Cushing Syndrome: A Short Primer for the Hair Loss Specialist

What is Cushing Syndrome and How do we Evaluate it?

Cushing syndrome is a rare condition whereby the body produces too much cortisol. The incidence is thought to be around 1 in 200,000 individuals. There can be many reasons for the excess cortisol and the goal of evaluating patient’s with suspected Cushing syndrome is first to confirm that the diagnosis is truly correct and then to figure out the exact ‘source’ of the problem. Multiple specialists are involved in the evaluation and management of Cushing syndrome including Endocrinology, Radiology, Neurosurgery, General Surgery, Dermatology, Psychiatry, Gynecology and Urology.

Hair specialists are not often the first to diagnose endogenous Cushing syndrome - but they certainly can be. Hair loss is not usually the first reason that a patient with Cushing syndrome comes to medical attention. However, it certainly can be. We’ve reviewed the relationship between hair loss and Cushing Syndrome in another article. Mild cases of Cushing syndrome is probably underdiagnosed and so there are many cases that are being missed in the world. Given the morbidity and mortality that is attached to having undiagnosed and untreated Cushing syndrome, lives can be dramatically altered by recognizing a case of Cushing syndrome early on in its development. I use a Cushing Syndrome Checklist to help trainees understand some of the features and work up of Cushing syndrome.

It is an astute physician who recognizes that a patient who appears in the hair loss clinic with androgenetic alopecia but who also has depression, proximal muscle weakness, bruising and facial plethora may have Cushing syndrome. Dermatologists also need to understand Cushing syndrome very well given that “iatrogenic” Cushing syndrome (exogenous Cushing syndrome) caused by topical steroids, steroid injections and oral steroids is common.

Let’s get to it!

Endogenous and Exogenous Cushing Syndrome (CS)

Excessive cortisol may be due to a problem inside the body or may be due to a problem outside the body. Problems inside the body are referred to be “endogenous” and problems outside the body are referred to as “exogenous” or “iatrogenic”. Worldwide, exogenous CS represents the most common cause of Cushing syndrome as a result of medically prescribed topical, oral, intralesional or intranasal glucocorticosteroids.

“Endogenous” causes include issues occurring in the pituitary gland, adrenal gland or from another organ system that lead to a rise in cortisol levels.

a)  Cushing Disease.  When the problem of excess cortisol lies in the pituitary gland,  the Cushing syndrome is renamed ‘Cushing Disease’.   About 1 in 500,000 individuals have Cushing disease. 75 % of endogenous Cushing syndrome is due to a pituitary cause – usually a pituitary microadenoma that secretes ACTH and causes bilateral adrenal hyperplasia.  Patients with pituitary microadenomas are  more often women than men (7:1 ratio) and often in the 20s or 30s and have slightly elevated cortisol and androgens.  The full age range, however,  is from childhood to the 70s.

b)    Adrenal Cushing Syndrome. When the problem of excessive cortisol lies in the adrenal gland, the Cushing syndrome is called Adrenal Cushing syndrome or ACTH independent Cushing syndrome. This accounts for 15-20 % of the causes of endogenous Cushing syndrome.  Most patients with Adrenal Cushing syndrome have a benign adrenocortical adenoma (10 % of all Cushing syndrome) followed closely by adrenal carcinomas (8 % of all Cushing syndrome). Nodular adrenal hyperplasia is a less common cause (1 % of all Cushing syndrome).

c)    Ectopic ACTH Syndrome.When the excessive cortisol is due to ACTH production in another part of the body besides the pituitary gland or adrenal gland, the Cushing syndrome is often referred to as ectopic ACTH syndrome.  About 10 % of patients with Cushing syndrome are due to ectopic ACTH syndrome. Patients with ectopic ACTH syndrome are usually male age 40-60. These patients have elevated ACTH levels that are often due to various types of tumors. Lung cancers, pheochromocytomas and carcinoids are a potential cause of ectopic ACTH.  Weakness, weight loss, hyperpigmentation are common. Regardless of the exact cause of the Cushing syndrome, all 3 types of endogenous Cushing lead to over production of cortisol by the adrenal glands.  

