Cushing’s syndrome is caused by prolonged exposure to high levels of cortisol, whether from medications you take or from your body overproducing it. The diagnosis is notoriously tricky because the symptoms overlap with common conditions like obesity and high blood pressure, and the biochemical tests used to confirm it each have blind spots. Getting from suspicion to a definitive diagnosis often takes years and involves layered rounds of blood, urine, and saliva tests followed by imaging and sometimes invasive sampling procedures.
How Cortisol Gets Out of Control
Your adrenal glands, which sit on top of your kidneys, produce cortisol under the direction of a hormonal chain of command. The hypothalamus in your brain releases a signal (CRH) that tells the pituitary gland to release ACTH, which in turn tells the adrenals to pump out cortisol. When cortisol levels rise high enough, the system is supposed to dial itself back down. Cushing’s syndrome happens when something breaks that feedback loop and cortisol stays elevated for weeks, months, or years.
The causes split into two broad camps: exogenous, meaning something from outside the body, and endogenous, meaning a problem originating within the body. The exogenous form is far more common.
The Most Common Cause You Might Not Expect
The single most frequent cause of Cushing’s syndrome is taking corticosteroid medications. Drugs like prednisone, prednisolone, and dexamethasone are prescribed for conditions ranging from asthma and autoimmune disease to organ transplant management. When taken at high doses or for long stretches, they flood the body with synthetic cortisol and produce the same constellation of symptoms as endogenous disease: a rounded “moon” face, weight gain concentrated in the trunk, high blood pressure, metabolic problems, and thinning skin that bruises easily.1International Journal of Medical and Pharmaceutical Case Reports. Prolonged Prednisolone Use Induced Iatrogenic Cushing Syndrome: A Case Report
The risk is not limited to pills. Prolonged use of potent topical steroid creams, particularly clobetasol, has produced full-blown Cushing’s syndrome, especially in children and in countries where these creams are available without prescription.2PubMed. Exogenous Cushing’s syndrome due to topical corticosteroid application: case report and review literature In one striking case, a patient developed the syndrome from an over-the-counter arthritis supplement that turned out to contain hidden dexamethasone.3PubMed Central. A Case of Iatrogenic Cushing’s Syndrome following Use of an Over-the-Counter Arthritis Supplement Injected steroids for joint pain and even steroid inhalers for asthma can occasionally do the same, though the risk scales with dose and duration.
If your doctor suspects your Cushing’s symptoms come from prescribed steroids, the solution is conceptually simple but practically difficult: taper the medication slowly. The adrenal glands, which have been suppressed while the synthetic cortisol did their job, need time to wake back up. Recovery of normal adrenal function can take twelve months or longer, and abrupt withdrawal risks a dangerous cortisol crash.
Endogenous Causes, from Pituitary Tumors to Rare Adrenal Diseases
When the body itself makes too much cortisol without the help of outside medications, doctors further classify the problem by whether it is “ACTH-dependent” or “ACTH-independent.” This distinction matters because it determines where to look for the source.
In ACTH-dependent cases, something is producing too much ACTH, which whips the adrenals into overproduction. The most common culprit is a small, benign pituitary tumor called an adenoma. This specific scenario has its own name: Cushing’s disease (as opposed to Cushing’s syndrome, the umbrella term). These tumors are usually tiny, often under a centimeter, but they churn out ACTH relentlessly.4PubMed Central. Cushing’s disease: a multidisciplinary overview of the clinical features, diagnosis, and treatment
Less often, a tumor somewhere else in the body produces ACTH on its own. This is called ectopic ACTH syndrome, and it accounts for roughly 5 to 15 percent of Cushing’s syndrome cases.5PubMed Central. A rare case of ectopic ACTH syndrome caused by primary renal neuroendocrine tumor The tumors responsible are typically neuroendocrine tumors in the lungs, thymus, or pancreas, though they can crop up in unusual places. These tumors are sometimes so small they elude detection for years. In one reported case, the ectopic source was not found until sixteen years after the initial Cushing’s diagnosis.6JCEM Case Reports. The Elusive Neuroendocrine Tumor: Finding the Ectopic ACTH Source 16 Years After the Diagnosis of Cushing Syndrome
In ACTH-independent cases, the adrenal glands themselves are the problem. They produce cortisol without waiting for instructions from ACTH. This can happen because of a solitary cortisol-producing adrenal adenoma (the most common adrenal cause), a rare adrenal cancer, or a group of bilateral adrenal hyperplasias where both glands enlarge and overproduce. These ACTH-independent causes account for up to about 20 percent of endogenous Cushing’s syndrome in adults.7PubMed Central. Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotropin-independent Cushing syndrome) In young children, the proportion is much higher, approaching half of all cases.
