What is Cushing's Syndrome

The following presentation was originally written by Prof. Dr. med. Wiebke Arlt, University of Birmingham, Great Britain, and in 2012 and 2020 by Prof. Dr. med. Martin Fassnacht, University Hospital W├╝rzburg, updated.

Clinical picture and symptoms

The clinical picture of Cushing's syndrome is the result of a pathologically increased production of the adrenal hormone cortisol. The vast majority of Cushing's diseases are caused by a benign tumor in the pituitary gland that causes an overproduction of the ACTH hormone. If this is the case, it is called Cushing's disease (Cushing's disease). This ACTH then stimulates adrenal hormone production, causing an increase in cortisol in the blood. In addition, the source of ACTH overproduction can also be found in other organs (so-called ectopic Cushing's syndrome). In addition, adrenal gland tumors (benign adenomas or malignant carcinomas) can directly produce cortisol.

One of the signs of the disease is that Weight gain, especially on the trunk. Hamster cheeks and sometimes a round so-called full moon face also appear. Typically, your arms and legs stay slim. This can result in stretch marks on the abdomen, hips and armpits that are similar to stretch marks, but are wider and through minor bleeding often appear red (red stripes - Striae rubrae). However, only a very small proportion of people who gain weight have Cushing's syndrome. Cushing's syndrome leads to increased vascular fragility also to the more frequent occurrence of bruises as well as to a poor wound healing. As further signs on the skin, there may be increased body hair of the male type (= hirsutism) in an affected woman and in both sexes acne come. The skin can also become thinner overall ("parchment skin"). Typically, the monthly menstrual period of affected women becomes irregular or does not occur at all (amenorrhea). Often it comes to one Loss of muscle strength (Myopathy), which particularly affects the muscles of the buttocks and thighs. This typically creates difficulties climbing stairs or getting up from a crouch. Furthermore, too much cortisol can have a negative effect on the mind and affect the mood and trigger an increase in anxiety and depressive thoughts as well as mood swings.

Too much cortisol also has serious metabolic and circulatory effects. So it can be an appearance Diabetes come (diabetes mellitus), which corresponds to the so-called adult diabetes type. The effect of cortisol on the blood pressure regulation system in the kidney can increase high blood pressure lead and at the same time go hand in hand with a depletion of the body in potassium. A low level of potassium in the blood is potentially dangerous for the maintenance of normal circulatory function, especially a regular heart rhythm. Too much cortisol also has an unfavorable effect on the bones and leads to a loss of bone mass (osteoporosis). Depending on how pronounced Cushing's disease is, this can lead to fractures of the vertebral bodies, which is usually expressed as sudden back pain.

Diagnostic procedure

Endocrinological function diagnostics

If the clinical picture suggests Cushing's syndrome, the first step is to prove the disease by means of laboratory tests. There are currently 3 standard tests for this, at least one (often several) of which are used. The so-called dexamethasone test tries to suppress the body's own cortisol production by taking tablets in the evening. If a blood sample the next morning shows that the body continues to produce too much cortisol, this can be interpreted as an indication of Cushing's syndrome. The same applies if the cortisol excretion in the 24-hour urine or the cortisol in the saliva or blood is significantly increased late in the evening.

Once evidence of Cushing's disease has been provided, the Differential diagnostics through further tests with blood samples (CRH test, high-dose dexamethasone test) to confirm that the cause of the disease is to be found in the pituitary gland (pituitary gland), which applies in approx. 80% of cases. In a minority of sufferers, the cause can be the adrenal gland itself (adrenal Cushing's syndrome) or an accumulation of cells outside of the adrenal gland and pituitary gland (so-called ectopic Cushing's syndrome). Cushing's adrenal syndrome is easy to diagnose, but sometimes it is difficult to differentiate between a tumor in the pituitary gland or elsewhere in the body. In particular, if no tumor is found in the pituitary gland in the imaging (see below) and the test results are ambiguous, a so-called selective petrosal sinus catheter carried out. Under X-ray control, a tiny catheter tube is pushed into the blood vessels close to the pituitary gland and the examination of the blood taken there can determine whether the source of the hormone overproduction is the pituitary gland.

Imaging procedures

The most authoritative method of imaging the pituitary gland is the Magnetic resonance tomography (also MRI)which can represent tumors up to 2 mm in size. Nevertheless, even if the cause of the disease is pituitary, it is sometimes not possible to detect a tumor on the MRI image. Typically, pituitary tumors that cause Cushing's disease are very small, and if they are smaller than 2 mm, magnetic resonance imaging cannot show them. Therefore, an inconspicuous magnetic resonance image of the pituitary does not mean that the cause of the disease is not to be found there. If the cause is not in the hyophysis, the other organs must be examined using computed tomography or magnetic resonance imaging.

Therapy options

surgery

The treatment of choice for treating a pituitary tumor causing Cushing's disease is surgical removal of the tumor. This should usually be done through a minimally invasive so-called transsphenoidal pituitary surgery. This operation should be done in a neurosurgery specializing in pituitary operations.

radiotherapy

If the pituitary surgery does not cure Cushing's disease and a second operation is not promising or also unsuccessful, irradiation of the pituitary may be useful. This often leads to a drop in hormone production several years after the irradiation, but it can be a sensible option in the long term. Because of the long period between radiation and the onset of action, additional treatment with drugs that inhibit cortisol production may be necessary temporarily (see under drug therapy). Just like an operation, radiation can also lead to the long-term failure of one or more pituitary functions (pituitary insufficiency).

Medical therapy

Cushing's disease can be treated temporarily with medication in preparation for the operation or if an operation was unsuccessful. In recent years, numerous drugs have been approved for this in Germany (in alphabetical order: ketoconazole, metyrapon, osilodrostat, pasireotide) so that the selection can be tailored to the needs of the patient. For this purpose, the patient should definitely present himself to a specialized center.

Bilateral adrenal removal (adrenalectomy)

If neither of the methods described succeeds in controlling the hormone overproduction, it is sometimes useful and necessary to remove both adrenal glands. If the adrenal glands are removed, they can no longer produce too much cortisol. However, this also means that lifelong hormone replacement therapy is then required to compensate for the now completely lacking function of the adrenal gland. Usually this is achieved by taking hydrocortisone and fludrocortisone.

Aftercare

After a successful operation, it takes a long time, usually months, but sometimes several years, until the normal function of the pituitary and adrenal glands has recovered. Until then, it is often necessary to replace the cortisol in the form of tablets (hydrocortisone). The change from an excess of cortisol to a normal cortisol level in the blood is often perceived by patients as a lack of cortisol. It may take months for the body to get used to its new equilibrium and during this time the patient has to adjust to headaches, body aches, tiredness and exhaustion at times. In the long term, however, curing Cushing's disease means returning to normal life. It should not be forgotten that untreated Cushing's disease often leads to premature death in the long term.