“Exogenous” causes are among the most common reason for Cushing syndrome.  As mentioned above, exogenous causes are due to administration of various types of corticosteroids – in which case the condition is called “iatrogenic” Cushing syndrome.

Cortisol and Cushing Syndrome: An Important Point

It is important to point out that a patient can have a normal cortisol level and still have Cushing syndrome. Also, a patient with an elevated cortisol level does not automatically have a diagnosis of Cushing syndrome. A patient can have elevated cortisol for many reasons, yet not have the manifestation of symptoms and signs that truly defines Cushing syndrome. These patients are said to have pseudo-Cushing syndrome (pseudo CS) Pseudo Cushing is therefore a physiological hypercortisolism in the absence of true Cushing syndrome.  For example, a patient who is stressed may have blood tests that show elevated cortisol levels but yet not have Cushing syndrome.  Depression, alcoholism, eating disorders, obesity, malnutrition, hyperthyroidism, complicated diabetes, hypothalamic amenorrhea, strenuous exercise, estrogen supplementation and pregnancy can lead to elevated cortisol in the absence of Cushing syndrome.  Again, these patients are said to have pseudo Cushing syndrome (pseudo CS) rather than true Cushing syndrome.  These patient have an abnormal overnight dexamethasone suppression test and 24 hour urine cortisol, and do not have a normal diurnal variation in cortisol levels. Dexamethasone-suppressed corticotrophin releasing hormone (CRH) stimulation (Dex-CRH) test may be performed by an endocrinologist to differentiate pseudo-CS from true CS. This is a sophisticated tests that generally only endocrinologists perform.

When do we suspect Cushing syndrome? Symptoms and Signs of Cushing Syndrome

There are a variety of symptoms and signs of Cushing syndrome.  The symptoms and signs vary from person to person.  It’s important to understand that not all patients have florid symptoms and so a very high index of suspicion is needed. In addition, the symptoms that patients with Cushing syndrome have overlap with common symptoms in the general population.

In our hair loss clinic, we use a Cushing Syndrome Checklist when working with training physicians and specialists about Cushing Syndrome. We use the checklist to help us take a really good history. Certain features are really important to get us thinking about Cushing syndrome including facial plethora, weight gain, muscle weakness, bruising and striae.

But the symptoms and signs of Cushing syndrome are quite varied. They include weight gain, moon face, hyperhidrosis, acne, broken capillaries, easy bruising, abdominal striae, insomnia, decreased libido, irregular periods in women, depression, polyuria, polydipsia, diabetes, osteoporosis, proximal muscle weakness, poor wound healing, kidney stones, headaches, sore joints, high cholesterol, high blood pressure. A full list is given in the attached Cushing Syndrome Checklist.

Proximal muscle weakness, easy bruising, red/purple striae more than 1 cm and facial plethora are amongst the more common signs. These can be remembered by the mnemonic (memory tool):

“ Stop! Wait in Line! - …Cushion Her Bruised Skin, Weak Muscles and Thin Bones so your patient doesn’t cry out “Ahh” when you Perform your Plethora of Different Tests”

to remember

Stop = striae, Wait = weight gain, moon face, truncal obesity, buffalo hump, in Line = Another reminder about Striae in case the first was not remembered. C= Cushing, Her= Hirsutism, Bruised skin = B=Bruising, Weak Muscles = proximal muscle weakness, Thin Bones= osteoporosis, Cry= depression, AHH = acne and hirsutism, plethora= plethora (facial), different tests = high cholesterol, high blood sugars (diabetes), and high blood pressure

While many of the signs and symptoms of Cushing's syndrome are nonspecific, the features of this simple memory tool here best distinguish 5 key features of Cushing's syndrome.

Cushing Syndrome in Children

Children can also develop Cushing syndrome. One of the most common presentation in children is progressive weight gain with a halting of growth. In other words, children get heavier and heavier but do not grow taller and taller. Other signs of Cushing in children are weight gain (90%), growth regardation (83%), hirsutism (78%), violaceous striae (61 %), acne (47%), hypertension (47%), fatigue (44%), early sexual development (38 %), bruising (25%), sleep disturbance (8%), mental changes (19%). The remaining symptoms are common to adults.

Who Should we be screening for Cushing Syndrome ?

