Cushing’s Syndrome: Symptoms, Causes, Treatment
Cushing’s Syndrome: This lecture reviews Cushing’s syndrome definition, symptoms, signs, causes, diagnosis, treatment, and more!
Guest Author
Guest Author: Charlotte Watson
This lecture was written by guest author Charlotte Watson, and the medical illustrations were created and provided by EZmed.
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What is Cushing’s Syndrome?
Cushing’s, or Cushing, syndrome is a condition in which there is too much cortisol in the body.
This physiological state in which the body is exposed to high levels of cortisol is called hypercortisolemia or hypercortisolism.
Cortisol is often referred to as the “stress hormone” as it is released during times of stress or danger.
Cortisol helps the body respond to stress, along with other functions discussed below.
There are 2 main types of Cushing’s syndrome:
Exogenous (caused by factors outside of the body)
Example: Chronic corticosteroid medication use
Endogenous (caused by factors inside the body)
Examples: Adrenal adenoma, adrenal carcinoma, pituitary adenoma, etc.
More on the different types and causes below….keep reading!
Cushing’s Syndrome vs Cushing’s Disease
Cushing’s syndrome is an endocrine disorder in which cortisol levels are too high in the body.
There are a number of underlying causes that can lead to Cushing’s syndrome - one of which is an ACTH-producing pituitary tumor.
When Cushing’s syndrome is caused by an ACTH-producing pituitary tumor, then this is known as Cushing’s disease.
In other words, Cushing’s disease is a specific subtype of Cushing’s syndrome caused by a pituitary tumor (typically a pituitary adenoma).
Regardless of etiology, sustained high levels of cortisol can be problematic.
We will discuss below what causes Cushing’s syndrome, the subtype of Cushing’s disease, and why high cortisol can be dangerous.
Cushing’s Syndrome vs Cushing’s Disease: Definitions of Cushing’s syndrome vs Cushing’s disease
Anatomy of the Adrenal Glands
To better understand Cushing’s syndrome, let’s briefly look at where cortisol comes from in the body!
Cortisol is produced and released by the adrenal glands.
The adrenal glands are retroperitoneal structures located above (superior to) the kidneys.
As a result, the adrenal glands are sometimes referred to as the suprarenal glands.
There are 2 adrenal glands in the body, one located above each kidney.
The right adrenal gland has a pyramidal shape, and the left adrenal gland has a crescent or semi-lunar shape.
The adrenal glands are made up of 2 main parts:
Adrenal Cortex (outer part)
Adrenal Medulla (inner part)
Memory Trick: Cortex = Corners; Medulla = Middle
The adrenal cortex and medulla have different embryological origins, which explains their differing functions.
The cortex is derived from the mesoderm, while the medulla is derived from neural crest cells.
The neural crest cells differentiate into functional chromaffin cells.
The outer adrenal cortex differentiates further into 3 functional layers or zones:
Zona Glomerulosa (outermost layer)
Zona Fasciculata (middle layer)
Zona Reticularis (innermost layer)
Memory Trick: Use the acronym GFR (which is a common kidney blood test) to remember the adrenal cortex layers from superficial to deep
Adrenal Gland Anatomy: The adrenal gland is located above the kidney and is made up of the adrenal cortex and adrenal medulla. The adrenal cortex is made up of the zona glomerulosa, zona fasciculata, and zona reticularis
Function of the Adrenal Glands
Let’s briefly review the function of the adrenal glands and where cortisol comes from, as this will be important to understand Cushing’s syndrome!
Adrenal Cortex
The adrenal cortex produces and secretes steroid hormones synthesized from cholesterol.
The functions and hormones of the adrenal cortex include:
Zona Glomerulosa = Produces mineralocorticoids
Namely: Aldosterone
Helps regulate electrolytes and blood pressure by facilitating sodium/ water reabsorption and potassium excretion in the kidneys
Stimulated by the renin-angiotensin-aldosterone system (RAAS)
Zona Fasciculata = Produces glucocorticoids
Namely: Cortisol
Helps regulate and increase glucose levels, bone metabolism, blood pressure, and sympathetic nervous system activity
Stimulated in response to stress and pituitary ACTH (see below)
Zona Reticularis = Produces gonadocorticoids or adrenal androgens
Namely: DHEA
Precursor for testosterone and estrogen synthesis
Stimulated in response to pituitary ACTH
Memory Trick: Use “Salt, Sugar, Sex” to remember the adrenal cortex hormone functions by zone from superficial to deep.
Note: Cortisol will be most pertinent to this Cushing’s syndrome lecture
Adrenal Medulla
The adrenal medulla produces and secretes catecholamines.
