Cushing's disease

Cushing's disease is a rare condition: Each year, about 1–2 out of every 1 million people are diagnosed with it *. Women are affected about four times more often than men *, *. The disease usually develops between the ages of 30 and 40 *, *.

Cushing's syndrome is the umbrella term for symptoms and physical changes caused by a prolonged excess of the hormone cortisol—regardless of the cause.

In Cushing's disease, the excess cortisol is caused by a pituitary adenoma, which is usually benign. The tumor produces elevated levels of the hormone ACTH, thereby stimulating the adrenal glands to release too much cortisol. Cushing’s disease is thus a specific form of Cushing’s syndrome and, at about 60–70 %, its most common endogenous cause *, *, *.

Diagnosing Cushing's disease is a complex process that involves several steps.

First, various hormone tests are used to determine whether the body is actually producing too much cortisol. If this condition, known as hypercortisolism, is confirmed, Cushing’s syndrome is present.

Next, the cause of the excess cortisol is investigated to determine whether an ACTH-producing pituitary adenoma – and thus Cushing’s disease – is present.

If excess cortisol is confirmed, the ACTH level in the blood is measured. ACTH stimulates the adrenal glands to produce cortisol.

• Low ACTH level: The cause is likely to be in one of the adrenal glands.
• Normal or elevated ACTH level: A possible cause is an ACTH-producing tumor—usually a pituitary adenoma (Cushing’s disease), or, less commonly, a tumor in another part of the body.

If Cushing’s disease is suspected, the pituitary gland is examined using magnetic resonance imaging (MRI). Since the tumors are often very small, special MRI sequences are used. If necessary, a high-resolution 7-tesla MRI scanner is also available at Inselspital.

If the MRI does not reveal a clear tumor or if the cause remains unclear, additional tests may be necessary:

• Petrosal sinus sampling: ACTH levels are measured in blood vessels near the pituitary gland using a catheter. This helps determine whether the excess ACTH originates from the pituitary gland or from a tumor elsewhere in the body.
• PET/CT or other imaging techniques: These are used to search for an ACTH-producing tumor outside the pituitary gland.
• Special hormone tests: The high-dose dexamethasone suppression test, as well as desmopressin or CRH stimulation tests, can provide additional clues to the cause in selected cases.

Since the diagnostic process is complex, the findings should be evaluated by a specialized endocrinology center.

The first-line treatment is usually surgical removal of the pituitary adenoma. 

For large tumors, or when surgery alone is not sufficient, several treatment methods may be combined: Options include medications to lower cortisol levels, radiation therapy, or a combination of various approaches. In rare cases, removal of both adrenal glands may be necessary.

Surgery is the treatment of choice. The pituitary adenoma is usually removed through the nose. In approximately 75–80 % of cases, cortisol production returns to normal after the procedure *, *, *. Since the tumors are often very small and located close to healthy pituitary tissue, extensive surgical experience and careful surgical planning are particularly important.

Depending on the tumor’s location and size, the procedure is performed endoscopically or microscopically. For larger tumors, the endoscopic technique may offer advantages; for small, centrally located adenomas, both procedures yield comparable results *, *. Whenever possible, the tumor is removed completely and along its natural borders *, *.

If the tumor is not visible on MRI

Even if the tumor is not visible, surgery may still be an option provided that the tests clearly indicate the pituitary gland as the cause. Often, petrosal sinus sampling is performed beforehand. If no adenoma is found during surgery, part of the pituitary gland may be removed in selected cases *. The chances of a cure are then approximately 60–70 %.

If the tumor cannot be completely removed

Partial removal may also be beneficial: it reduces the size of the tumor and can facilitate further treatment. Afterward, the disease can often be better controlled with medication and/or radiation therapy.

Examination of the removed tissue reveals whether the tumor was actually responsible for the hormone secretion. Certain characteristics can also provide clues about the tumor’s behavior and the risk of a relapse (recurrence).

Pituitary adenomas, also known as PitNET, are classified into different cell lines based on specific transcription factors. Tumors associated with Cushing’s disease belong to the so-called T-Pit cell line. Three types are distinguished:

• Densely granular tumors: These often cause severe Cushing’s disease, even when they are still very small.
• Loosely granular tumors: These are usually somewhat larger and often cause less distinct symptoms.
• Crook-cell adenomas: These are rare and may grow more aggressively.

Crook-cell adenomas and tumors with an elevated cell division rate are considered potentially more aggressive. In these cases, particularly frequent monitoring is recommended *, *.

It is important to note that not every tumor in the T-Pit cell lineage actually produces hormones.

If the hormone-secreting pituitary adenoma has been successfully removed, the cortisol level usually drops significantly within 48 hours. For this reason, it is monitored closely during the first few days after surgery *.

A cortisol level below 55 nmol/l is a very good indication of successful treatment. In over 90 % of patients, a long-term cure can then be expected *, * , *.

A level below 140 nmol/l immediately after surgery also suggests successful treatment. However, with levels between 55 and 140 nmol/l, the risk of relapse is about 20% *.

After a successful surgery, a temporary cortisol deficiency often occurs. For this reason, cortisol is initially replaced with medication, and the dose is gradually reduced. The body’s own production usually recovers within a few months, but it may also take a year or longer. In some cases, it does not recover completely *, *.

Radiation therapy may be considered if a residual tumor remains after surgery and the disease is not adequately controlled. It is used in particular when repeat surgery is not possible or involves high risks.

In radiosurgery, the tumor is targeted with highly precise radiation. However, it may take some time for the treatment to take full effect. During this time, medication is usually necessary to control the excess cortisol.

In approximately 50–70 % of patients treated, the disease can be controlled with radiation therapy *. If the tumor is located close to the optic nerves, treatment may be more difficult. In addition, other hormonal functions of the pituitary gland may be impaired. The therapy should be planned and carried out at a specialized center.

In cases of severe cortisol excess that cannot be adequately controlled by other methods, removal of both adrenal glands (bilateral adrenalectomy) may be considered in rare cases. This immediately stops the excess cortisol production. Subsequently, the missing adrenal hormones must be replaced with medication for the rest of the patient’s life.

In approximately 20–40% of those affected, the pituitary tumor may continue to grow afterward. This condition, known as Nelson’s syndrome, requires regular hormone and MRI monitoring *, *. If there is significant tumor growth, surgical removal is the preferred treatment whenever possible *.

Cushing’s disease can affect various organ systems and lead to serious complications. Therefore, these complications must be detected early, monitored regularly, and treated specifically. These include:

• High blood pressure
• Cardiovascular diseases
• Diabetes mellitus
• Osteoporosis
• Thrombosis prevention in high-risk patients
• Infection prevention in cases of very high cortisol levels

Even if, for example, blood sugar control and heart function improve after successful treatment, regular follow-up care remains important.

When using drug therapy, potential effects on other organs must be monitored. For example, treatment with ketoconazole requires regular monitoring of liver function tests.