Cushing’s disease causes

Last updated Aug. 7, 2023, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

Cushing’s disease is a hormonal condition caused by a tumor in the brain’s pituitary gland, which ultimately leads to the overproduction of a steroid hormone called cortisol, a condition also referred to as hypercortisolism. While tumors in Cushing’s disease are usually benign, or noncancerous, their presence results in high cortisol levels that are the hallmark of the disorder and cause its symptoms, which include weight gain and skin problems.

What causes Cushing’s disease?

Cushing’s disease typically is caused by a tumor in the pituitary gland, which is located at the base of the brain, behind the bridge of the nose. This pea-sized gland normally is responsible for producing and releasing a variety of signaling molecules that help control the activity of multiple systems in the body.

The specific type of tumor that usually causes Cushing’s disease is referred to as a pituitary adenoma. Such tumors are classified as microadenomas if they are small, measuring less than one centimeter in diameter, or macroadenomas if they’re larger than one centimeter in diameter. The adenomas that cause Cushing’s disease typically are benign, meaning they are not cancer-causing.

In Cushing’s disease, pituitary tumors produce and release high amounts of a signaling molecule called adrenocorticotropic hormone or ACTH. This signaling molecule normally helps control the activity of the adrenal glands, which are located atop the kidneys and produce a variety of steroid hormones, including cortisol.

The high levels of ACTH in Cushing’s disease trigger the adrenal glands to produce excessive amounts of cortisol.

Because cortisol is usually produced in response to stress, it is commonly referred to by the term the stress hormone. Normally, when a person is under stress, cortisol helps trigger the body’s fight or flight responses, changing how the body uses energy and prompting wakefulness and alertness.

In Cushing’s disease, cortisol levels remain abnormally elevated for a long period of time, ultimately leading to the development of disease symptoms.

While anyone can develop Cushing’s disease, the condition is more likely to arise in people between the ages of 20 and 50. The disease also is three times to five times more common in women than in men.

Cushing’s disease vs. Cushing’s syndrome

Cushing’s disease is a specific clinical entity in which a pituitary tumor leads to high levels of the cortisol hormone. Cushing’s syndrome is a broader umbrella term that refers to any condition characterized by high cortisol levels, regardless of the underlying cause. As such, all cases of Cushing’s disease are types of Cushing’s syndrome, but not all cases of Cushing’s syndrome are due to Cushing’s disease.

Cushing’s syndrome can be broadly classified as endogenous, from within the body, or exogenous, from outside the body.

In endogenous Cushing’s syndrome, excess cortisol levels are due to problems within the body itself, most commonly a tumor. Exogenous Cushing’s syndrome refers to a form of Cushing’s that arises due to external factors — typically as a side effect of certain medications.

Given that high cortisol levels are the cause of symptoms in all forms of Cushing’s syndrome, signs and symptoms are similar in all types. Consequently, it is often necessary to perform medical tests to identify the underlying cause and confirm the diagnosis, particularly in endogenous forms of the syndrome.

Tumors

Endogenous Cushing’s syndrome occurs when the body’s own biology goes awry, leading to the excessive production of cortisol. The most common form of endogenous Cushing’s syndrome is Cushing’s disease, an ACTH-dependent form of the syndrome in which excess cortisol levels are driven by a pituitary tumor that produces and releases ACTH. Cushing’s disease accounts for up to 70% of all cases of endogenous Cushing’s syndrome.

More rarely, tumors in other parts of the body may cause endogenous Cushing’s syndrome. Generally, there are two ways in which this can happen:

• In about 10%-15% of cases, an ACTH-producing tumor found outside the pituitary gland triggers the excess production of cortisol in the adrenal glands. When Cushing’s arises as a result of such a tumor, typically found in the lungs, pancreas, or thyroid, or in the thymus gland, it is referred to as ectopic Cushing’s syndrome. Like Cushing’s disease, ectopic Cushing’s is considered an ACTH-dependent form of the syndrome.
• In another 10%-15% of cases, a benign or malignant tumor in the adrenal glands produces high levels of cortisol, causing the syndrome to develop. Such cases are considered ACTH-independent forms of Cushing’s, as they are not driven by ACTH.

Surgery to remove the disease-causing tumor usually is the first line of treatment for Cushing’s disease and other types of endogenous Cushing’s syndrome. If surgery is ineffective or cannot be performed, medications may be used to help lower cortisol levels.

Use of corticosteroid medications

Corticosteroids, or glucocorticoids, used to reduce inflammation, are a group of medications that work by mimicking the activity of cortisol. Common examples include prednisone, prednisolone, cortisone, and hydrocortisone.

Because cortisol has potent anti-inflammatory effects, these medicines are invaluable tools for treating diseases driven by excessive inflammation.

However, exposure to high levels of corticosteroids also can lead to the development of Cushing’s. This is referred to as exogenous or iatrogenic, meaning medication-induced Cushing’s syndrome, and is the most common form of Cushing’s syndrome. It also is considered an ACTH-independent form of Cushing’s.

It’s generally recommended that anyone taking corticosteroids, especially people who are taking these medicines long term, should be aware of the signs and symptoms of Cushing’s syndrome so that they can seek medical attention as soon as possible if such symptoms arise. Clinicians prescribing these medicines and pharmacists should educate patients on their potential side effects.

Exogenous Cushing’s syndrome usually resolves once a person stops taking corticosteroids. However, it is often necessary to slowly taper the use of these medications, rather than stopping them abruptly, as that may lead to withdrawal symptoms and other complications.

Familial Cushing’s disease

Some rare genetic conditions can increase a person’s risk of developing tumors in hormone-producing glands, known as endocrine glands. These are the pituitary and adrenal glands, among others. Because the genetic mutations that cause some of these conditions can be passed from parents to their biological children, these disorders can run in families.

Not everyone with these conditions is guaranteed to develop Cushing’s disease. But the heightened risk of endocrine tumors also increases the risk of developing a tumor that can cause Cushing’s disease or other forms of endogenous Cushing’s syndrome.

Some genetic disorders that have been associated with Cushing’s disease include:

• Carney complex, caused by mutations in the PRKAR1A gene
• multiple endocrine neoplasia types 1, 2a, 2b, or 4, arising due to mutations in the genes MEN1, RET, or CDKN1B
• tuberous sclerosis complex, caused by mutations in the genes TSC1 or TSC2
• McCune-Albright syndrome, caused by mutations in the GNAS gene
• familial isolated pituitary adenoma, arising due to mutations in the AIP gene
• DICER1 syndrome, caused by mutations in the DICER1 gene
• X-linked adrenal hypoplasia, caused by mutations in the NR0B1 gene.

Somatic mutations — those arising during a person’s lifetime and that are not inherited — in a gene called USP8 also have been associated with Cushing’s disease. These mutations, reported to have been found in nearly half of hormone-producing pituitary tumors, promote the excessive production of ACTH that characterizes the disease.

Tumors harboring USP8 mutations have been reported to be smaller, less invasive, and more likely to reappear following surgery. They also have been reported to be more prevalent in women and to respond favorably to certain medications, including Signifor (pasireotide).

Cushing’s Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.