Adrenal Medulla = Produces catecholamines
Namely: Epinephrine (adrenaline) and norepinephrine (noradrenaline)
Function in the sympathetic nervous system
Stimulated in response to “fight or flight” situations
Adrenal Gland Function: Diagram showing the hormones produced and secreted by the adrenal gland including mineralocorticoids (aldosterone), glucocorticoids (cortisol), androgens (DHEA), and catecholamines (epinephrine and norepinephrine)
The HPA Axis
Now that we know where cortisol comes from (adrenal cortex - see above), let’s review the pathway of cortisol production!
This is VERY important in understanding Cushing’s syndrome - so don’t skip this part!
Cortisol release and regulation involves a pathway from the hypothalamus, through the anterior pituitary gland, to the adrenal gland.
This is known as the hypothalamic-pituitary-adrenal (HPA) axis.
Normal HPA axis steps:
Hypothalamus produces and secretes corticotropin-releasing hormone (CRH)
CRH travels to the anterior pituitary gland via the hypophyseal portal system
CRH binds to receptors on the anterior pituitary gland, stimulating the synthesis and release of adrenocorticotropic hormone (ACTH)
ACTH is released into the bloodstream, where it travels to the adrenal glands
ACTH stimulates the adrenal cortex to synthesize and release cortisol (along with other adrenal cortex hormones, i.e. androgens)
Cortisol enters the bloodstream to carry out its various functions
Negative Feedback Loop:
Circulating cortisol in the bloodstream negatively feedbacks on the hypothalamus and the anterior pituitary gland
This suppresses further release of CRH and ACTH, respectively
This prevents cortisol levels from increasing further, and prevents excessive cortisol levels in the body
The HPA axis is stimulated in response to circadian rhythms and stressors.
The negative feedback loop helps regulate and prevent the continued rise of cortisol.
Cortisol is naturally released in the morning for humans, in line with our circadian rhythm.
Throughout the day, there is a smaller pulsatile secretion of cortisol every 90 minutes.
HPA Axis Function: Hypothalamic-pituitary-adrenal axis diagram of hormones involved including corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol
Effects of High Cortisol
Now that we know how cortisol is produced and where it comes from (see above), let’s review what happens to the body when there are high levels of cortisol.
As previously mentioned, the main problem in Cushing’s syndrome is there is too much cortisol.
Cortisol is normally involved in:
Metabolic control
Water balance in the body
Electrolyte balance in the body
The immune response in the body
Growth
Cardiovascular status
Reproduction
Development
What happens when there is too much cortisol, and why is this a problem?
Immune System
High cortisol can decrease the immune system response by suppressing B-cell production, suppressing T-cell proliferation, and inhibiting neutrophil margination.
This can result in:
Immune system suppression (prone to infections)
Inability to fight infections
This is why patient’s with Cushing’s syndrome are at high risk for infections, especially fungal infections
Sympathetic Nervous System
High levels of cortisol can increase the activity and sensitivity of the sympathetic nervous system by upregulating adrenergic receptors.
This can result in:
Increased blood pressure
This is why patient’s with Cushing’s syndrome can experience hypertension
Blood Glucose
High cortisol can increase blood glucose levels by stimulating gluconeogenesis and glycogenolysis in the liver, increasing lipolysis in adipose tissue, increasing proteolysis in tissues, inhibiting insulin secretion in the pancreas, and inhibiting insulin-mediated glucose uptake into cells.
This can result in:
Increased blood glucose (hyperglycemia)
This is why patient’s with Cushing’s syndrome are at increased risk for hyperglycemia and diabetes mellitus
Adipose Tissue
High cortisol can increase fat breakdown (lipolysis) in the peripheral extremities and redistribute the fat to the central part of the body.
This can result in:
Thin extremities and central obesity
This is why patient’s with Cushing’s syndrome can have a “moon-like” face, buffalo hump, abdominal obesity, and thin extremities
Muscle, Bone, Skin
High cortisol can increase protein breakdown (proteolysis) and inhibit collagen synthesis in muscle tissue, connective tissue, and bone tissue.
This can result in:
Proximal muscle atrophy, brittle bones, and thin skin
This is why patient’s with Cushing’s syndrome can have muscle atrophy, osteopenia/osteoporosis, fractures, thin skin, abdominal striae, ecchymosis, and slow wound healing
Skin (ACTH-dependent)
When elevated cortisol is a result of high ACTH levels (see below), there can also be an increase in androgen release.
