Cushing's syndrome

Cushing’s syndrome, also known as hypercortisolism, is a collection of symptoms that develop due to very high levels of a hormone called cortisol in the body.

Introduction

Cushing’s syndrome, also known as hypercortisolism, is a collection of symptoms that develop due to very high levels of a hormone called cortisol in the body.

The symptoms of Cushing’s syndrome include:

  • weight gain
  • thinning skin that bruises easily
  • reddish-purple stretch marks on the thighs, stomach, buttocks, arms, legs or breasts
  • fat deposits that develop in the face, causing it to become round
  • decreased interest in sex

What causes Cushing’s syndrome?

Cushing’s syndrome often develops as a side effect of treatment with corticosteroids. Corticosteroids are widely used to reduce inflammation and treat autoimmune conditions (where the immune system malfunctions and attacks healthy tissue).

People who take high doses of corticosteroids, long-term, often have a build-up of cortisol in their blood. This type of Cushing’s syndrome is sometimes called iatrogenic Cushing’s syndrome.

A less common cause of Cushing’s syndrome is where a tumour (growth) develops inside one of the body's glands, causing it to produce an excessive amount of hormones. This type of Cushing’s syndrome is known as endogenous Cushing’s syndrome.

Read more about the causes of Cushing’s syndrome.

Diagnosing Cushing's syndrome

Cushing’s syndrome can be difficult to diagnose because the symptoms are similar to those of other, more common conditions, such as an underactive thyroid gland and high blood pressure.

Your doctor will need to know whether you have been taking medication and you'll probably need to have a urine test, blood test and/or a saliva test to measure the levels of cortisol in your body.

Read more about how Cushing's syndrome is diagnosed.

Treating Cushing’s syndrome

The main treatment for iatrogenic Cushing’s syndrome is to decrease or withdraw the use of corticosteroids. However, this must be done gradually to avoid any unpleasant side effects.

For endogenous Cushing’s syndrome, surgery to remove the tumour is usually recommended. If surgery is unsuccessful, or it is not possible to remove the tumour safely, medication can be used to counter the effects of the high cortisol levels.

Although treatment is effective, it can take some time to bring the symptoms under control. Anytime from a few weeks to a few years in some cases.

Left untreated, Cushing's syndrome can cause high blood pressure which increases the risk of heart attack and stroke.

Read more about treating Cushing’s syndrome.

Symptoms

The pattern of symptoms in Cushing’s syndrome can be highly unpredictable.

In some cases, the symptoms can develop quickly and be very severe. In other cases, the symptoms can develop gradually and be much milder.

Weight gain and fat deposits

Weight gain is the most common symptom of Cushing's syndrome, particularly on the chest, stomach and face. It occurs because cortisol causes fat to be redistributed to these areas.

People with Cushing's syndrome tend to have:

  • slim arms and legs compared with their chest and stomach
  • fat deposits on the back of the neck and shoulders; this is known as a 'buffalo hump'
  • a red, puffy and rounded face

Children who develop Cushing’s syndrome tend to be obese and have slow growth rates.

Skin changes

Symptoms that affect the skin include:

  • thin skin that bruises easily because cortisol causes proteins in the skin to break down and tiny blood vessels to become weak
  • reddish-purple stretch marks on the thighs, stomach, buttocks, arms, legs or breasts because cortisol makes the skin fragile
  • spots on the face, chest or shoulders
  • darkened skin on the neck
  • swollen ankles due to a build-up of fluid (oedema)
  • heavy sweating (hyperhidrosis)
  • bruises, cuts, scratches and insect bites can take a long time to heal

Bones and muscles

People with Cushing's syndrome often have muscle weakness in their hips, shoulders, arms and legs.

Too much cortisol can also cause the bones to become brittle (osteoporosis). This may lead a bone breaking during normal day activities, such as bending and lifting.

Depression and mood

Depression is common in people with Cushing’s syndrome. It is also common to feel unusually tired all the time, which can contribute to feelings of depression.

Many people with Cushing’s syndrome also experience rapid mood swings and have emotional reactions that may seem inappropriate, such as laughing or crying for no apparent reason.

Other symptoms

Other symptoms of Cushing’s syndrome include:

Causes

Most cases of Cushing's syndrome are related to the use of corticosteroid medication.

This is known as Iatogenic Cushing's syndrome.

Corticosteroids are used to:

Corticosteroids are available in a number of different forms, including tablets (oral corticosteroids), sprays and inhalers (inhaled corticosteroids), creams and lotions (topical corticosteroids) and injections.

To help prevent side effects, corticosteroids are usually prescribed at the lowest possible effective dose. However, in people with severe symptoms that fail to respond to other forms of treatment, the only effective alternative is to prescribe a long-term course of high-dose corticosteroids.

Corticosteroids contain a synthetic (man-made) version of the cortisol hormone. Prolonged use can lead to cortisol levels building up and triggering Cushing’s syndrome. Misusing corticosteroids, or taking more than the recommended dose, also increases your risk of developing Cushing’s syndrome.

The risk of developing Cushing’s syndrome is higher in people who take oral corticosteroids (tablets), but it can also affect those who misuse inhaled or topical corticosteroids.

