Cushing syndrome, named after the famous neurosurgeon, Harvey Cushing who first described it, is
an endocrine disorder with elevated cortisol levels in the blood.
In some cases, Cushing syndrome results from a pituitary adenoma making excess ACTH, and
in those situations it’s called Cushing disease.
Normally, the hypothalamus, which is located at the base of the brain, secretes corticotropin-releasing
hormone, known as CRH, which stimulates the pituitary gland to secrete adrenocorticotropic
hormone, known as ACTH.
ACTH, then, travels to the pair of adrenal glands, on top of each kidney, where it specifically
targets cells in the adrenal cortex.
The adrenal cortex is the outer part of the adrenal gland and is subdivided into three
layers- the zona glomerulosa, the zona fasciculata, and the zona reticularis.
Zona fasciculata is the middle zone and also the widest zone and it takes up the majority
of the volume of the whole adrenal gland.
The ACTH specifically stimulates cells in this zone to secrete cortisol, which belongs
to a class of steroids, or lipid-soluble hormones, called glucocorticoids.
Glucocorticoids are not soluble in water, so most cortisol in the blood is bound to
a special carrier protein, called cortisol-binding globulin, and only about 5% is unbound or
free.
In fact, only this small fraction of free cortisol is biologically active, and its levels
are carefully controlled.
Excess free cortisol is filtered in kidneys and dumped into the urine.
Free cortisol in the blood is involved in a number of things and it’s part of the
circadian rhythm.
Cortisol levels peak in the morning, when the body knows we need to “get up and go”
and then drop in the evening, when we’re preparing for sleep.
In times of stress, the body needs to have plenty of energy substrates around, so cortisol
increases gluconeogenesis, which is the synthesis of new glucose molecules, proteolysis, which
is the breakdown of protein and lipolysis, which is the breakdown of fat.
Cortisol also helps to maintain the blood pressure by increasing the sensitivity of
peripheral blood vessels to catecholamines- epinephrine and norepinephrine, and this narrows
the blood vessel lumen.
Cortisol helps to dampen the inflammatory and immune response by reducing the production
and release of inflammatory mediators, like prostaglandins and interleukins, as well as
inhibiting the proliferation of T-lymphocytes.
Finally, cortisol receptors are present in the brain, where their full effect is still
actually unclear but might influence things like mood and memory.
For all this to work properly, though, the levels of free cortisol have to stay within
the normal range.
To do that, the body uses negative feedback, which means that high levels of cortisol tell
the hypothalamus and pituitary gland to decrease their secretion of CRH and ACTH, respectively.
Less CRH also tells the pituitary to make less ACTH, so the pituitary ends up having
two reasons not to make ACTH.
With less ACTH floating around, the zona fasciculata gets less stimulation to make cortisol, and
eventually, cortisol levels go back down to the normal range again.
In Cushing syndrome, cortisol levels are constantly higher than normal, so its effects are exaggerated.
Excess cortisol leads to severe muscle, bone and skin breakdown which are the major protein
stores of the body.
It also leads to elevated blood glucose levels, and that leads to high insulin levels.
Insulin, among its many actions, preferentially targets adipocytes or fat cells in the center
of the body - around the waist and buttocks.
In those cells, the insulin activates lipoprotein lipase, which is an enzyme that helps those
adipocytes accumulate more fat molecules.
The result is central obesity.
In addition, to this the high cortisol levels cause hypertension for two reasons.
First, they amplify the effect of catecholamines on blood vessels.
Second, cortisol starts cross-reacting with mineralocorticoid receptors, which normally
only binds a related steroid hormone - mineralocorticoids which are secreted from the zona glomerulosa
layer of the adrenal cortex.
In other words because the cortisol is structurally similar to mineralocorticoid it can bind to
that receptor and it can trigger the mineralocorticoid effect - which is mainly to increase blood
pressure by retaining fluid.
High levels of cortisol also inhibit the secretion of gonadotropin- releasing hormone from the
hypothalamus, which messes up normal ovarian and testicular function.
Excess cortisol also dampens the inflammatory and immune response, making individuals more
susceptible to infections.
Finally, high levels of cortisol seem to impair normal brain function but the exact mechanism
of that is unclear.
Cushing syndrome can happen because of exogenous cortisol meaning that it comes from “outside”
usually in the form of medications, or because of endogenous cortisol - meaning that the
excess cortisol is made by the body.
The majority of cases of Cushing syndrome occur in individuals using exogenous steroid
medications over a long period of time - often to treat autoimmune and inflammatory disorders,
like asthma or rheumatoid arthritis.
That’s because the molecular structure of exogenous steroid medications is so similar
to cortisol that they mimic its actions on various tissues.
In fact, exogenous steroid medications can also cause negative feedback on the hypothalamus
and the pituitary gland.
This causes a decrease in CRH and ACTH, which in turn, shuts down cortisol production from
the zona fasciculata.
Over time, this lack of stimulation can cause zona fasciculata to physically shrink or become
atrophic.
Since that's the widest part of the adrenal cortex, it can have a measurable effect on
the overall size of the adrenal gland.
