Cushing’s syndrome: when cortisol floods the blood

Overview: What is Cushing's syndrome?

Cortisol is a vital endogenous hormone that is produced in the adrenal cortex. Cortisol belongs to the group of glucocorticoids, which have an effect on your metabolism, cardiovascular and nervous system, among other things. Cortisol is also known as the stress hormone because your body produces more of it when it is constantly exposed to increased demands.

If the level of cortisol in your body is too high in the long term, a group of symptoms develops which are summarized by the term Cushing’s syndrome. The clinical picture is named after the American doctor Harvey Cushing.

Cushing’s syndrome is one of the rare diseases. For this reason, and because there can be numerous signs, it takes an average of three years before a diagnosis is made. Women are affected three to four times more frequently than men. Most cases occur between the ages of 20 and 50. But children and the elderly can also suffer.

Depending on why too much cortisol is circulating in your body, medical experts distinguish between two forms of Cushing’s syndrome:

• Endogenous Cushing’s syndrome: In this rarer form, which originates “internally”, hypercortisolism is usually caused by tumors in the pituitary gland, in the adrenal cortex or, more rarely, by other tumors.
• Exogenous Cushing’s syndrome: This form caused from “outside” is the result of drug therapy with glucocorticoids in the form of tablets, injections or infusions

Cushing's syndrome: causes and risk factors

Cushing’s syndrome is always caused by a prolonged excess of cortisol in the body, known as hypercortisolism.

Exogenous Cushing’s syndrome: caused by medication

More often, Cushing’s syndrome has external causes. This type of exogenous Cushing’s syndrome is caused by long-term treatment with certain medications:

Glucocorticoids (cortisone): The inactive precursor of cortisol in the body is called cortisone. Synthetically produced glucocorticoids, which are used as medication, are also known colloquially as cortisone. After your body has converted it into cortisol, the active ingredient cortisone has an anti-inflammatory and immune-suppressing effect. We therefore use cortisone, for example, to treat many autoimmune diseases and chronic inflammations such as multiple sclerosis, Crohn’s disease and ulcerative colitis.

In high doses and administered over a longer period of time, the medication can lead to undesirable side effects that correspond to the symptoms of endogenous Cushing’s syndrome. In addition, taking the medication can lead to habituation, so that a rapid discontinuation of the medication results in a short-term adrenal insufficiency.

Endogenous Cushing’s syndrome: the body’s own overproduction

The rare endogenous Cushing’s syndrome occurs when the body produces too much cortisol without external influences. This can occur both ACTH-dependent and ACTH-independent:

ACTH-dependent endogenous Cushing’s syndrome

If endogenous Cushing’s syndrome develops in an ACTH-dependent manner, this means that your organism produces too much of the control hormone ACTH, which subsequently causes the adrenal glands to produce too many glucocorticoids. The most common causes are benign tumors (adenomas) or malignant tumors (carcinomas) that produce ACTH:

• Central Cushing’s syndrome: In this more common form, hypercortisolism is caused by a benign tumor of the pituitary gland (Cushing’s disease).
• Paraneoplastic or ectopic Cushing’s syndrome: The cause of this form is an atypically high ACTH output, usually caused by so-called neuroendocrine tumors.

ACTH-independent endogenous Cushing’s syndrome

If an endogenous Cushing’s syndrome develops independently of the control hormone ACTH, then the reasons for this lie in the adrenal gland itself (i.e. adrenal).

In these cases, adenomas or carcinomas of the adrenal cortex are responsible for the increased cortisol production. In rare cases, benign tissue growths on both adrenal glands (so-called hyperplasia) are also responsible for the disease.

Frequency of Cushing’s syndrome

In most cases, Cushing’s syndrome appears in the exogenous form, i.e. as a result of long-term drug treatment with glucocorticoids.

Endogenous Cushing’s syndrome (hypercortisolism) is a rare disease with a frequency of around 2-5 cases per 1 million inhabitants per year. Women between the ages of 30 and 50 are particularly affected.

Symptoms: a variety of changes

The hormone cortisol performs a wide range of tasks in the human organism. For example, it is involved in protein, sugar and fat metabolism, regulates blood pressure and influences the immune system. Because of this multitude of functions, the characteristics of Cushing’s syndrome are also diverse.

The main symptoms of Cushing’s syndrome are as follows:

• So-called trunk obesity, i.e. fat deposits that mainly form on the trunk of the body, i.e. the upper body, abdomen and hips. Arms and legs are not affected, but are often conspicuously thin due to muscle weakness.
• The typical moon face (facies lunata), i.e. a round, reddened face
• High blood pressure (hypertension)
• Absence of menstruation (amenorrhea) in women

A whole range of other symptoms may occur, but not necessarily. As a rule, they do not all appear at the same time.

