Cushing's Syndrome

The symptoms of Cushing's syndrome vary and often appear slowly over time.

You may have:

• Weight gain, especially around the waist. This is the most common symptom. You might also have a round face or extra fat around the neck and upper part of the back (buffalo hump).
• Skin changes, such as bruising, acne, or dark purple-red stretch marks on your belly.
• Mood changes, such as feeling irritable, anxious, or depressed.
• Muscle and bone weakness. This may cause backaches, broken bones (especially the ribs and spine), or loss of muscle tone and strength.
• Changes in sex hormone levels. In women, this may cause irregular periods and growth of facial hair. In men, it may cause erection problems or changes in sex drive.
   

Cushing's syndrome can also lead to other health problems, such as high blood pressure, type 2 diabetes, glaucoma, and cataracts.

The most common cause is taking steroid medicines, such as prednisone, for a long time.

These medicines act like cortisol in your body. They are used to treat many diseases, including lupus, asthma, and rheumatoid arthritis. They are also used after an organ transplant.

You can also get Cushing's syndrome because your body makes too much cortisol. This can happen if you have:

• A tumor in your pituitary gland that makes extra ACTH, and that causes the adrenal glands to make more cortisol. This is called Cushing's disease. These tumors usually aren't cancer.
• A tumor in your lung or pancreas that makes ACTH, and that causes the adrenal glands to make more cortisol. Sometimes these tumors are cancer.
• A tumor in your adrenal glands that makes extra cortisol. Some of these tumors are cancer.

Cushing's syndrome can be hard to diagnose because many things can make your cortisol level higher than normal. Our neuroendocrinology experts at the Stanford Pituitary Center have the highest expertise in diagnosing and treating Cushing's syndrome.

To find out if you have Cushing's syndrome, a doctor will:

• Ask questions about the medicines you take, your symptoms, and, if you are a woman, your periods.
• Take your blood pressure, look for skin changes, and check for changes in your weight and for any signs of cancer.
• A doctor can usually find out from these exams if steroid medicine is causing the problem.

If you don't take steroid medicine or your doctor thinks something other than medicine is causing your symptoms, you may have tests, such as:

• Tests to check the level of cortisol and other hormones in your blood and urine.
• A test to measure cortisol in your saliva in the late evening, when the level normally drops.
• A CT scan or MRI to look for a tumor on your adrenal glands, pituitary gland, or another organ.

Tests for Causes of Cushing’s Syndrome

1. ACTH level: This test helps distinguish an adrenal source (ACTH independent) from an ACTH dependent cause. A very low ACTH level suggests the problem is coming from the adrenal glands, and not the pituitary gland.
2. High dose Dexamethasone suppression test: This test helps to distinguish patients with excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors. Patients are given 2 mg dexamethasone by mouth every 6 hours for 2 days. A 24-hour urine collection for cortisol is performed on the second day of the test. Cortisol suppression suggests a pituitary tumor. A similar test is performed using a single dose of 8 mg at midnight, and a fasting blood draw for cortisol the next morning.
3. Petrosal sinus sampling: This test may be required to separate pituitary from ectopic causes of ACTH-dependent Cushing's syndrome in patients with a normal pituitary gland on brain MRI scan. Catheters are placed through a vein in the upper thigh/groin region and are threaded through the blood vessels to the petrosal sinuses, which surround the pituitary gland. ACTH levels higher in the petrosal sinuses than in a forearm vein indicate the presence of a pituitary adenoma (Cushing's disease); similar levels suggest ectopic ACTH syndrome.

Treatment for Cushing's syndrome depends on the cause.

If long-term use of steroid medicine is the cause of Cushing's syndrome:

• Your doctor will help you lower your dose or gradually stop taking it. It may take a while for the symptoms to go away.
• Do not stop taking steroid medicine on your own. That can be very dangerous. Your doctor will help you change your medicine or lower the dose slowly.