This is because ACTH stimulates the zona reticularis to release androgens in addition to the zone fasciculata to release cortisol.
There can also be an increase in melanocyte-stimulating hormone (MSH) production because MSH and ACTH are made from the same precursor.
Increased androgens and MSH can result in:
Acne and hirsutism in patient’s with Cushing’s syndrome/disease (due to increased androgens)
Hyperpigmentation in patient’s with Cushing’s syndrome/disease (due to increased MSH)
Electrolyte and Water Balance
High cortisol can act on the mineralocorticoid receptors in the kidneys, leading to similar effects of aldosterone.
This can result in:
Increased sodium/water reabsorption and increased potassium secretion in the kidney
High Cortisol Hormone Effects: Cortisol function and the effects of high cortisol levels in the body seen in Cushing’s syndrome
Symptoms of Cushing’s Syndrome
Now that we understand how cortisol affects the body (see above), we can apply those effects to the symptoms of Cushing’s syndrome.
Patients with Cushing’s syndrome typically have a very characteristic and distinct appearance, often referred to as a “cushingoid” appearance on physical examination.
Signs and Symptoms of Cushing’s syndrome include:
Skin & Appearance:
A round, “moon-like” face
Disproportionate fat distribution
Central/abdominal obesity
“Buffalo hump” - fat deposits in the patient's upper back
Ecchymosis (bruising)
Abdominal striae (stretch marks)
Proximal muscle wasting/atrophy/weakness
Acne
Facial and body hair growth (hirsutism) - especially women
Thinning skin
Slow wound healing
Hyperpigmentation in ACTH-dependent Cushing’s
Metabolic:
Weight gain
Hyperglycemia / Diabetes Mellitus
Osteopenia / Osteoporosis
Slow wound healing
Cardiovascular:
Hypertension
Immunity:
Prone to infections (fungal)
Behavioral:
Insomnia
Cushing’s Syndrome Symptoms: Cushing’s syndrome symptoms and signs include moon face, buffalo hump, weight gain, central obesity (cushingoid features), etc.
Causes of Cushing’s Syndrome
As previously mentioned, Cushing's syndrome is caused by high levels of cortisol.
But what causes the excess cortisol?
The excess cortisol levels can either be:
ACTH-dependent
Pituitary tumor (Cushing’s disease)
Ectopic ACTH-producing tumor
Excessive CRH production
ACTH-independent
Adrenal tumor (endogenous)
Hyperactive adrenal glands (endogenous)
Corticosteroid medication use (exogenous)
ACTH-dependent
The high cortisol levels in ACTH-dependent Cushing’s is a result of elevated ACTH levels.
Remember ACTH stimulates the adrenal glands to produce and release cortisol (see above).
The excess ACTH could be from:
An ACTH-secreting pituitary tumor (Cushing’s disease)
ACTH being produced elsewhere in the body
Excessive CRH production
(1.) When Cushing’s syndrome is caused by an ACTH-secreting pituitary tumor (usually a pituitary adenoma), it is known as Cushing’s disease.
Cushing’s disease makes up about 80% of all ACTH-dependent Cushing’s syndrome cases.
(2.) The source of excessive ACTH may also come from elsewhere in the body, known as ectopic secretion.
This could be from an ectopic ACTH-producing tumor.
The most common cause of ectopic ACTH production is small cell lung cancer.
(3.) Finally, excess CRH can be released from a tumor such as pheochromocytoma, medullary thyroid carcinoma or prostate cancer.
Excess CRH has a cascading effect down the HPA axis, causing excessive ACTH, and therefore excessive cortisol production.
ACTH-independent
The high cortisol levels in ACTH-independent Cushing’s is a result of excess cortisol directly.
ACTH and CRH are not elevated (hence independent of ACTH) due to cortisol negative feedback - see above.
The excess cortisol could be from:
An adrenal tumor (endogenous)
Hyperactive adrenal glands (endogenous)
Corticosteroid use (exogenous)
ACTH-independent Cushing’s syndrome may be caused by endogenous (internal) or exogenous (external) sources.
Endogenous:
Endogenous ACTH-independent Cushing’s syndrome may be from hyperactive adrenal glands, or from an adrenal tumor such as an adrenal adenoma or carcinoma.
The adrenal tumor is located within the adrenal cortex and secretes cortisol excessively.
Adrenal adenomas (benign) are more common than adrenal carcinomas (cancerous).
Exogenous:
ACTH-independent Cushing’s syndrome may also be caused by exogenous (external) corticosteroid use.
Corticosteroid medications can act like endogenous cortisol, and can share the same effects as cortisol on the body.
