Cushing Syndrome

What happens in Cushing syndrome

Cortisol is made by the two adrenal glands, which sit on top of the kidneys. Its release is controlled by ACTH, a hormone from the pituitary gland at the base of the brain. Normally cortisol rises in the morning and falls to very low levels around midnight. It raises blood sugar, controls inflammation, helps maintain blood pressure and breaks down protein for fuel.

When cortisol stays high all day and night, those effects become harmful: muscle and skin protein is broken down, fat is redistributed to the trunk, blood sugar and blood pressure climb, and bones thin.

Cushing syndrome symptoms

Symptoms build up slowly, often over years, and may be mistaken for ordinary weight gain. The features most specific to Cushing syndrome are:

• Moon face: a rounded, full, often flushed face
• Buffalo hump: a fat pad on the back of the neck and between the shoulders, and fat above the collarbones
• Wide purple stretch marks (striae) on the belly, thighs, breasts or armpits, usually more than 1 cm wide
• Easy bruising and thin, fragile skin
• Weakness of the thighs and upper arms (proximal myopathy), noticed as difficulty climbing stairs or getting up from a chair

Other common features:

• weight gain centered on the belly, with relatively thin arms and legs
• high blood pressure and high blood sugar or diabetes
• slow wound healing and frequent infections
• acne and, in women, excess facial hair and irregular or absent periods
• low sex drive and erectile problems
• thinning bones (osteoporosis) and fractures, including of the spine and ribs
• mood changes: irritability, anxiety, depression, poor sleep and memory problems
• kidney stones and increased thirst and urination

In children, the main sign is weight gain combined with slowed growth in height.

Causes

External (exogenous) Cushing syndrome

Steroid medicines are by far the most common cause. They include prednisone, prednisolone, dexamethasone and hydrocortisone, used for asthma, rheumatoid arthritis, lupus, inflammatory bowel disease and after organ transplants. High-dose inhaled, injected (for example into joints) and strong skin steroid creams can also cause it, especially with long use.

Internal (endogenous) Cushing syndrome

When the body makes too much cortisol itself, the cause is usually one of these:

Cushing syndrome vs Cushing's disease

Cushing syndrome is the umbrella term for the effects of too much cortisol from any cause. Cushing's disease means only the type caused by an ACTH-producing pituitary tumor.

Pseudo-Cushing states

Heavy alcohol use, severe depression, poorly controlled diabetes and severe obesity can raise cortisol modestly and cause some of the same features. Cortisol returns to normal when the underlying problem is treated.

Diagnosis

Your doctor will first check whether you take, or recently took, any steroid medicine, including creams, inhalers and joint injections. If not, the Endocrine Society recommends one or more of these screening tests:

1. Late-night salivary cortisol: you collect saliva at home around 11 pm on two nights. Cortisol should be very low at that time.
2. 24-hour urine free cortisol: you collect all urine for a full day, usually on at least two occasions.
3. 1 mg overnight dexamethasone suppression test: you take a dexamethasone tablet at 11 pm and have blood drawn the next morning. Normally cortisol falls to a very low level. In Cushing syndrome it does not.

Some medicines, especially estrogen-containing birth control, can make results misleading, so tell the doctor about everything you take. Abnormal results are confirmed with repeat or different tests.

Finding the source

• Blood ACTH level: low ACTH points to an adrenal cause; normal or high ACTH points to the pituitary or an ectopic tumor.
• Imaging: pituitary MRI, adrenal CT scan, or chest and body scans for an ectopic tumor.
• Inferior petrosal sinus sampling: a specialized test that measures ACTH in veins draining the pituitary, used when MRI does not show a clear tumor.

Treatment

Steroid-related Cushing syndrome

The aim is the lowest effective steroid dose, or switching to a non-steroid treatment for the underlying disease. Never stop steroid tablets suddenly after more than a few weeks of use. Your adrenal glands will have shut down and need time to restart, so the dose is tapered over weeks to months.

Tumor-related Cushing syndrome

• Surgery is the first choice: removal of the pituitary tumor through the nose (transsphenoidal surgery), removal of the affected adrenal gland, or removal of the ectopic tumor.
• Medicines that lower cortisol are used when surgery is not possible, has not worked, or while waiting for it. They include osilodrostat, metyrapone, ketoconazole or levoketoconazole, pasireotide, and mifepristone, which blocks cortisol's effects.
• Radiation therapy to the pituitary if a tumor remains after surgery.
• Removal of both adrenal glands is a last resort that cures the cortisol excess but requires lifelong hormone replacement.

After successful surgery, cortisol levels drop below normal for a while. You will need hydrocortisone replacement, sometimes for a year or more, and an emergency plan for illness.

Treating the effects

Blood pressure, diabetes, bone thinning and mood problems need treatment in their own right. People with active Cushing syndrome have a higher risk of blood clots, especially around surgery, and may be given blood thinners.

Complications

Untreated Cushing syndrome increases the risk of heart attack, stroke, deep vein thrombosis, diabetes, serious infections, fractures and depression. Long-standing untreated disease shortens life expectancy, which is why prompt diagnosis matters.

Outlook

Most people improve markedly once cortisol is normal. The face and body shape usually change within months, but muscle strength, bone density, mood and memory can take a year or longer to recover, and some changes may persist. Endogenous Cushing syndrome can recur, so follow-up with an endocrinologist continues for years.

Frequently asked questions

What are the first signs of Cushing syndrome?

Early signs are often weight gain around the belly and face, a flushed round face, thinning skin that bruises easily, and new high blood pressure or blood sugar. Wide purple stretch marks and weakness when climbing stairs are more specific signs that should prompt testing.

What is the most common cause of Cushing syndrome?

Taking glucocorticoid steroid medicines such as prednisone for months is the most common cause. Among people who make too much cortisol themselves, a small, benign pituitary tumor (Cushing's disease) is the most common source, followed by adrenal tumors.

Can Cushing syndrome go away?

Yes, in most cases. Steroid-related Cushing syndrome fades as the dose is reduced. Removing a cortisol-producing tumor cures most people with endogenous disease. Recovery of muscles, bones and mood can take a year or more, and some people need long-term follow-up for recurrence.

Can stress cause Cushing syndrome?

Everyday stress does not cause Cushing syndrome. Stress raises cortisol briefly, but the levels and pattern are far lower than in Cushing syndrome. Severe depression, heavy drinking and severe obesity can cause mild cortisol elevation, called pseudo-Cushing, which resolves when the underlying condition is treated.

Which doctor treats Cushing syndrome?

An endocrinologist, a specialist in hormone disorders, confirms the diagnosis and coordinates treatment. Pituitary neurosurgeons, endocrine surgeons, oncologists and radiation specialists are involved depending on the cause. Steroid-induced cases are often managed together with the doctor who prescribed the steroids.

How is Cushing syndrome different from weight gain or metabolic syndrome?

Ordinary obesity and metabolic syndrome share belly fat, high blood pressure and high blood sugar. Cushing syndrome adds features rarely seen otherwise: thin, easily bruised skin, wide purple stretch marks, thigh muscle weakness and bone thinning at a young age. Cortisol tests separate them.