Endogenous Cushing’s syndrome

A much rarer type of Cushing's syndrome, known as endogenous Cushing's syndrome is caused by the body producing more cortisol than it needs.

The most common reason for this is a tumour (an abnormal growth of cells) which develops in the pituitary gland.

The pituitary gland is a pea-sized gland in the brain. It produces a hormone called adrenocorticotropin hormone (ACTH) which stimulates the adrenal glands, which in turn release cortisol into the blood.

The tumour can disrupt the normal workings of your pituitary gland so that it produces excessive amounts of ACTH, this causes the adrenal glands to produce too much cortisol.

Less commonly, a tumour develops inside one of the adrenal glands, leading to endogenous Cushing’s syndrome.

Another less common cause, is a tumour developing inside the lungs and producing the ATCH hormone, known as ectopic ACTH syndrome. This type of Cushing’s syndrome is more common in men.

Tumours that develop inside the pituitary or adrenal gland are usually benign (non-cancerous). Other than the symptoms of Cushing’s syndrome, they do not usually pose a serious threat to a person's health. Tumours that develop inside the lung can sometimes be cancerous. However, it is unclear why these tumours develop.

Diagnosis

Diagnosing Cushing’s syndrome can often be challenging, particularly when the symptoms are mild.

As the symptoms of Cushing’s syndrome are similar to those of other, more common conditions, such as an underactive thyroid gland and high blood pressure (hypertension), you may be referred for a number of different tests. As a result, it could be several months before Cushing's syndrome is confirmed.

Your will want to know whether you are taking any medication because the use of corticosteroids is the main cause of Cushing’s syndrome.

Tell your doctor about all the medication you are taking, including tablets, creams and lotions, plus any natural remedies. Some natural remedies contain steroids.

Testing for cortisol

If Cushing's syndrome is suspected, the amount of cortisol in your body will be measured using one or more of the following tests:

A saliva test is most accurate when it is carried out in the middle of the night, so you may be asked to stay in hospital overnight.

Before taking a urine test, you may be given a medication called dexamethasone. If you are otherwise healthy, dexamethasone should decrease your cortisol levels. If your cortisol levels are unaffected, it could be due to Cushing’s syndrome.

None of the above tests are completely accurate or reliable, but if you have one or more abnormal results, you will usually be referred to an endocrinologist (a doctor who specialises in treating hormonal conditions). They should be able to confirm or rule out a diagnosis of Cushing’s syndrome.

Finding the underlying cause

After being diagnosed with Cushing’s syndrome, it will be necessary to establish the underlying cause (unless you are currently taking corticosteroids). Finding out what is causing Cushing's syndrome will help determine your course of treatment.

The first stage is to find out whether Cushing’s syndrome is being caused by high levels of the adrenocorticotropin hormone (ACTH) in your blood.

If it is, it would suggest that there is a tumour in your pituitary gland or, less commonly, in your lungs. Low levels of ACTH would suggest that there is a tumour in one of your adrenal glands.

A suspected tumour can usually be confirmed by a magnetic resonance imaging (MRI) scan, which uses a strong magnetic field and radio waves to produce detailed images of the pituitary gland.

Occasionally, despite having an MRI scan, it can be difficult to determine exactly where the tumour is located. In such circumstances, a further test, known as petrosal sinus sampling, may be recommended.

A blood sample will be taken from the veins of your pituitary gland and your forearm, and the level of ACTH in both samples will be compared. If the level is higher in the pituitary vein, the cause is probably a tumour in your pituitary gland. If levels are similar, the cause is probably a tumour elsewhere in your lungs. Further X-rays and MRI scans of your chest may be carried out to check the tissues of your lungs.

It can often take a considerable amount of time before all of the investigations have been completed and a full diagnosis is made. Repeated X-rays and scans are sometimes required.

While waiting for the test results, your doctor may decide to treat your Cushing's syndrome with medication, such as [metyrapone], to reduce the amount of cortisol. If this is the case, you will have to stay in hospital for a few days so that you can be monitored while taking the tablets.

You may also have a special type of X-ray called a DEXA scan, which can be used to check for any weakening of your bones (osteoporosis).

Treatment

Treatment for Cushing's syndrome will depend on what is causing the high levels of cortisol to accumulate in your body.

If your Cushing's syndrome is caused by the long-term use of corticosteroids (iatrogenic Cushing’s syndrome), you will need to gradually reduce your dosage to the lowest possible dose required to control the condition being treated (see below).

If your Cushing's syndrome is caused by a tumour (endogenous Cushing’s syndrome), the following treatment options are available:

Reducing corticosteroid use

It is usually not safe to suddenly stop taking corticosteroids.

If you have been taking corticosteroids for a long time, your body may stop producing natural steroids. If you suddenly stop taking your medication, you may experience symptoms such as fatigue, vomiting and diarrhoea.

Also, you may need to continue taking your medication until the symptoms of the condition being treated are under control.

If you have only been taking corticosteroids for a few days, it may be possible to safely stop the dose straight away.

There is no ‘one size fits all’ plan for withdrawing treatment with corticosteroids. However, for most people, a gradual reduction is recommended. After a while a blood test should tell if your body is producing natural steroids.

