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.

100 thoughts on “Cushing Syndrome – causes, symptoms, diagnosis, treatment, pathology”

  1. this fkin health problem ruined my life in many aspects, i feel happy that my doctor decided to cut my cortisol treatment before i grew up, i don't even want to think about it, only because of genetic asthma 🙁

  2. Great video! However, I would like to have heard about bilateral adrenalectomy ( bla) as treatment. Would love to see you do Pheos and Conn's next!

  3. Sir!! Don't you think insulin should inhibit the lipase enzyme…thereby accumulating the fat…😅

  4. My brother has been facing obesity problems for over 2 years. Even after multiple visit to various specialist we never understand what was happening with his body. Because of this video, we checked his cortisol levels and found out that it is 5 times the normal range. THANK YOU GUYS FOR THE VIDEO. Hopefully an endocrinologist will be able to help us out. Once again thanks a lot

  5. You people have done a great job..
    We would like to see videos on physical examination of patients,
    System wise accurate examination of patients..Thanku CHEERS!!

  6. Osmosis make a ligma thing vid, due to Fortnite Tuber Ninja, who died during his video, so please make this video as I truly dont know about this type of disease, as this may help me on my reasearch.

  7. Thank you i have this very syndrome and i'm 16 and half. It is very annoying thing to have and i'm in the hospital in this very moment

  8. I usually watch youtube on x1.5 or sometimes even x2. I signed up for osmosis but i cudnt watch the videos over there as the speed was painfully slow. Guys plz do something. 😩😩

  9. So spectacular content. But we should also remember that due to the hyperstimulation of the adrenal cortex, aldosterone, another hormone of the organ, is being overstimulated. Aldosterone regulates salt and water balance of the body; therefore, an increase of the said hormone would increase the the blood volume and contributes to the present hypertension. That is the reason why it also affects one's weight and predisposed to leg swelling, or more detrimental, heart problems.
    NEVERTHELESS, I appreciate this in depth presentation of many health topics that aids students or medical savvy to learn and understand more about our complex yet magnificent body. Thumbs up.

  10. I think my grandma has fishing but the exogenous type. She is using corticosteroid for her asthma for over 40 years. She has this body shape, with thin legs and large belly and the hump on the back. I don't know how to tell her to go and check it out, or even if her doc is aware of this condition.

  11. Something is going on with me… I had a cortisol test. it was. 8.1 . Endo repeated the test and wanted me to take it at 8 am, it was 26.4 that a.m.. She did a dexamethasone suppresion test and it was 0.7 Let me add that from taking that pill, I lost 6 pounds in one day.. 24 hours I lost 6 pounds and 2 pants sizes from my waist.. My red puffy face, became more normal with no red color. I do have a fat hump I call it and past purple strae.. Not any new strae.. Could I have an issue. Help, My endo is horrible.

  12. actually i still confuse about the effect of cortisol. It increase gluconeogenesis so theres more glucose and thers convertion to lipid that cause central obesitiy. But also we know that cortisol increase lipolysis too. emm so yea if anyone know the answer pls help me:(

  13. The best website for medical learning i had read about cushions for about 6 years and it’s the first time I actually understand it

  14. I am in the process of being diagnosed with Cushing's. I return my salvia test today. I have already had 3 other exams and taken altogether along with the salvia test I am that much closer to a cure. I don't let fear take a hold of me. I hang on tightly to hope that there is a 80% cure rate. Right now I am excited and nervous to face the truth. I have been suffering from this for at least 10 years and it has taken that long to get this close to hopes of remission.

  15. My cushings is due to prednisone for allergy induced asthma. Trying to find more info and ways to bring my body back to homeostasis.

  16. i was just diagnosed with cushings and this video was very helpful in understanding whats really going on:) thank you

  17. My husband is a doctor but hes at the hospital and he dont have time to teach me so he sent me this. Im reviewing for ASCP…
    I hate being stupid 🤯😔😥

  18. Oh God I have this and my hormones are going wild
    I v always been a sick kid growing up, but no one has told me about this case. No matter how many times I d be hospitalized. Thank u♡
    I m glad I stopped taking antiinflamatory meds. No more crazy outburst and now I have a flat stomach. Didn't even know that was possible. BUT I LOST DA BOOTY :"C gym here I come

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