Cushing's syndrome: what a high cortisol does and doesn't mean

Cushing's syndrome is having too much cortisol, the body's main stress hormone, for a long stretch of time, and it can come from any source. A single high morning cortisol does not prove it, because cortisol is supposed to peak in the morning and rises with stress, illness, and even the blood draw itself. The diagnosis turns on showing that cortisol has lost its normal control, and the most common cause is prescribed steroid medication, not an internal tumor. ¹⁵

What is Cushing's syndrome?

Cortisol is the hormone your body raises to handle stress, keep blood pressure up, and free up blood sugar for energy. Cushing's syndrome is what happens when cortisol stays too high for months, whatever the source. That flood of cortisol reshapes the body over time, which is why the condition has such a recognizable look.

The wording trips people up, so here is the split. Cushing's syndrome is the state of cortisol excess from any cause. Cushing's disease is one particular cause of that syndrome: a benign tumor in the pituitary (a pea-sized gland under the brain) that over-makes ACTH (adrenocorticotropic hormone, the pituitary's signal telling the adrenal glands to release cortisol). So every case of Cushing's disease is Cushing's syndrome, but most Cushing's syndrome is not Cushing's disease. ¹

What causes high cortisol?

The single most common cause of Cushing's syndrome is external. It is glucocorticoid steroid medication, drugs such as prednisone or dexamethasone prescribed for asthma, arthritis, or autoimmune disease. When a tumor is behind it, the internal sources break down as follows. ⁵

Those percentages describe the internal (endogenous) causes only; steroid medication remains the leading cause across everyone. ³⁵

What are the symptoms of high cortisol?

High cortisol over months tends to redistribute weight, thin the skin, weaken muscle, and unsettle mood. No one has every sign, and mild cases can look like ordinary weight gain or stress, which is part of why the diagnosis is slow.

The mix of central weight gain, purple stretch marks, easy bruising, and muscle weakness together points more strongly at cortisol excess than any one of them alone. ⁴⁵

Why one high morning cortisol is not a diagnosis

Cortisol is meant to swing across the day. It peaks within an hour of waking, then drifts down to its lowest around midnight. It also rises with stress, illness, pain, poor sleep, heavy drinking, and even the anxiety of a blood draw. So a single high cortisol reading, a morning cortisol most of all, is expected physiology far more often than it is disease.

What separates Cushing's syndrome from a stressful morning is control. In a healthy body, rising cortisol switches off the signals that make it, and the level bottoms out at night. In Cushing's, that brake fails. The diagnosis rests on catching lost control in one of three ways: cortisol does not fall after a low dose of dexamethasone (a synthetic steroid taken as a tablet), it stays high late at night, or a 24-hour urine collection shows a raised daily total. ¹

How is Cushing's syndrome diagnosed?

No single test settles it. The Endocrine Society advises starting with one of three first-line screens and requires at least two clearly abnormal results before the diagnosis is pursued, precisely because stress and illness can push any one test up. ¹

We recommend testing for Cushing's syndrome in ... patients with unusual features for age (e.g. osteoporosis, hypertension); patients with multiple and progressive features, particularly those more predictive of Cushing's syndrome.Endocrine Society Clinical Practice Guideline, Nieman et al., JCEM 2008 [[1]]

That 1.8 mcg/dL cutoff is the standard threshold for normal suppression on the low-dose test. ¹

Once two tests confirm the excess, the next question is where it comes from. A blood ACTH level splits the causes in two. When ACTH is high or normal, the problem is ACTH-driven (ACTH-dependent): usually a pituitary tumor (Cushing's disease), or less often an ectopic tumor elsewhere. When ACTH is low, an adrenal gland is making cortisol on its own (ACTH-independent), pointing to an adrenal tumor. Imaging and further specialist tests follow from there. ³

1. 1ScreenOne of the three first-line tests, chosen to fit your situation.
2. 2ConfirmA second, different test; at least two clearly abnormal results are needed before the diagnosis is pursued.
3. 3Locate the sourceA blood ACTH level separates a pituitary or ectopic cause (ACTH-dependent) from an adrenal one (ACTH-independent).
4. 4Image and treatScans and specialist testing pinpoint the tumor; treatment, often surgery, is decided by an endocrinologist. [[2]]

How the tests are done, and who should be screened

The overnight dexamethasone test is a 1 mg tablet taken around 11pm with a single blood draw the next morning at about 8am. The late-night salivary test is a small swab you chew at home near midnight, usually on two separate nights. The 24-hour urine test means collecting every drop of urine over a full day into one container. None requires fasting. A clinician orders these when there is a real reason to suspect Cushing's, and they are generally covered by insurance when clinically indicated.

Testing is aimed at people with several progressive features of cortisol excess, those with unusual problems for their age (such as osteoporosis or high blood pressure in a young person), anyone with an adrenal mass found on a scan, and people on long-term steroids who develop the syndrome. It is not a test to run on everyone with a stressful week or one high reading. ¹

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