First-Line Screening Tests
When a doctor suspects Cushing’s syndrome based on physical signs, the first step is to confirm that cortisol levels are genuinely elevated. Three screening tests are commonly used, and guidelines recommend at least two abnormal results before proceeding further.
- 24-hour urinary free cortisol: You collect all your urine over a full day, and the lab measures how much cortisol your body excreted. When measured with modern methods, this test has shown a sensitivity around 97 percent and specificity around 91 percent, making it at least as accurate as other first-line options used individually or in combination.8The Journal of Clinical Endocrinology & Metabolism. Screening Tests for Cushing’s Syndrome: Urinary Free Cortisol Role Measured by LC-MS/MS The practical downside is that collecting urine for 24 hours is inconvenient, and incomplete collections skew results.
- Late-night salivary cortisol: Cortisol normally drops to its lowest point late at night. People with Cushing’s syndrome lose this natural dip. You collect a saliva sample around 11 p.m. using a small cotton swab at home. Studies have found this test picks up roughly 92 to 93 percent of confirmed Cushing’s cases.9The Journal of Clinical Endocrinology & Metabolism. Late-Night Salivary Cortisol as a Screening Test for Cushing’s Syndrome10The Journal of Clinical Endocrinology & Metabolism. Nighttime Salivary Cortisol: A Useful Test for the Diagnosis of Cushing’s Syndrome It is simple and painless, which makes it easy to repeat, but shift workers and people with irregular sleep schedules can get unreliable readings.
- Overnight dexamethasone suppression test: You take a low dose of dexamethasone (a synthetic steroid) at bedtime, then have your blood drawn the next morning. In a healthy person, the dexamethasone tells the pituitary to stop releasing ACTH, and cortisol drops. In someone with Cushing’s syndrome, cortisol stays stubbornly high. Both the overnight version and the two-day low-dose version show high sensitivity and specificity.11PubMed. Overnight 1 mg dexamethasone suppression test and 24 h urine free cortisol-accuracy and pitfalls when screening for Cushing’s syndrome However, one study of 103 patients found that about 18 percent of people with Cushing’s disease showed cortisol suppression below the traditional cutoff on the overnight test, producing a false-negative result. This means the test should not be used alone to rule out the diagnosis.12The Journal of Clinical Endocrinology & Metabolism. The Low-Dose Dexamethasone Suppression Test: A Reevaluation in Patients with Cushing’s Syndrome
No single test is perfect, which is why the standard approach is to use at least two, and sometimes all three, to build confidence before moving to the next stage.