Even though this results in less endogenous cortisol production it still doesn’t quite
compensate for the huge levels of exogenous cortisol, and that causes Cushing syndrome
to develop.
In addition to taking exogenous steroid medications, Cushing syndrome can also result from increased
levels of endogenous cortisol.
The most common reason for that is excess ACTH.
The leading cause of that is a pituitary adenoma, which is a benign tumor of the pituitary gland
- and this specific condition is called Cushing disease.
The exact reason for the development of this sort of benign tumor isn’t known - but unlike
a malignant tumor - the cells don’t invade neighboring tissues or spread to other parts
of the body.
Instead, the pituitary adenoma simply grows in size and secretes too much ACTH.
The excess ACTH overstimulates zona fasciculata of both adrenal glands, which grow larger
and secrete excess cortisol.
Apart from pituitary adenomas, there are ectopic sources of ACTH like small cell lung cancer,
and in these cases the excess ACTH is coming from somewhere other than the pituitary.
Another common cause of endogenous Cushing syndrome is tumors of the adrenal glands that
make excess cortisol - like adrenal adenomas, which are benign tumors, and adrenal carcinomas,
which are malignant tumors.
In both adrenal adenomas and carcinomas, the cells of the zona fasciculata within the adrenal
cortex start dividing abnormally and secrete excess cortisol.
As before, the excess cortisol provides negative feedback to the hypothalamus and pituitary
gland, suppressing CRH and ACTH production.
Although this doesn’t have any effect on zona fasciculata of the involved adrenal gland,
since the neoplastic cells are autonomous, meaning that they have grown independent from
any stimulatory signals, the zona fasciculata of the uninvolved, normal adrenal gland shrinks
and produces less than the standard amount of cortisol.
The net result, though, is still abnormally high levels of cortisol, and that causes Cushing
syndrome to develop.
Regardless of the cause, the symptoms of Cushing syndrome are directly related to the effects
of excess cortisol on its various target tissues.
Resulting from the increased breakdown of most types of tissue, the individual presents
with muscle wasting and thin extremities, skin thinning, easy bruising and abdominal
striae or lines, as well as fractures due to osteoporosis or brittle bones.
At the same time, there’s fat redistribution, so classic findings include a round, full
moon shaped face, a buffalo hump - which is a fatty hump on the upper back, and truncal
obesity - where fat gathers around the abdomen and trunk rather than in the limbs.
Finally, excess cortisol causes hyperglycemia or high blood sugar levels that can progress
to diabetes mellitus, hypertension or increased blood pressure along with a high risk for
cardiovascular disease, as well as increased vulnerability to infections, poor wound healing,
amenorrhea or absent menstrual bleeding and psychiatric- mental disturbances.
Diagnosis of Cushing syndrome is initially based on measuring the free, or unbound cortisol
in a 24-hour urine sample, in order to assess the total amount of cortisol excreted in the
urine over a 24-hour period.
Alternatively, blood or saliva tests late at night can help check if there’s a normal
daily rise and fall of cortisol levels.
Another option is also the dexamethasone suppression test, which is when a person is given a low
dose of dexamethasone, which is an exogenous steroid that suppresses ACTH production in
the pituitary gland.
Normally that should cause a decrease in serum cortisol levels, but if Cushing syndrome is
caused by endogenous cortisol production, then the serum cortisol levels should remain
unchanged.
If that test is positive, the next step is to determine the exact cause of endogenous
cortisol production, and ACTH plasma levels can be checked.
Low ACTH levels can be seen in adrenal adenomas and carcinomas, whereas high ACTH levels can
be seen in Cushing disease and ectopic ACTH production.
If the ACTH level is high, the next step is to give an injection of a high dose of dexamethasone.
Unlike pituitary adenomas, ectopic sites of ACTH productions typically don’t respond
even to high doses of dexamethasone, and the serum cortisol remains high.
After all that, imaging can be used.
An MRI of the pituitary gland, in the case of Cushing disease, a CT of the adrenals,
when adrenal pathology is suspected, or a CT of the chest, abdomen, or pelvis, if there
seems to be an ectopic site of ACTH production.
Treatment of Cushing syndrome depends on the underlying cause.
If it’s due to exogenous medications, then the offending drug is gradually decreased
and eventually stopped if possible.
It’s important to avoid sudden steroid withdrawal, though, because that can cause an adrenal
crisis which is life threatening.
That’s because the adrenal glands may be atrophied and may need months to recover fully,
and during that time, the body needs the exogenous steroids to function normally.
If Cushing syndrome is due to a pituitary adenoma - like in Cushing disease - then surgical
excision of the adenoma may be needed.
Alternatively, medications such as adrenal steroid inhibitors, like ketoconazole and
metyrapone can be helpful - especially for cases of ectopic ACTH production or adrenal
carcinomas that have already spread.
All right as a quick recap, Cushing syndrome is any condition or situation that causes
increased levels of cortisol.
It can be exogenous, meaning drug-related, or endogenous, meaning that it’s from an
adrenal tumor or excess ACTH from a pituitary adenomas, in which case it’s called Cushing
disease, or from an ectopic site like small cell lung cancer.