If a pituitary tumor is the cause:

• Surgery to remove the tumor offers the best chance for recovery. This surgery requires great skill and should be done at a major medical center where doctors specialize in pituitary surgery.
• If surgery to remove the tumor isn't possible or hasn't worked, you may have other options to consider such as medicine, radiation, or surgery to remove the adrenal glands. You and your doctor can talk about the pros and cons of each option.

If an adrenal tumor is the cause:

• Surgery to remove the tumor is usually done if the tumor is not cancer (benign). If the tumor is cancer, the whole gland is removed.
• Medicine may be tried if surgery isn't an option.

If a tumor of the lungs or another organ is the cause, the tumor will be removed or treated with radiation or medicines.

Cushing's Disease and Negative MRI

Patients with Cushing’s disease often present with a “negative” MRI study, showing no evidence of tumor. Inferior petrosal sinus sampling is mandatory to confirm that the source of ACTH production is the pituitary gland.

The first step is these cases is to make sure the MRI study is of high-quality, as frequently patients do not obtain the best possible imaging. At Stanford Pituitary Center we have developed with our expert neuroradiologists the best possible imaging protocol to maximize chances of microadenoma identification; this includes a 1-mm fine-cut T1 sequences with and without contrast in all 3 spatial planes, dynamic sequences, and a flair post-contrast sequence.

If imaging is still not conclusive, intraoperative exploration is required, following the technique described by Professor Oldfield that Dr. Juan Fernandez-Miranda learnt from him during his tenure at University of Virginia (2007-2008). This starts with wide surgical exposure to carefully explore all surfaces of the gland, including those in contact with the medial wall of the cavernous sinus, as microadenomas may cause mild bulging in the surface of the gland. Next, vertical incisions separated by 2-mm are performed to gently explore the inside of the gland, starting at the site of highest suspicion. Finally, when no adenoma is identified, and selective removal is not possible, a partial hypophysectomy is performed by removing a quarter of the gland on each side and at the bottom of the gland and preserving the central core of the gland. This technique maximizes chances of microadenoma removal while minimizing risk of pituitary dysfunction.

Treatment for Ectopic Cushing’s Syndrome

If the evaluation suggests the presence of ectopic Cushing's syndrome, then the treatment is directed to the source. For example, if a carcinoid tumor in the lung is detected, then there are several options for therapy, including surgical excision.

Treatment for Adrenal Growth

If an adrenal growth is the underlying cause, then surgical removal of the abnormal adrenal gland is necessary.

Treatment options if the initial therapy is not effective

If the patient has Cushing's syndrome due to excess ACTH levels and the primary tumor has not been resected, there are several next step options. Repeat surgery can be considered to try again to remove the tumor. Surgical removal of both adrenal glands (bilateral adrenalectomy) can also be performed, as this will result in normalization of the effects of Cushing’s syndrome. This therapy will lead to required replacement of adrenal gland hormones, including cortisol and a medication that controls sodium and potassium balance.

Another option is the use of medical therapy. There are several medical therapies that work by reducing adrenal gland production of cortisol. These medications include ketoconazole and aminoglutethamide.

There are several new medical agents recently available that may help further with medical control of Cushing’s syndrome. Korlym (mifepristone) is a cortisol blocker. This medication, given as a pill, blocks cortisol wherever it goes, and can lead to improvement in appearance and medical consequences in the majority of people.

Signifor (pasireotide) is a new medicine that works like somatostatin at the primary tumor and reduces ACTH in approximately one-third of patients.

Another new medication, Isturisa (osilodrostat) is a medication that blocks the adrenal gladn to lower cortisol levels in most people. It is tolerated very well.

A 32 year-old man, presented with truncal obesity, diabetes, and hypertension; preoperative studies were compatible with Cushing’s disease. The MRI showed a large and invasive tumor. Intraoperatively it was invading the medial wall of the cavernous sinus bilaterally, and both were removed successfully achieving complete resection and functional remission that remains five years after surgery.