Figuring Out Where the Problem Is Coming From
Once excess cortisol is confirmed, the critical question becomes: is the cortisol overproduction being driven by ACTH or not? A simple blood test measuring ACTH levels helps here. If ACTH is low or undetectable, the problem is in the adrenal glands themselves, and the next step is usually an adrenal CT scan. If ACTH is in the normal-to-high range, the cortisol excess is ACTH-dependent, meaning something is producing too much ACTH.13JAMA. Cushing Syndrome: A Review
Once ACTH-dependent disease is identified, the harder challenge begins: is the ACTH coming from the pituitary (Cushing’s disease) or from somewhere else (ectopic)? A pituitary MRI is usually the first imaging step, and when it shows a clear tumor, the answer can be straightforward. But many pituitary adenomas are so small they do not show up on imaging, and incidental pituitary abnormalities are common in the general population, so a visible lesion does not always confirm the diagnosis.14PubMed. Cushing Syndrome: Diagnostic Workup and Imaging Features, With Clinical and Pathologic Correlation
Additional biochemical tests help. During a high-dose dexamethasone suppression test, pituitary tumors usually respond by partially reducing cortisol, while ectopic sources typically do not. A CRH stimulation test works on a similar principle. Combining the low-dose dexamethasone test with CRH stimulation has shown sensitivity of 97 percent and specificity of 94 percent for distinguishing pituitary from ectopic ACTH production in one series, outperforming the high-dose dexamethasone test alone.15The Journal of Clinical Endocrinology & Metabolism. Discriminatory Value of the Low-Dose Dexamethasone Suppression Test in Establishing the Diagnosis and Differential Diagnosis of Cushing’s Syndrome
When the Source Remains Ambiguous
In cases where biochemical tests and imaging do not agree, doctors turn to a procedure called inferior petrosal sinus sampling. The petrosal sinuses are veins that drain blood directly from the pituitary gland. A radiologist threads thin catheters through groin veins up to these sinuses and draws blood samples simultaneously from both sides, comparing ACTH concentrations there with ACTH in blood drawn from a peripheral vein. If ACTH is much higher at the pituitary end, the source is a pituitary tumor. If the levels are roughly equal, the ACTH is coming from elsewhere.
This procedure is considered the gold standard for distinguishing Cushing’s disease from ectopic ACTH syndrome.16PubMed Central. Pitfalls in Performing and Interpreting Inferior Petrosal Sinus Sampling: Personal Experience and Literature Review In a large study of 215 patients, a ratio of pituitary-to-peripheral ACTH of 2 or higher in baseline samples correctly identified 95 percent of patients with Cushing’s disease, with no false positives.17PubMed. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome Administering CRH during the procedure pushes accuracy even higher, with one series reporting 97 percent sensitivity and 100 percent specificity.18The Journal of Clinical Endocrinology & Metabolism. A Critical Analysis of the Value of Simultaneous Inferior Petrosal Sinus Sampling in Cushing’s Disease and the Occult Ectopic Adrenocorticotropin Syndrome
Despite these impressive numbers, the procedure requires highly experienced interventional radiologists and is not available at every hospital. The timing matters too: if cortisol happens to be in a normal phase during sampling, results can be misleading.
The Pseudo-Cushing’s Problem
One of the most frustrating aspects of diagnosis is that certain common conditions can raise cortisol enough to mimic Cushing’s syndrome on screening tests. Heavy alcohol use, major depression, poorly controlled diabetes, severe obesity, and polycystic ovary syndrome can all activate the body’s stress hormone axis and push cortisol into abnormal territory.19PubMed Central. Approach to patients with pseudo-Cushing’s states These situations, sometimes called physiologic or non-neoplastic hypercortisolism, can share clinical features with true Cushing’s syndrome to the point where even experienced endocrinologists have difficulty telling them apart.20European Journal of Endocrinology. Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)
The most reliable way to distinguish the two is often addressing the underlying condition and retesting. If you stop drinking heavily and your cortisol normalizes, for instance, the elevated cortisol was a consequence, not a cause. When that approach is impractical, combining a dexamethasone suppression test with a CRH stimulation test the following morning helps: people with true Cushing’s syndrome tend to show a brisk cortisol rise after CRH, while those with physiologic hypercortisolism usually do not.