The Endocrine Society Guidelines recommend screening for CS if

1.    Patient has weight gain and central redistribution of fat

2.    There are multiple progressive features of CS

3.    Patient has unusual features given age (osteoporosis/hypertension in young pt)

4.    All children with retarded growth (i.e. decreasing height percentile and increasing weight)

5.    Adrenal incidentaloma compatible with adenoma.

Exogenous use of corticosteroids should be ruled out.

Tests for Cushing Syndrome: A Look at the Screening Tests

There is a logical approach to evaluating Cushing syndrome. First, “screening tests” are done followed by “diagnostic tests” followed the tests of ACTH dependency and imaging.  It is critically important for first line physicians to recognize how to use and not use the screening tests.

The first point to make about testing is that a random AM cortisol test is unreliable. We do not make diagnosis of Cushing syndrome based on this test.

There are three important “screening tests” to consider in the work up and evaluation of Cushing syndrome. None of these are perfect! However, these tests help identify if the patient might have ‘hypercortisolism.’

These three tests include:

 a) The UFC test. 24 hour urine collection for free cortisol (a positive test shows increased levels)

b) The ODST. An overnight low dose 1 mg dexamethasone suppression test (a positive test shows that AM cortisol levels remain high and are not suppressed as normally would be expected in healthy individuals)

c) The LNSC test. midnight or ‘bedtime’ or ‘late night’ salivary cortisol level (showing that bedtime levels don’t drop to low levels as would normally be expected).

In my province, the cost of an AM cortisol for the ODST is $ 34.00 CAD and the cost of a urinary free cortisol is $ 34.00 CAD. A LNSC is only available through the Vancouver General Hospital Outpatient Lab and fees are around $ 80-100.  Our patients pick up kits for home use between 8 am and 430 pm.

Let’s take a closer look at these screening tests: 

a)    Late night salivary cortisol (LNSC)

Cortisol levels often fall to their lowest levels at bedtime. Salivary cortisol levels are accurate to detect changes in cortisol. Patients with CS have salivary cortisol levels that remain high at bedtime.  The LNSC test is considered by many as the first line test. It has much better sensitivity and specificity than the UFC. It can detect mild cases of Cushing syndrome much better than the UFC test.  

Salivary testing is more difficult to access in some areas. For this reason, it’s not always chosen as the first line test and UFC still tends to be the more common test followed by DST followed by LNSC testing. Despite this, if one has access to the LNSC test, it’s a great test

The LNSC test is easy, non-invasive and can be done at home. Patients store the sample at room temperature and mail back to the lab at room temperature.  This test is not a good one to choose in shift words as their bedtime level may be different. It is also unreliable in smokers, the very ill and those with severe depression and those who brush their teeth too vigorously. Just like the UFC, there is variability in the LNSC and this test might be repeated twice. A test result above 4 nmol/L (145 ng/dL) suggests Cushing syndrome.

Patients who do this test must continue their normal sleep wake lifestyle, avoid tobacco and avoid vigorous teeth brushing. Topical or inhaled steroids must be stopped.

b)    1 mg (or 2 mg) overnight Dexamethasone Suppression Test (1 mg - 2 mg ODST)

For the overnight low dose dexamethasone suppression test, patients are given 1 mg dexamethasone at 11 pm  and this is followed by measurement of a cortisol level the next morning at 8 am. The dexamethasone is prescribed by the doctor and patients pick it up from the pharmacy days before they plan to do the test. In obese individuals, some endocrinologists advise using 2 mg instead of 1 mg to reduce the high rate of false positives. In children, a dose of 0.3 mg/m2 is used. (I use online calculators such as here).

An AM cortisol level above 50 nmol/L (1.8 μg/dl) suggests a positive test and indication of hypercortisolism.

If cortisol levels are suppressed (i.e. are low), then the patient likely does not have Cushing syndrome. If the test is elevated when the morning cortisol is checked, the patient has a positive screen. An elevated morning cortisol does not necessarily mean the patient has Cushing but a suppressed test means the patient probably does not have Cushing syndrome.   Exercise and poor sleep can sometime give a false positive result. Patients who are rapid metabolizers or those with poor GI absorption may also have a false positive result.

