively charged bicarbonate into the extracellular space,
causing an increase in pH.
The middle layer is the zona
fasciculata, and the cells there make the hormone cortisol as well as other
glucocorticoids. Cortisol is also needed in times of emotional and physical
stress like arguing with a friend or fleeing from a pack of raccoons. In those
situations, the hypothalamus—which is an almond-size structure that
sits at the base of the brain, releases corticotropin-releasing hormone is released
from and received by the pituitary gland, the pea-sized structure
sitting just underneath the hypothalamus. In response, the pituitary gland
sends out adrenocorticotropic hormone, or ACTH, which travels through
the blood to the zona fasciculata of the adrenal glands and signals cells there
to release cortisol.
Cortisol is a lipid-soluble molecule, meaning it can mingle with fats, which allows it to easily pass through the plasma membrane of cells and bind to the receptors inside. In fact, almost everybody cell has cortisol receptors, so it affects a huge variety of functions in the body! One of cortisol’s main jobs though is to increase blood glucose levels by promoting gluconeogenesis in the liver; gluconeogenesis is the formation of glucose from noncarbohydrate sources, like amino acids or free fatty acids. Cortisol also gets the muscles to break down proteins into amino acids and gets adipose tissues to break down fats into free fatty acids, both of which provide the liver with more raw materials to work with. So basically, cortisol keeps blood glucose levels high, and this is in contrast to the hormone insulin, which causes glucose to be taken up by various body tissues, so essentially cortisol acts to counteract this effect to make sure that the body can respond appropriately to those raccoons or other stressors. Finally, the innermost layer is the zona reticularis, and cells there make a group of sex hormones called androgens, including one called dehydroepiandrosterone, which is the precursor of testosterone. So the adrenal glands are involved in testosterone production in both men and women, but the amount that the adrenals contribute is pretty small, relative to the testes in men, which accounts for the very different levels of androgens in men versus women. In men, high levels of androgens are responsible for the development of male reproductive tissues and secondary sex characteristics like facial hair and a large larynx or Adam’s apple.
In women, low levels of testosterone
are responsible for a growth spurt in development, underarm and pubic hair
during puberty, and an increased sex drive in adulthood. The exact mechanism for
adrenal androgen production is not well understood, but like cortisol, it seems
to be stimulated by an adrenocorticotropic hormone released from the pituitary
gland. So, that all brings us back to primary adrenal insufficiency, which is
where the adrenal cortex gets progressively damaged over time. In developed
countries, the most common cause is autoimmune destruction, when the body’s own
immune cells mistakenly attack the healthy adrenal cortical tissues, though the
precise reason why this happens isn’t clear. In developing countries the most common
cause is tuberculosis; in this case, the infection spreads from the lungs to the
adrenal glands, causing inflammation and destruction in the adrenal cortex.
Another important cause is
metastatic carcinoma, which is where cancer spreads to the adrenal cortex from
somewhere else in the body. Regardless of the cause, it turns out that the
adrenal cortex has a high functional reserve, meaning that a small amount of
functional tissue can still do a pretty decent job of churning out enough hormones to meet the body’s needs. As a result of this though, once there
are symptoms, it’s usually a sign that a majority, sometimes up to 90%, of the
adrenal cortex has been destroyed. The symptoms of primary adrenal
insufficiency correspond to which layers of the adrenal cortex have been
destroyed. When the zona glomerulosa is destroyed, aldosterone levels fall and
that leads to high potassium levels in the blood, or hyperkalemia, and low
sodium levels in the blood, or hyponatremia.
With less sodium around in the
blood, water moves out of the blood vessels, which results in a low blood
volume, or hypovolemia. Finally, fewer photons are lost, meaning more build-up
in the blood and those result in acidosis, and more specifically metabolic acidosis, since it’s caused by the kidneys. These electrolyte changes
and hypovolemia can cause symptoms like cravings for salty foods with
simultaneous nausea and vomiting, fatigue, and dizziness that worsen with
standing. When the zona fasciculata is destroyed, cortisol levels fall and that
leads to inadequate glucose levels during times of stress. This means that
while being chased by a pack of raccoons, instead of feeling ready to sprint a
person might feel weak, tired, and disoriented.
Also, those decreased levels of
cortisol cause the pituitary gland to become overactive since usually, cortisol has negative feedback that affects the pituitary gland. So it ends up
producing pro-opiomelanocortin, which is a precursor to an adrenocorticotropic hormone,
but it also turns out to be a precursor to a melanocyte-stimulating hormone, the hormone
that leads to skin pigment production. So when your pituitary gland is overactive,
it ends up making more melanocyte-stimulating hormones, resulting in
hyperpigmentation, or darkening of the skin, especially in sun-exposed areas
and joints, like the elbows, knees, and knuckles.
In some extreme cases of primary
adrenal insufficiency, the zona reticularis can be affected as well, and
androgens levels can fall. This decrease doesn’t affect men much because remember
the testes are the major source of male androgens. However, women can experience
a loss of pubic and armpit hair and decreased sex drives. Oftentimes,
the slowly progressive chronic symptoms of primary adrenal insufficiency are
missed or ignored until a major stressor, like a serious injury, surgery, or
infection, suddenly causes the symptoms to become really severe. In other words, the body has a sudden increased need for aldosterone and cortisol, and the failing
adrenal cortex simply can’t deliver. This is known as Addisonian crisis, or
acute primary adrenal insufficiency, and it usually happens when the majority
of the zona glomerulosa and zona fasciculata is destroyed. It can cause sudden pain in the lower back, abdomen, or legs, with severe vomiting and diarrhea,
followed by dehydration; low blood pressure; and loss of consciousness.
Left untreated, an Addisonian crisis
can be fatal. Addisonian crises can also arise from Waterhouse-Friderichsen
syndrome, when a sudden increase in blood pressure causes blood
vessels in the adrenal cortex to rupture, filling up the adrenal glands with
blood and causing tissue ischemia and adrenal gland failure. Primary adrenal
insufficiency can be diagnosed with an adrenocorticotropic hormone stimulation test.
During the test, a small amount of synthetic adrenocorticotropic hormone is
given, and the amount of cortisol and aldosterone produced in response is
measured, which helps you figure out how well the adrenal glands are working. Usually, individuals with primary adrenal insufficiency are treated with hormones to
make up for the lack of cortisol, aldosterone, and androgens. They typically
have to be taken for the rest of an individual’s life, and stopping the hormone
replacements can lead to an Addisonian crisis.
All right, as a quick recap, primary
adrenal insufficiency is a failure of the adrenal cortex - specifically, the
zona glomerulosa which causes low aldosterone, as well as the zona fasciculata
which causes low cortisol, and in severe cases, the zona reticularis, which
causes low androgens.
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