Cushing’s syndrome happens when your body is exposed to too much cortisol, a stress hormone produced by the adrenal glands, over an extended period. The most common cause by far is taking prescription corticosteroid medications like prednisone or dexamethasone. When the condition develops from your body’s own overproduction of cortisol, it affects roughly 13 out of every million people per year.
Corticosteroid Medications: The Most Common Cause
The majority of Cushing’s syndrome cases are “exogenous,” meaning the excess cortisol comes from outside the body in the form of synthetic glucocorticoid medications. Prednisone, prednisolone, dexamethasone, and hydrocortisone are the most frequently involved drugs. These medications mimic cortisol’s effects and are widely prescribed for conditions like asthma, rheumatoid arthritis, lupus, and inflammatory bowel disease.
What catches some people off guard is how many forms these medications come in. Pills and IV infusions carry the highest risk, but joint injections, skin creams, enemas, inhaled steroids, and even certain eye drops can contribute if used at high doses or over long periods. Inhaled steroids pose a lower risk, and using a spacer device while rinsing your mouth after each dose further reduces absorption into the bloodstream. The good news is that exogenous Cushing’s syndrome typically resolves once the medication is tapered and discontinued, though that process has to be done gradually under medical guidance to avoid adrenal crisis.
Pituitary Tumors and Cushing’s Disease
When excess cortisol comes from inside the body, the single most common source is a small, usually benign tumor on the pituitary gland, a pea-sized structure at the base of the brain. This specific scenario has its own name: Cushing’s disease (as opposed to the broader term Cushing’s syndrome). These tumors produce too much ACTH, the hormone that tells your adrenal glands to make cortisol. With the signal constantly turned up, the adrenal glands churn out cortisol around the clock.
Most pituitary tumors behind Cushing’s disease are microadenomas, meaning they’re smaller than 10 millimeters. They’re almost always noncancerous, but their effects can range from mild elevations in cortisol to severe, full-blown Cushing’s syndrome depending on how much ACTH they release. Because these tumors are so small, they can be difficult to detect on imaging, which is one reason diagnosis often takes years.
Tumors in the Adrenal Glands
Your two adrenal glands sit on top of your kidneys and are the direct source of cortisol. Several types of growths can cause them to overproduce it independently, without any signal from ACTH.
- Adrenal adenomas are common, benign tumors. Most are discovered incidentally on imaging done for other reasons and rarely produce excess cortisol, but a subset of them do.
- Macronodular hyperplasia causes the adrenal glands to enlarge with multiple nodules, each contributing to excess cortisol production.
- Adrenal carcinoma is a rare but aggressive cancer. Unlike adenomas, adrenal carcinomas usually produce excess cortisol, and the hormone levels they generate tend to be very high.
Because the adrenal glands are making cortisol on their own in these cases, ACTH levels in the blood are typically low or undetectable. That distinction helps doctors figure out where the problem is coming from.
Ectopic ACTH: Tumors Elsewhere in the Body
In rarer cases, a tumor located outside the pituitary gland produces ACTH, flooding the adrenal glands with signals to make cortisol. This is called ectopic ACTH syndrome. The tumors most commonly responsible include:
- Small cell lung tumors
- Benign carcinoid tumors of the lung
- Islet cell tumors of the pancreas
- Medullary carcinoma of the thyroid
- Tumors of the thymus gland
Ectopic sources can be particularly tricky to diagnose because the tumors may be small and slow-growing, especially carcinoid tumors. Some patients go through repeated scans over months or even years before the source is located. The cortisol levels in ectopic ACTH syndrome tend to be very high, and symptoms can develop rapidly compared to pituitary-driven cases.
Genetic and Inherited Factors
Most cases of Cushing’s syndrome are not inherited. The pituitary tumors that cause Cushing’s disease typically arise from somatic mutations, genetic changes that occur spontaneously in individual cells during a person’s lifetime rather than being passed down from parents.
In rare instances, however, Cushing’s disease appears as part of a broader genetic syndrome. Multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenoma (FIPA) are two inherited conditions that can include pituitary tumors among their features. Researchers have also studied mutations in genes like PRKAR1A and CDKN1B in families with multiple members affected by pituitary or adrenal tumors. These genetic forms are uncommon enough that routine genetic testing isn’t standard for most patients, but a family history of endocrine tumors may prompt a doctor to look deeper.
Conditions That Mimic Cushing’s Syndrome
Several common conditions can raise cortisol levels enough to produce symptoms that overlap with Cushing’s syndrome without any tumor being present. This phenomenon, sometimes called pseudo-Cushing’s, results from chronic overstimulation of the body’s normal stress-hormone pathway. Depression, obesity, uncontrolled diabetes, chronic alcoholism, obstructive sleep apnea, polycystic ovarian syndrome, eating disorders, and severe physical stress can all push cortisol high enough to cause weight gain, facial rounding, and other Cushing’s-like features.
The cortisol elevation in these situations is generally milder than in true Cushing’s syndrome and resolves when the underlying condition is treated. Still, distinguishing pseudo-Cushing’s from the real thing is one of the most challenging problems in endocrinology, and it’s a major reason why diagnosis often requires multiple rounds of testing.
How Doctors Identify the Cause
Once a doctor suspects Cushing’s syndrome based on symptoms like unexplained weight gain concentrated in the face and trunk, purple stretch marks, easy bruising, and muscle weakness, the first step is confirming that cortisol levels are genuinely elevated. A 24-hour urine collection measures how much cortisol your body is excreting over a full day. Patients with Cushing’s syndrome generally show levels above 100 micrograms per 24 hours, though there is wide variation and no single cutoff works for everyone.
The dexamethasone suppression test is another key tool. In the overnight version, you take a 1-milligram tablet of dexamethasone at 11 p.m., then have your blood drawn at 8 a.m. the next morning. In a healthy body, the dexamethasone tells the pituitary to stop sending cortisol-production signals, so morning cortisol should drop. If it stays elevated, that suggests the normal feedback loop isn’t working. A high-dose version of the test, using 8 milligrams, helps distinguish a pituitary source from an ectopic one, since pituitary tumors will often partially respond to the higher dose while ectopic tumors typically ignore it.
From there, blood tests measuring ACTH levels point doctors toward the source. High ACTH means the problem is either in the pituitary or an ectopic tumor. Low ACTH points to the adrenal glands themselves. Imaging with MRI (for the pituitary) or CT scans (for the adrenal glands, lungs, and abdomen) follows to locate the specific growth responsible.