Cushing Syndrome Treatments and Medications

Living with the stressors of daily life can be challenging. When we become stressed, our body responds by producing a hormone called cortisol, also known as a ‘stress hormone’. This vital hormone helps us respond to situations by keeping us alert, energized, and motivated. Cortisol plays important functions in our body such as helping us metabolize energy, lowering inflammation, regulating blood sugar and blood pressure, maintaining a regular sleep cycle, and even helping form memories. However, producing too much cortisol can cause many health issues including Cushing’s syndrome. People with this condition chronically produce cortisol, even when it is not needed. Thankfully, there are treatment options that can reverse many of the symptoms.

What is Cushing syndrome?

Cushing’s syndrome (hypercortisolism) occurs when people have cortisol levels that are significantly higher than normal. There are four main causes of Cushing’s syndrome, each one requiring slightly different treatment. For all causes, the incidence of Cushing’s syndrome is 3-8 times higher in women than men and most commonly affects individuals 20-50 years of age.

1. Iatrogenic Cushing’s syndrome is the most common type and is caused by administration of corticosteroids such as prednisone in non-physiologic doses. Exogenous steroids suppress the adrenal glands, causing them to stop producing hormones. With more than 10 million people prescribed systemic glucocorticoids every year, the exact incidence of Cushing’s syndrome is very underreported.

2. The second most common cause is an adrenocorticotropic hormone (ACTH) secreting tumor in the pituitary gland. ACTH release from this tumor, called a pituitary adenoma, tells the adrenal glands to make excess cortisol, even when it is not needed. The reported incidence of pituitary adenomas in the United States account for 6.2 to 7.6 cases per million person-years.

3. The third most common cause of Cushing’s syndrome, accounting for 15-20% of cases, is adrenal tumors. These adrenal adenomas and adrenal carcinomas secrete excess cortisol as well as other endocrine hormones, including the androgens testosterone and estrogen.

4. Ectopic ACTH-secreting tumors are located outside of the pituitary gland or adrenal gland and produce ACTH. These are typically located in the lung, thymus, pancreas, or thyroid. Ectopic ACTH production accounts for 15-20% of cases of Cushing’s syndrome.

Symptoms of Cushing’s disease may include:

• Visible symptoms:

  • Rapid weight gain and obesity

  • Easy bruising

  • Purple stretch marks (striae) on the chest, arms, and stomach

  • Excess deposition of fat in the abdomen, face, neck, and between the shoulders (buffalo hump)

  • Easily injured skin that is slow to heal

  • Acne

• Physiological changes

  • Menstrual cycle disruptions

  • Hirsutism (male-pattern face and body hair in women)

  • Headaches

  • Decreased sex drive

  • Elevated blood sugar with new onset Type 2 diabetes

  • Mood swings

  • High blood pressure

  • Muscle weakness

  • Low bone density and osteoporosis

  • Kidney dysfunction

  • Electrolyte imbalances

  • Weakened immune system

How is Cushing syndrome diagnosed?

Cushing’s syndrome is diagnosed by a combination of clinical presentation and laboratory findings. Your primary healthcare provider will ask you about the symptoms you have been having and they will want to take a complete health history, which includes all your medications, past medical history, your family’s medical history, as well as any surgeries you may have had in the past and any medications or supplements you take. They will also perform a focused physical exam which includes examination of the body and organ systems relevant to your symptoms.

After this, blood tests are taken to check levels of cortisol, blood glucose, and metabolites. Based on the results of your blood tests and physical exam, patients may be referred for imaging or to specialists which may include an endocrinologist or surgeon.

Dexamethasone suppression test

One of the first laboratory tests ordered is the low-dose dexamethasone suppression test. This test will help confirm a diagnosis of Cushing’s syndrome. For this test, a 1 mg dose of dexamethasone is taken at 11 pm, and the amount of cortisol in your blood is checked the following morning at 8 am. In healthy people, dexamethasone will cause a decrease in ACTH, which in turn will result in lower amounts of cortisol released by the adrenal glands. People with Cushing’s syndrome, cortisol does not usually go down after a dose of dexamethasone due to abnormal production of ACTH or cortisol.

This test is very sensitive with reliable results. Based on the results of this test, you may be required to take additional laboratory tests including blood tests to check your levels of ACTH.

24-hour urinary free cortisol

This alternative screening test requires collection of urine over 24 hours. If the levels of cortisol in the urine are more than four times the normal value, Cushing syndrome is the likely cause.

High-dose dexamethasone suppression test

Individuals with confirmed Cushing’s syndrome may take a high-dose dexamethasone suppression test to determine the ultimate cause of the condition (Cushing disease vs. adrenal tumor vs. ectopic ACTH tumor).

Corticotropin-releasing hormone (CRH) stimulation test

If the laboratory tests reveal that cortisol levels were not suppressed by dexamethasone, intravenous CRH can help confirm a diagnosis of either Cushing’s disease, ectopic production of cortisol, or an adrenal tumor as the cause of elevated cortisol.

Imaging tests

If the etiology is determined to be a tumor, specific hormonal studies will be performed to establish the site of the disease, followed by contrast tomography (CT) or magnetic resonance imaging (MRI) of the area.

Cushing syndrome treatment options

Treatment of Cushing’s syndrome generally depends on the cause. Withdrawing the offending agent, radiation therapy, or surgical removal of the cortisol secreting tumor are the most common and effective treatments. While these treatments may cure the cause of Cushing’s syndrome, they come with their own negative side-effects. And even then it usually takes several months for the endogenous production of cortisol to return and symptoms to go away.

Recently, the Food and Drug Administration (FDA) approved a new medication called Isturisa (osilodrostat) to help with achieving normal cortisol levels and symptom management.