It is only safe to stop taking steroids completely once your body is producing them naturally. This can take from a few months to more than a year. During this time you may need treatment for some of the symptoms of Cushing's syndrome, such as medication to lower your blood pressure.

Cortisol-inhibiting medications

Cortisol-inhibiting medications are designed to block the adverse effects of cortisol. They tend to be used short-term as a preparation for surgery or for a short time after surgery or radiotherapy to help make these treatments more effective.

Occasionally, cortisol-inhibiting medications are used on a long-term basis in people unwilling or unable to have surgery. Ketoconazole and [metyrapone] are two widely used cortisol-inhibiting medications.

Ketoconazole is not licensed for the treatment of Cushing’s syndrome. This means the manufactures designed and tested the medication for treating another condition (fungal infection), and it was subsequently found to also be useful for treating Cushing’s syndrome.

However, there have been no large scale safety trials of ketoconazole in people with Cushing’s syndrome. The doctor in charge of your care will be able to provide more information about ketoconazole.

Find out more about the [medicines that are licensed to treat Cushing's syndrome].

Surgery

Surgery may be needed to remove a tumour in the pituitary gland or adrenal gland. Removing a tumour from the lungs is much more challenging and may not be possible.

Pituitary gland removal

Surgery to remove a tumour in the pituitary gland is known as transsphenoidal adenoectomy. Under general anaesthetic, the surgeon removes the pituitary tumour either through your nostril or an opening made in your upper lip.

This type of surgery has a good track record of success. More than 80% of cases are cured. If necessary, the procedure can be repeated, usually with very good results.

Adrenal gland removal

In most cases, only one adrenal gland will need to be removed. To do this, laparoscopic (keyhole) surgery is usually used.

During the procedure, the surgeon makes a small incision in your abdomen and passes tiny instruments through it to remove your adrenal gland. The advantage of this approach is that you will feel less pain after surgery and have minimal scarring.

Laparoscopic surgery has a good record of success, with over 65% of people’s symptoms being completely cured.

In some cases, removing both of your adrenal glands may be recommended, so that they are unable to produce cortisol. This may be needed if your Cushing’s syndrome symptoms put your long-term health at risk – for example, if you have poorly controlled high blood pressure (hypertension).

Lung tumour

If the tumour is located deep inside your lung, it may not be possible to destroy or remove it safely without seriously damaging the lung.

If this is the case, an alternative approach may be recommended, such as using cortisol-inhibiting medication or completely removing the adrenal glands to stop the production of cortisol.

Radiotherapy

Radiotherapy may be recommended if pituitary gland surgery is unsuccessful or if you are unable to have surgery. It involves using high-energy X-rays to shrink the tumour.

A type of radiotherapy known as stereotactic radiosurgery (SRS) is increasingly being used to treat pituitary tumours. It uses a series of movable frames to hold your head in a precise position. A computer is then used to send energy rays to the exact location of the pituitary tumour.

SRS minimises the chances of other parts of your brain being accidentally damaged. It usually takes just one session. As the procedure is only available at a number of specialised centres, it's likely you will have to travel to receive treatment. There may also be a waiting list for treatment.

The results of SRS are good, with around 75% of people's symptoms being completely cured.

Complications of surgery

Complications can sometimes develop following surgey for Cushing's syndrome. Loss of hormonal function and Nelson's syndrome are two possible complications. These are described below.

Loss of hormonal function

The surgeon will try to save as much of your pituitary or adrenal gland as possible to preserve their normal functions of producing hormones. However, in some cases, this may not possible, particularly if you have a large tumour.

If you have both of your adrenal glands removed, you'll lose normal hormonal function. Radiotherapy also increases your risk of losing normal hormonal function.

If you lose normal hormonal function, you'll need to take synthetic (man-made) hormones. This is sometimes known as hydrocortisone replacement therapy (not to be confused with hormone replacement therapy, which is often used to treat the menopause).

Hydrocortisone comes in tablet form. Most people need to take two to three tablets a day. If your glands recover their normal function after a few months, treatment can be stopped. However, it may be that you need to take hydrocortisone for the rest of your life.

Most people tolerate hydrocortisone well, but it can take a while to work out the best dose for you. During this time, you may experience some Cushing's syndrome-like side effects, such as weight gain and thinning of your skin.

Nelson’s syndrome

Nelson’s syndrome is a fairly common complication that occurs in people who have had both of their adrenal glands removed because they were unresponsive to surgery or radiotherapy.

Nelson’s syndrome is a rapidly growing tumour inside your pituitary gland. The symptoms include:

  • darkening of your skin
  • headaches
  • vision problems, such as partial vision loss](yourmd:/condition/visual-impairment/introduction) or [double vision

The cause of Nelson’s syndrome is poorly understood. One study carried out several years ago found that one in four people who had both adrenal glands removed went on to develop Nelson’s syndrome. However, this figure is likely to be lower today due to improvements in the treatment of Cushing’s syndrome.

The recommended treatment for Nelson’s syndrome is to surgically remove the tumour. This may be followed by an additional course of radiotherapy.

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