The ODST should be avoided in suspected cases of cyclical Cushing syndrome. The UFC and LNSC are better tests in these cases.  The DST is the ideal test to consider in patients with Cushing syndrome due to an adrenal incidentaloma.

c)    24 hr UFC test (24 hr UFC, or simply UFC)

The UFC was once considered the ‘gold standard’ and many authors still believe that it a very good test. . However, it’s important to realize that the test has low sensitivity and specificity and will often miss mild cases of mild Cushing syndrome. To do this test, patients collect their urine at home and return it back to the lab. High fluid intake by the patient, incomplete collection and kidney disease (GFR<60) can further make this unreliable. The UFC test is not a test to choose in patients with kidney disease.

Urinary cortisol tests have a high incidence of false negative and are often repeated 2-3 times if there is a high suspicion of the disease.  There is a great variability of cortisol excretion and that’s why repeating is so important. Again, it is important to emphasize that UFC is often negative in mild cases of Cushing syndrome so a negative test should not detract.  Urinary cortisol lacks sensitivity and really should not be used along to exclude Cushing syndrome.  A negative test certainly does not mean a patient does not have CS.

Each lab will set a number as their own cut off number for a positive result.  Results above this number indicate hypercortisolism.

The UFC test should be avoided in cases of suspected mild Cushing syndrome or in those with kidney disease or suspected pseudo Cushing syndrome.  The ODST and LNSC are better tests in these cases.  The UFC is the ideal test if Cushing syndrome is suspected during pregnancy.

There is no perfect test and all have potential for false positive and false negative.  The late nigh salivary cortisol is one of the best tests and is viewed by many as the test of choice.  At least two first-line tests should be abnormal to diagnose Cushing syndrome but generally speaking if one of the first line tests is positive, I refer to an endocrinologist.

These three screenings tests have false positives and false negatives and input of an endocrinologist is helpful.  If the screening tests are negative and the index of suspicion for Cushing syndrome is low, then the work up is finished and the patient probably does not have Cushing syndrome. If a screening test is negative but index of suspicion is high, screenings tests may be repeated or more screenings tests done.  Generally Urinary free cortisol is repeated 2 or 3 times before stating it is negative. Midnight salivary cortisol may also need two tests given how variable the salivary cortisol can be.

From Screening Test to Confirmatory Tests

One the patient is shown to have ‘hypercortisolism’ (i’e’ one or more of these 3 screenings tests are felt to be positive), the next step is to perform various “confirmatory tests” and then to localize the precise source. These tests are a lot more sophisticated and include such tests as ACTH blood tests, potassium measurements, high dose dexamethasone suppression test, corticotrophin releasing hormone testing and inferior petrosal sinus sampling. Testing usually begins by measuring an ACTH level. If ACTH levels are high, and a pituitary source is suspected an MRI of the pituitary is done. If ACTH levels are high, and an ectopic source of ACTH is suspected a chest x-ray and CT of the chest is done. If ACTH levels are low/normal (ie ACTH independent CS), a CT scan of the adrenals is done.

Treatment of Cushing Syndrome

Treatment of CS is important to reduce both morbidity and mortality. Undiagnosed or untreated CS increases the risk of cardiovascular disease, poor wound healing, fractures, infection and depression. In children, it is associated with growth retardation. Untreated Cushing syndrome also increases mortality. Cardiovasculcar disease and infections is a leading cause of death in Cushing syndrome. Older age, ACTH levels before surgery, duration of having high cortisol levels, diabetes and high blood pressure are known factors that increase the risk of death.

Treatment of Cushing syndrome will depend on the precise cause. If pituitary Cushing is the cause (ie so called Cushing disease),  a neurosurgeon may perform surgery on a pituitary adenoma. If the adrenal gland is the cause, a surgeon will perform adrenal surgery.  Sometimes adrenal surgery is also performed in pituitary Cushing if cortisol levels are not suppressed.  

 Radiation and various medical therapies are also administered in some refractory cases and in some special circumstances.

 Referral to centres with specific expertise in Cushing syndrome is the ideal plan as outcomes are often better. Not all patients have access to neuroendocrinologists and pituitary neurosurgeons but this is ideal.

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Androgenetic Hair Loss in Cushing Syndrome

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