Long-term, high-dose corticosteroid use can be responsible for causing Cushing’s syndrome.
Corticosteroids are frequently used to reduce inflammation in inflammatory conditions, or to suppress the immune system in auto-immune diseases.
Example uses include asthma, COPD, rheumatoid arthritis, lupus, inflammatory bowel disease, etc.
Exogenous steroid use is the most common cause of Cushing's syndrome, and is even more common than Cushing’s disease.
As a result, it is important to review patient medications and ask the patient about corticosteroid use.
Cushing’s Syndrome Causes: Causes of Cushing’s syndrome include ACTH-dependent (pituitary tumor, etc.) and ACTH-independent (adrenal tumor, etc.) types
Risk Factors for Cushing’s Syndrome
Risk factors for Cushing’s syndrome include:
Being female
Receiving long-term corticosteroid therapy
Presence of an adrenal or pituitary tumor
Diagnosis and Tests
We now know the different causes of Cushing’s syndrome (see above).
Let’s review how to diagnose these different causes!
Make sure to use the handy diagram at the end to help summarize it all!
Step 1: Low-Dose Dexamethasone Test
When Cushing’s syndrome is suspected, the first diagnostic test should confirm if cortisol levels are inappropriately high.
This can be done with a low-dose dexamethasone suppression test.
How does this test work?
The patient receives a 1mg dose of dexamethasone (corticosteroid) at night.
The plasma ACTH and cortisol levels are measured in the morning.
Under normal conditions, administering dexamethasone would suppress ACTH and cortisol production (through negative feedback on the pituitary gland).
This would normally lead to a low cortisol level when measured in the morning.
In Cushing’s however, the low dose of dexamethasone does not suppress the excessive drive to produce cortisol (no matter the underlying cause - see below).
The patient will continue to produce high levels of cortisol, and the morning cortisol level will be elevated as a result.
Step 2a: 24-Hour Urinary Free Cortisol
After a low-dose dexamethasone suppression test has been performed, the second line confirmatory test is a 24-hour urinary free cortisol.
How does this test work?
Urine is collected over 24 hours.
Cortisol concentration is measured in the collected urine.
Normally cortisol should not be elevated in the urine.
If the cortisol levels in the urine over a 24 hour period are high, then this could suggest Cushing’s syndrome.
But why can’t we just measure serum cortisol?
Serum cortisol levels are unstable and fluctuate under various conditions and throughout the day.
Therefore in order to measure cortisol over a period of time, this must be done through the urine.
Step 2b: Saliva Cortisol Test
Cortisol can also be measured in the saliva.
A saliva cortisol test is another second line confirmatory test after a low-dose dexamethasone suppression test has been performed.
If cortisol levels are elevated in the saliva, then this could also suggest Cushing’s syndrome.
Important
The above tests (steps 1 and 2) tell you if Cushing’s syndrome is present, but they do not tell you which specific type or the underlying cause.
That takes us to the next step below!
Step 3: Plasma ACTH
After a diagnosis of Cushing's syndrome is confirmed with a low-dose dexamethasone suppression test, further testing can be done to determine the underlying cause.
Firstly, plasma ACTH can be measured.
If a low-dose dexamethasone suppression test results in high cortisol and low ACTH, then an ACTH-independent cause of Cushing’s syndrome is most likely.
This is because the dexamethasone is appropriately suppressing the pituitary gland (so a pituitary tumor is less likely), and an ectopic ACTH-producing tumor is less likely since ACTH is low.
As a result, this scenario is most likely due to exogenous steroid use or an adrenal tumor.
Remember, cortisol has a negative feedback effect on the hypothalamus and pituitary gland, but not the adrenal gland, which is why dexamethasone does not suppress an adrenal tumor.
The next step is to rule out exogenous corticosteroid use by reviewing the patient’s medication history.
Once exogenous corticosteroids have been ruled out, adrenal imaging can be obtained to assess for an adrenal tumor.
Summary:
High cortisol and low ACTH = ACTH-independent Cushing’s syndrome
Investigate for exogenous steroid use or adrenal tumor
Exogenous steroid use -> found out in patient history
Adrenal tumor -> imaging of the adrenal gland
Step 4: High-Dose Dexamethasone Test
If a low-dose dexamethasone suppression test results in high cortisol and high ACTH, then it is most likely an ACTH-dependent cause of Cushing’s syndrome.
This could be due to a pituitary tumor or an ectopic ACTH-producing tumor (both result in high ACTH and high cortisol).
Why doesn’t a low-dose dexamethasone test suppress a pituitary tumor?
