What is it?

Cushing’s syndrome is an endocrine disorder that presents with a constellation of signs and symptoms resulting from long term exposure to cortisol. Cortisol is a hormone produced by the adrenal glands (endocrine glands located above the kidneys) which is important for normal growth and metabolism. Cushing’s syndrome develops when you are taking too much corticosteroid medication (exogenous Cushing’s syndrome) for various medical conditions, or when your body produces too much cortisol (endogenous Cushing’s syndrome).

What are the signs and symptoms?

The signs and symptoms of Cushing’s syndrome can vary depending on the amount of excess cortisol. The effects on the body is multifactorial and include the following:

• Unintentional weight gain. The trunk is getting more fat while arms and legs get thinner. The face may become puffy and more rounded. Fat pad on the back of neck can also be noted.
• There is flushing or reddening of the face. The skin becomes thin and brittle. There can be bruises which bleed easily. For women, there may be unusual facial and body hair growth. Broad and purple stretch marks around the abdomen can also be seen.
• There is reduced bone mass and strength, which can lead to fractures.
• There is muscle weakness, thinning of buttocks and upper leg muscles, which may result in difficulty climbing stairs or getting up from a chair.
• Elevation of blood pressure.
• Elevation of blood sugar, or impaired glucose tolerance.
• There may be decreased sexual drive; menstrual irregularities in women.
• Neurological manifestations such as Irritability, depression, forgetfulness or impaired memory.
• There is increased susceptibility to infections.

What are the causes?

Intake of excess corticosteroid medication

Cushing’s syndrome can develop from taking oral corticosteroid medicines, such as prednisone or dexamethasone, in high doses and in prolonged periods of time. Cushing’s syndrome can also develop in a small number of people from other forms of corticosteroid medications, like injectable steroids for knee or joint pains, inhaled steroids for asthma or emphysema, and corticosteroid creams applied over the skin for various skin disorders such as atopic dermatitis (eczema).

When your body produces too much cortisol

Endogenous Cushing’s syndrome can occur when your body produces too much cortisol or too much ACTH that regulates the production of cortisol. It may be one of the following:

• Pituitary gland tumor (pituitary adenoma) is a usually a benign (non-cancerous) tumor of the pituitary gland (located at the base of the brain) which produces excessive amount of ACTH, which in turn stimulates the adrenal glands to make more cortisol. When this form of the syndrome develops, it is called Cushing’s disease. It is the most common form of endogenous Cushing’s syndrome, affecting more women than men.
• An ACTH-secreting tumor is a rare tumor that develops in an organ that normally doesn’t produce ACTH. Excess ACTH will stimulate the adrenal gland in turn to produce excessive cortisol. These tumors are usually found in the lungs, pancreas, thyroid or thymus gland, and can either be benign (non-cancerous) or malignant (cancerous).
• Primary disorders of the adrenal glands cause increased production of cortisol. The most common is an adrenal adenoma, which is a non-cancerous tumor of the adrenal gland. Cancerous tumors of the adrenal cortex are rare. Sometimes, benign, nodular enlargement of both adrenal glands appear and can result in Cushing syndrome.

How is it diagnosed?

If you are taking corticosteroid medications in excess or in the long term, it can already be pointed out as the reason for Cushing’s syndrome, and no more testing is needed.

However, if intake of corticosteroid medications has been ruled out, your doctor will request for several tests, which may include the following:

• Blood tests measure the level of hormones in the body and determine whether there is excess production of cortisol. Specialized tests may also be done to determine the level of cortisol.
• Urine test. Cortisol in excessive amounts can be found in the urine. A 24-hour urine collection may be requested to measure the amount of cortisol. If an excessive amount of cortisol is found in the urine, it may translate to an excessive amount of cortisol in the blood.
• Imaging tests such as computed tomography (CT) scan or a magnetic resonance imaging (MRI) may be requested to get images of your pituitary or adrenal glands to detect the presence of tumors.
• Saliva test. The amount of cortisol present from a saliva taken late at night can be measured to detect elevated levels of cortisol. Cortisol levels normally increase and fall throughout the day.
• Petrosal sinus sampling is a specialized test where samples of your blood is taken from the vein and tested to determine if the Cushing’s syndrome originates from the pituitary or somewhere else.

How is it treated?

If the cause of Cushing’s syndrome is long-term use of corticosteroid medications, your doctor can help adjust your medications to keep signs and symptoms under control.

If the cause of Cushing’s syndrome is a tumor, your doctor may recommend a complete surgical removal. Pituitary tumors are removed by a neurosurgeon. Tumors found in the adrenals, lungs or pancreas are removed by a surgeon by standard operation or minimal invasive procedure such as laparoscopic surgery.

Radiation therapy is reserved for inoperable tumors or when tumors are not completely removed, or for patients who are not suited for surgery.

There are several medications used to control cortisol production when surgery or radiation won’t work. It may also be given to control Cushing’s syndrome signs and symptoms if a patient is too sick to minimize the surgical risk. Medications include metyrapone, ketoconazole, mitotane, or etomidate, which blocks excessive production of cortisol from the adrenal gland. Mifepristone is a drug that blocks the effect of cortisol on your tissues and it is approved for patients with type 2 diabetes or elevated blood sugar. Side effects from these medications may include weakness, nausea, vomiting, body pains, headaches, high blood pressure, neurological side effects or liver toxicity.

What are the complications?

If left untreated, the complications of Cushing’s syndrome include:

• Excess cortisol leads to obesity, hypertension, diabetes, and high cholesterol levels which are risks for heart attack or stroke.
• The condition may lead to a condition of hypercoagulable state, meaning your blood clots more easily, which may lead to vascular occlusion and thrombosis.
• Neurological complications, such depression, anxiety, memory dysfunction, poor visual memory, impaired decision making and sleep disturbance may happen.
• Excess cortisol can result in suppression of your immune system leading to increased susceptibility to infection and sepsis (severe infection).
• The bones can become brittle and lose strength, resulting in osteoporosis and fractures.

When to see an endocrinologist?

If you are experiencing signs and symptoms indicative of Cushing syndrome contact your doctor for proper evaluation and treatment.

References:

1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015 Aug 29;386(9996):913-27. doi: 10.1016/S0140-6736(14)61375-1. Epub 2015 May 21. PMID: 26004339.
2. Jameson, J. L. et al. Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill; c2018. Chapter 379, Disorders of the Adrenal Cortex; p 2719-2739.
3. Melmed, S. et al. Williams Textbook of Endocrinology, 14th ed. Philadelphia: Elservier; c2020. Chapter 15, The Adrenal Cortex; p 480-541.
4. https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/symptoms-causes/syc-20351310.