Primary adrenal insufficiency, also known
as Addison’s disease, is a rare endocrine disorder that happens when the adrenal gland
isn’t able to produce enough of the hormones that the body needs, particularly aldosterone
and cortisol. The reason it’s called “primary” is
that the underlying problem is localized to the adrenal gland itself, rather than a problem
of a hormone that acts on the adrenal gland or elsewhere in the body. Primary adrenal insufficiency can develop
acutely or chronically, and a really famous example of someone having this condition is
John F. Kennedy, who was diagnosed at age 30. Now, there are two adrenal glands, one above
each kidney, and each one has an inner layer called the medulla and an outer layer called
the cortex which is subdivided into three more layers, the zona glomerulosa, zona fasciculata,
and the zona reticularis. The outermost layer is the zona glomerulosa,
and it’s full of cells that make the hormone aldosterone. Aldosterone is part of a hormone family or
axis which work together and are called the renin-angiotensin-aldosterone system. Together these hormones decrease potassium
levels, increase sodium levels, and increase blood volume and blood pressure. Aldosterone is secreted in response to elevated
levels of renin, and it’s role is to bind to receptors on two types of cells along the
distal convoluted tubule of the nephron. 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
a process of osmosis, water also moves into the blood, which increases blood volume and
therefore blood pressure. The other function of aldosterone is to stimulate
the proton ATPase pumps in alpha-intercalated cells which causes 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 which 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 every body cell has cortisol
receptors, so it affects an 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 top the hormone insulin, which causes glucose to be
taken up by various body tissues, and so essentially cortisol acts to counteract this effect this
in an effort 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 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 of the 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 protons are lost, meaning more
build up in the blood and that results in an acidosis, and more specifically a 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 worsens 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 causes
the pituitary gland to become overactive, since usually cortisol ihas a negative feedback
effect the pituitary gland. So it ends up producing pro-opiomelanocortin,
which is a precursor to adrenocorticotropic hormone, but it also turns out to be a precursor
to 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 hormone, 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, as well as a decreased sex drive. 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 are destroyed. It can cause a sudden pain 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, which is 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 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. Thanks for watching, you can help support
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