Other possible symptoms

• The so-called buffalo or bull neck, which means that more fat accumulates on the neck.
• Elevated cholesterol levels: Those affected often have a large amount of cholesterol in their blood.
• Diabetic metabolic condition: Because the blood sugar is elevated due to the excess cortisol, the body releases more insulin. This creates a situation similar to diabetes.
• Muscle weakness and reduced bone density: cortisol breaks down collagen, connective tissue and bone material.
• Bone and back pain after fractures, for example of the spine
• Skin changes: The skin density decreases (parchment skin), sometimes red stretch marks appear, especially on the stomach. Impaired wound healing, acne and boils can also occur.
• Masculinization: Women grow more body hair in areas typical for men, i.e. on the chin, upper lip or chest (hirsutism).
• Potency problems and declining libido in both sexes
• Psychological problems: mood swings, anxiety, depressive symptoms

Cushing's syndrome: diagnosis at the USZ

Cushing’s syndrome is a rare disease and requires special clinical experience and expertise as well as technical requirements in order to make a diagnosis quickly and reliably and to draw the right therapeutic conclusions. The Department of Endocrinology, Diabetology and Clinical Nutrition has established special outpatient clinics for adrenal and pituitary diseases, where patients are treated according to the latest recommendations and guidelines. The clinic itself plays a leading role in national and international research projects that give patients access to the latest developments in this field.

If there is a clinical suspicion that you are suffering from Cushing’s syndrome, we will first take a thorough medical history with you to find out whether medication is responsible for an exogenous form of the disease. If this is not the case, we will measure the cortisol level in your blood, saliva and urine. A value that is too high is the main feature of the syndrome.

For the dexamethasone inhibition test (short test), you will be given the glucocorticoid dexamethasone in the evening. This signals to your body that it should no longer produce its own cortisol. If you still have an elevated cortisol level in your blood the next morning, this is a good indication of Cushing’s syndrome. However, stress, depression or various medications can also distort the result. For this reason, we will probably also measure the hormone in your 24-hour urine and/or in a daily saliva profile to be on the safe side.

If there are indications of endogenous Cushing’s syndrome, we must clarify whether it is an ACTH-dependent or an ACTH-independent form. For this reason, we have the concentration of the hormone ACTH determined in the blood serum:

• If ACTH levels are low, a tumor on the adrenal cortex, for example, could have caused adrenal Cushing’s syndrome.
• If the ACTH level is elevated, this is usually due to a benign tumor of the pituitary gland (Cushing’s disease). However, malignant tumors (carcinomas) can also stimulate the production of ACTH and thus trigger Cushing’s syndrome.

The next step is to determine whether tumors have triggered Cushing’s syndrome. Further functional tests and imaging procedures such as computer tomography, X-ray, angiography or scintigraphy are used for this purpose.

Cushing's syndrome: prevention, early detection, prognosis

You can only prevent the more common exogenous Cushing‘s syndrome caused by medication. If you need to take a glucocorticoid (e.g. cortisone) for another condition, such as asthma or rheumatoid arthritis, this should be done under strict medical supervision. It is important that the therapy is closely monitored by your doctor and is only temporary.

The much rarer form of endogenous However, you cannot prevent Cushing‘s syndrome. The same applies to early detection of Cushing’s syndrome. It is possible for the exogenous variant if the therapy is closely monitored. There is no possibility of early detection for the endogenous form, partly because the symptoms are so varied.

Prognosis Cushing’s syndrome

The prognosis for exogenous Cushing’s syndrome is good. It is crucial to discontinue the triggering drug or reduce its dose. This should be done in consultation with your doctor. The prognosis for endogenous Cushing’s syndrome depends on how well the triggering disease, usually a tumor, can be treated.

The course of Cushing’s syndrome depends on the cause. In most cases, treatment ensures a favorable prognosis: the success rate is between 50 and 80 percent.

• If it occurs as a side effect of long-term treatment with certain medications, for example a glucocorticoid, it disappears again when you stop taking the medication.
• The syndrome can also be cured relatively well with early treatment if it is caused by a benign tumor of the pituitary gland (known as Cushing’s disease).
• Cushing’s syndrome, caused by a benign adrenal adenoma, is also relatively easy to cure.
• The prognosis is less positive if the cause was an adrenal carcinoma or another malignant tumor.

Cushing’s syndrome complications

Cushing’s syndrome can cause various complications that affect bone and muscle metabolism, among other things, and manifest themselves in osteoporosis or long-term muscle weakness. If it remains untreated, those affected can even die from it after months or years – for example due to infections, changes in blood salts or the consequences of high blood pressure. If they develop psychological symptoms, there is also an increased risk of suicide without treatment.

If long-term treatment with glucocorticoids is discontinued quickly and uncontrolled, life-threatening adrenal hypofunction may remain, which must be treated with further – low-dose – hormone replacement therapy.

Self-help groups

The exchange with people who are affected by the same disease can be a great support in coping with the disease. Advice on finding a suitable self-help group is available from Selbsthilfe Zürich. Self-Help Zurich and the University Hospital Zurich are cooperation partners in the national project “Health literacy thanks to self-help-friendly hospitals”.

Cushing's syndrome: treatment depends on the cause

The treatment of Cushing’s syndrome depends on its trigger. In any case, the aim of treatment is to normalize the elevated cortisol level. This is usually achieved by surgery, in rarer cases or as a bridging measure with medication. It can take up to several months for the effects of Cushing’s syndrome to subside.