Corticosteroid withdrawal

Individuals with iatrogenic Cushing’s syndrome secondary to corticosteroids will benefit most from discontinuing the medication(s). To avoid the unpleasant side effects associated with corticosteroid withdrawal, corticosteroids should not be abruptly discontinued or discontinued without being under the care of a healthcare provider. Your healthcare provider will suggest tapering (slowly decreasing) the dose of the medications.

Surgery

Surgical removal of a pituitary tumor will permanently cure Cushing’s syndrome in 60-70% of people. However, removing all or part of the pituitary gland may interfere with ovulation and sperm production. These individuals usually receive lifelong hormone replacement therapy.

Surgical removal of the adrenal glands will also stop cortisol production but requires lifelong glucocorticoid and mineralocorticoid replacement.

Surgery for this condition depends on the location of the tumor, the extent of the tumor, the individual’s baseline health status and severity of the condition. It is important that informed decision-making be used between the patient and the healthcare provider.

Radiation

When surgical options are not ideal, and cortisol producing tumors can not be completely removed, radiation to the affected area will reduce cortisol production by about half. The cortisol lowering effect for radiation takes 3-24 months, so medications are often used to bridge this time and assist in symptom reduction.

Cushing syndrome medications

If an individual is unable to have surgery or when surgery is unable to control hypercortisolism, medication can be used to help control cortisol production.

Signifor

Signifor (pasireotide) is a somatostatin analogue (SSA) injected subcutaneously (under the skin) twice daily in a. More recently, it is available in a long-acting release formulation called Signifor LAR, which allows for administration once per month. Somatostatin analogues act on the pituitary gland to reduce ACTH secretion and subsequently release of cortisol. Signifor has been extensively studied for safety and efficacy. The most concerning side effects include hyperglycemia, and it is recommended that individuals taking this medication have their blood glucose monitored regularly.

Cabergoline

Cabergoline is a dopamine-receptor agonist (DA) that primarily modulates the release of prolactin. It has been shown that dopamine receptors are also located in different types of pituitary tumors, contributing to the secretion of ACTH and therefore cortisol. While the actual incidence of successful remission varies widely in medical literature, the first successful clinical trials demonstrated normalization of cortisol levels and effective symptom management in 40% of individuals. Cabergoline is not an FDA-approved treatment for Cushing’s syndrome but is used “off-label” by some physicians to treat the disease. This drug is very well tolerated, with most negative side effects involving changes in mood such as depression, aggressive behavior, or psychosis.

Mifepristone

Korlym (mifepristone 300 mg tablets) is an oral glucocorticoid receptor (GR) agonist FDA-approved for the treatment of Cushing’s syndrome in individuals with concomitant Type 2 diabetes or glucose intolerance who have failed surgery or are not candidates for surgery. Korlym does not reduce cortisol secretion but instead mitigates its effect on peripheral tissues. By this mechanism, it is known to significantly improve hypertension and impairment of glucose metabolism. Because Korlym is a non-specific steroid agonist, it also binds androgen and progestin receptors, inhibiting their peripheral effects. This could be worrisome in women, as endometrial thickening and abnormal vaginal bleeding can occur.

Ketoconazole

Ketoconazole has been used worldwide to treat Cushing’s syndrome. It is an oral inhibitor of steroid synthesis and inhibits the release of ACTH. It was originally designed as an antifungal, but later discovered in laboratory studies to inhibit steroid production. One meta analysis estimated a symptom remission rate of 71% among Cushing’s disease patients treated with ketoconazole alone or alongside other treatment options, although ketoconazole may demonstrate lower remission rates in some types of Cushing’s disease. Its relatively rapid action makes it a good choice for individuals in need of more rapid relief. Male hypogonadism is a known side effect, so this medication is generally more favored in women. Additionally, strict monitoring of liver enzymes should be performed while taking this medication as it is known to cause hepatotoxicity.

RELATED: Antifungals

Lysodren

Lysodren (mitotane) is an adrenolytic, which means that it inhibits steroids produced by the adrenal cortex such as adrenaline, cortisol and noradrenaline. It accomplishes this by inducing a cytotoxic effect on the mitochondrial system in adrenal cells, resulting in cell death and inhibiting several enzymes involved in the adrenal synthesis of steroids. In a recent meta-analysis, almost 80% of individuals reported symptom remission when mitotane therapy was used as part of their treatment regimen. Notably, these effects take time; mitotane has a slow onset of action, requiring several months of administration multiple times a day. Mitotane is a fairly well-tolerated medication, however should be avoided in women who are pregnant or who desire to become pregnant due to its teratogenic effects.

Isturisa

Isturisa (osilodrostat) is the newest medication to receive FDA approval for the treatment of Cushing’s syndrome in individuals who either cannot undergo pituitary surgery or who have undergone pituitary surgery but still have the disease. Isturisa inhibits aldosterone synthase, the enzyme responsible for the conversion of precursors to cortisol and its derivatives. This medication is particularly useful for individuals with Cushing’s syndrome and high blood pressure, as it effectively reduces blood pressure in a dose-dependent manner. Women have been reported to have increased serum testosterone levels while taking this medication.

What is the best medication for Cushing syndrome?

There is not a single, best medication for the treatment of Cushing’s syndrome. Each individual will have specific needs that will determine if medication is even appropriate for their condition, and if so, which ones may be helpful. Factors to discuss with a healthcare provider that may affect this decision include:

• Cause of Cushing’s syndrome

• Lifestyle factors

• Associated comorbidities or metabolic derangements

• Gender-specific treatment side effects

• Current medications

• Patient age

It is important to note that medications are not curative for this condition. The only definitive cure is the complete removal of the offending agents and/or causative tumors. Endocrinologists are aware that there is a need for better medications to treat this condition and several new medications are in active clinical trials.

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