The low dose of dexamethasone is not a high enough dose to suppress a pituitary tumor, so the tumor continues to secrete ACTH.
Why isn’t an ectopic ACTH-producing tumor affected by the low-dexamethasone test?
An ectopic ACTH-producing tumor is not part of the negative feedback loop in the HPA axis.
Therefore, the dexamethasone would have no effect on the ACTH production from this tumor.
A high-dose dexamethasone suppression test can be done next to distinguish these ACTH-dependent causes.
How does this test work?
The patient receives an 8mg dose of dexamethasone, which is a high enough dose to suppress an ACTH-producing pituitary tumor (unlike the 1mg low dose).
Results: Low ACTH and Low Cortisol
Therefore, if plasma ACTH and cortisol levels are both low after a high-dose dexamethasone suppression test, then it is indicative of a pituitary tumor (Cushing’s disease).
In this scenario, dexamethasone suppresses the production of ACTH by the pituitary tumor and there is less cortisol production as a result.
Next steps:
Pituitary imaging can be performed to assess for a pituitary tumor.
If imaging does not show a pituitary tumor but one is suspected, then inferior petrosal sinus sampling (IPSS) can be performed.
IPSS involves taking a sample of blood from the inferior petrosal sinuses and testing it for ACTH.
A high ACTH level indicates the presence of a pituitary tumor.
Results: High ACTH and High Cortisol
If plasma ACTH and cortisol levels are both high after a high-dose dexamethasone suppression test, then an ectopic ACTH-producing tumor is suggested.
In other words, high-dose dexamethasone can suppress a pituitary tumor but does not suppress an ectopic ACTH-producing site.
This is because an ectopic ACTH-producing site is not part of the negative feedback loop.
Further imaging can be performed to assess for an ACTH-producing small cell lung cancer or other tumors.
Cushing’s Syndrome Diagnosis: Algorithm and flowchart to diagnose Cushing’s syndrome
Treatment
The symptoms and cushingoid features of a patient should reverse with proper treatment.
The treatment provided for each patient will depend on the underlying cause of their Cushing’s syndrome:
Exogenous corticosteroid use
Taper steroid dose down and wean patient off
Pituitary tumor
Resection of the tumor (transsphenoidal resection)
Adrenal tumor
Partial or total adrenal resection (adrenalectomy)
Chemotherapy, radiation, etc. if malignant
Ectopic ACTH-producing tumor
Resection depending on the site
Chemotherapy, radiation, etc. if malignant
Patients with an endogenous cause of high cortisol can be given medications that suppress cortisol production, called steroidogenesis inhibitors, such as metyrapone and ketoconazole.
These medications can improve patient outcome, especially those requiring surgery.
Patients who have a bilateral adrenalectomy will require full steroid replacement therapy, and should carry a steroid emergency card with them in case of a steroid crisis.
Cushing’s Syndrome Treatment: Management guidelines for the treatment of Cushing’s syndrome including surgery, medications, chemotherapy, etc.
Complications of Cushing’s Syndrome
The complications of untreated Cushing’s syndrome can be severe, with a high mortality rate.
Cushing’s syndrome complications include:
Cardiovascular disease
Refractory hypertension
Heart failure
Stroke
Venous thromboembolism
Osteopenia
Osteoporosis
Fractures
Diabetes mellitus
Frequent infections
Decreased quality of life
A possible complication following Cushing’s disease treatment with a bilateral adrenalectomy is called Nelson’s syndrome.
In Nelson’s syndrome, the pituitary tumor continues to enlarge and there is an increase in ACTH release.
This can lead to hyperpigmentation of the skin, and a bitemporal hemianopia as the optic chiasm is compressed by the enlarging pituitary tumor.
Cushing’s Syndrome Complications: Symptoms and complications of Cushing’s syndrome include hypertension, diabetes, osteoporosis, fractures, etc.
Pseudo-Cushing’s Syndrome
Pseudo-Cushing’s syndrome (PCS) is a clinical scenario in which a patient presents with the clinical signs, symptoms, and cortisol levels typical of a patient with Cushing’s syndrome.
However, the HPA axis is fully intact.
Instead, there is chronic activation of the HPA axis due to a secondary illness.
Secondary illnesses that can trigger this presentation include: chronic alcoholism, depression, obesity, malnutrition, PCOS, eating disorders, and uncontrolled diabetes (all of which are in the differential diagnosis for Cushing’s syndrome).
Once the underlying cause is treated and addressed, the cushingoid features should self-resolve.
Of note, PCS is also known as nonneoplastic hypercortisolism.
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