Cyclic Cushing’s Syndrome
Some people have cortisol levels that swing between clearly elevated and perfectly normal, sometimes cycling over days and sometimes over months. This pattern, called cyclic Cushing’s syndrome, makes diagnosis especially difficult because a test done during a normal phase will come back clean. The diagnosis formally requires at least three documented peaks of excess cortisol separated by two periods of normal levels.21PubMed Central. Cyclic Cushing’s Syndrome – A Diagnostic Challenge
In a large retrospective study of 110 patients with cyclic Cushing’s, the cycles were irregular in the vast majority, making them hard to predict or catch on a single office visit. Symptoms worsened during peaks in about 80 percent of patients and improved during troughs in about three-quarters. Imaging missed the responsible tumor in roughly a third of patients, and about 8 percent underwent surgery at the wrong anatomical site because the cycling pattern led to a misclassification of the source. Delayed diagnosis and delayed treatment each affected over 40 percent of patients.22The Lancet Diabetes & Endocrinology. Cyclic Cushing’s syndrome: a retrospective observational study of clinical challenges, diagnostic strategies, and outcomes Hair cortisol analysis, which provides a several-month retrospective window into average cortisol exposure, is being explored as one way to catch intermittent elevations that spot blood or urine tests miss.
Mild Autonomous Cortisol Secretion
Not all cortisol overproduction is dramatic. Many people have adrenal nodules discovered incidentally on imaging done for other reasons, and a surprising number of those nodules quietly produce small amounts of extra cortisol. This condition, now called mild autonomous cortisol secretion (MACS), is diagnosed in roughly 20 to 50 percent of patients found to have adrenal nodules.23PubMed. Mild Autonomous Cortisol Secretion: Approach to Diagnosis, Evaluation, and Management These patients do not develop the classic full-blown features of Cushing’s syndrome, but the subtle cortisol excess is associated with higher rates of diabetes, high blood pressure, abnormal cholesterol, bone fractures, and even increased mortality.24PubMed. Diagnostics and surgery of mild autonomous cortisol secretion (MACS)
The diagnosis is made when a dexamethasone suppression test shows cortisol fails to suppress below a specific cutoff, but the patient lacks the obvious clinical stigmata of full Cushing’s. Whether and when to surgically remove the nodule remains debated. Current thinking favors surgery when there is clear evidence the mild cortisol excess is worsening cardiometabolic problems that are hard to control with medication alone.
Cushing’s Syndrome in Children
In children, the presentation looks different from adults. Growth failure is often the most prominent early sign, sometimes appearing before weight gain becomes obvious. A child who is gaining weight but falling off their growth curve in height should raise suspicion, because normal childhood obesity typically accelerates growth rather than stunting it. In a study of children with Cushing’s caused by a rare genetic form of bilateral adrenal disease (primary pigmented nodular adrenocortical disease), all patients showed growth failure along with weight gain and early signs of virilization.25PubMed. Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing’s syndrome due to primary nodular adrenocortical hyperplasia
The distribution of causes also shifts. In young children under seven, adrenal causes are responsible for up to half of Cushing’s cases, a much higher proportion than in adults.7PubMed Central. Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotropin-independent Cushing syndrome) Some of these adrenal conditions have a genetic basis, including mutations in the gene PRKAR1A, which is linked to a hereditary syndrome that includes adrenal and other tumors. Genetic testing has become part of the workup for children with bilateral adrenal disease.
Cushing’s Syndrome in Dogs
If this condition sounds familiar because your veterinarian mentioned it in connection with your aging dog, you are not imagining the overlap. Cushing’s disease occurs spontaneously and quite commonly in dogs, making it one of the most frequently diagnosed endocrine conditions in canine medicine.26Trends in Endocrinology & Metabolism. Pituitary pars intermedia lobe function and dysfunction in dogs and horses In dogs, the pituitary form predominates, much as it does in humans. The signs include excessive thirst, frequent urination, a pot-bellied appearance, hair loss, and panting. Horses develop a related pituitary condition as well, though the specific cell type involved differs. The shared biology across species is one reason dogs and horses have served as natural models for studying pituitary-driven cortisol excess, offering insights that feed back into human medicine.