Definition

Cushing disease is characterized by an overproduction of adrenocorticotropic hormone (ACTH) from the pituitary gland.

This rare condition affects approximately 10 to 15 individuals per million annually and is a subtype of Cushing syndrome. Other variants of Cushing syndrome include exogenous Cushing syndrome, adrenal tumor-induced Cushing syndrome, and ectopic Cushing syndrome.

Causes

Cushing disease results from a tumor or hyperplasia (overgrowth) of the pituitary gland, a small endocrine organ located at the brain's base. The most common cause is a pituitary adenoma, a benign (noncancerous) tumor.

In Cushing disease, excessive ACTH production from the pituitary gland triggers an overproduction of cortisol, a hormone associated with stress response.

Cortisol, produced by the adrenal glands, plays a critical role in the body's response to stress. Nearly all cells contain receptors for cortisol. Its release is controlled by the hypothalamus, pituitary gland, and adrenal glands, collectively known as the hypothalamic-pituitary-adrenal (HPA) axis. In a healthy system, ACTH is secreted by the pituitary to stimulate the adrenal glands to produce cortisol. Excessive ACTH results in heightened cortisol production.

Cortisol in normal levels serves to:

• Regulate blood sugar levels
• Control metabolism
• Facilitate the conversion of carbohydrates, fats, and proteins into energy
• Dampen the immune response to inflammation
• Maintain blood pressure and fluid balance
• Aid in fetal development during pregnancy (for women)

Risk Factors

Cushing disease occurs more frequently in women, particularly those aged 20 to 50.

Symptoms

Symptoms of Cushing disease include:

• Upper body obesity, with thinner limbs
• A round, full, red face (moon face)
• Stunted growth in children

Common skin changes in Cushing disease include:

• Acne or frequent skin infections
• Purple stretch marks (striae) that are 1 cm or wider, typically appearing on the abdomen, thighs, upper arms, and breasts
• Fragile, easily bruised skin, especially on the arms and hands

Musculoskeletal symptoms include:

• Back pain during routine activities
• Bone pain
• Fat accumulation between the shoulders (buffalo hump)
• Bone weakness, leading to fractures in the ribs and spine
• Muscle weakness, contributing to exercise intolerance

For women, symptoms may include:

• Excessive hair growth on the face, neck, chest, abdomen, and thighs
• Irregular or absent menstrual cycles

For men, symptoms may include:

• Low libido or loss of sexual interest
• Erectile dysfunction

Additional symptoms or associated conditions include:

• Psychological changes, such as depression, anxiety, or altered behavior
• Fatigue
• Frequent infections
• Headaches
• Increased thirst and urination
• High blood pressure (hypertension)
• Elevated blood sugar (diabetes)

Diagnosis

Diagnosing Cushing disease can be challenging due to the broad range of symptoms and the fluctuating nature of elevated cortisol levels. As a result, cortisol may not always be elevated when tested.

The diagnostic process begins with a physical examination and a discussion of symptoms. Initial tests focus on confirming excessive cortisol levels in the body, followed by determining the underlying cause.

Tests to confirm elevated cortisol levels include:

• Urine test: Cortisol is measured in urine collected over a 24-hour period.
• Dexamethasone suppression test (low dose): This test helps assess cortisol suppression.
• Salivary cortisol levels (measured at midnight or early morning): A highly sensitive test for cortisol, saliva samples are collected between 11 p.m. and midnight. In healthy individuals, cortisol levels are usually low during this time, while individuals with Cushing's disease typically show elevated levels.

Tests to determine the cause of elevated cortisol include:

• Blood ACTH levels: In Cushing disease, cortisol levels are high, and ACTH levels are either normal or elevated.
• Brain MRI: If abnormal pituitary function is suspected, an MRI of the pituitary gland is conducted to locate the tumor.
• Corticotropin-releasing hormone test: This test stimulates the pituitary gland to release ACTH.
• Dexamethasone suppression test (high dose): This test differentiates Cushing disease from other causes of high cortisol.
• Inferior petrosal sinus sampling: This test measures ACTH levels in the veins draining blood from the pituitary gland.

Additional tests may include:

• Fasting blood glucose and HbA1c: To check for diabetes.
• Lipid and cholesterol tests
• Bone mineral density scan: To assess for osteoporosis.

Multiple screening tests may be necessary for a definitive diagnosis of Cushing disease.

Management

Treatment of Cushing disease often involves surgery to remove the pituitary tumor when possible. Typically, transsphenoidal microsurgery is performed. After the surgery, pituitary function gradually normalizes, with small tumor cases showing a 90% cure rate.

During recovery, cortisol replacement therapy may be required until the pituitary gland resumes ACTH production.

Radiation therapy may be recommended if the tumor is not fully removed or surgery does not yield improvement. Radiation targets remaining tumor cells, although results may take time to manifest.

If the tumor does not respond to surgery or radiation, medications may be prescribed to inhibit cortisol production. Drugs such as ketoconazole, metyrapone, mitotane, and osilodrostat block the adrenal glands from producing cortisol and can be used during radiation treatment.

In cases where surgery, radiation, and medication fail, adrenal gland removal may be necessary to halt excessive corticosteroid production. However, adrenalectomy can result in pituitary tumor growth (Nelson's syndrome).

Complications

Potential complications from Cushing disease include:

• Blood clots in the veins (deep vein thrombosis)
• Compression fractures in the spine
• Diabetes
• High blood pressure
• Infections
• Kidney stones
• Mood or mental disorders
• Weight gain

If left untreated, Cushing disease can lead to severe health issues, including death. Surgical removal of the tumor may offer a complete cure, though there remains a risk of recurrence.

Prevention

There is no known method to prevent the pituitary tumors that cause Cushing disease.

When to See a Doctor?

Consult your doctor if you experience any of the symptoms associated with Cushing disease.

If you have undergone surgery to remove a pituitary tumor, contact your doctor if there are signs of complications or if the tumor appears to have regrown.

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