Cushing's Disease (Pituitary Cushing's)

Cushing's disease vs Cushing's syndrome

The names cause confusion. Cushing syndrome is the umbrella term for any state of too much cortisol. Cushing's disease is one specific cause: a pituitary tumor.

So all Cushing's disease is Cushing syndrome, but most Cushing syndrome caused by medicines is not Cushing's disease.

How a pituitary tumor causes it

The pituitary gland at the base of the brain releases ACTH, which drives the adrenal glands above the kidneys to make cortisol. In Cushing's disease, a pituitary adenoma made of corticotroph cells releases ACTH without responding to normal feedback. Both adrenal glands enlarge and pour out cortisol day and night, losing the normal low point around midnight.

Most of these tumors are microadenomas, under 1 cm and often only a few millimeters, so they rarely press on the optic nerves. They are almost always benign. The cause is usually an acquired gene change in the tumor (often in the USP8 gene). It is rarely inherited, though it can occur in family syndromes such as MEN1.

Symptoms of Cushing's disease

Symptoms develop slowly over months to years, so they are easy to put down to aging or weight gain. The features most specific to Cushing's are:

• wide (over 1 cm) purple or red stretch marks on the belly, thighs or armpits
• easy bruising and thin, fragile skin
• weakness of the thigh and shoulder muscles, so rising from a chair or climbing stairs is hard
• a round, red face and fat pads above the collarbones and over the upper back

Other common features:

• weight gain centered on the trunk with thin arms and legs
• high blood pressure and high blood sugar or diabetes
• acne, extra facial or body hair, and irregular or absent periods in women
• low libido and erectile dysfunction in men
• poor sleep, irritability, depression, anxiety and memory problems
• bone thinning (osteoporosis), back pain and fractures, including of the ribs and spine
• slow wound healing and frequent infections
• in children, weight gain with slowing height growth

Diagnosis

Testing usually happens in two steps under an endocrinologist.

Step 1: confirm too much cortisol

At least two of these screening tests are used:

• Late-night salivary cortisol: a saliva sample at bedtime, often repeated. Normally cortisol is very low at night.
• 24-hour urine free cortisol: collected over a full day, usually twice.
• Low-dose dexamethasone suppression test: a tablet at 11 p.m., then a blood cortisol test the next morning. Normally cortisol falls. In Cushing's it does not.

You will be asked about any steroid medicines, including creams, inhalers, joint injections and supplements, because these can cause the same picture.

Step 2: find the source

• Morning ACTH: normal or high points to a pituitary or ectopic source. Low points to the adrenal gland.
• Pituitary MRI: shows a tumor in many cases, but a tiny adenoma can be invisible.
• Inferior petrosal sinus sampling (IPSS): thin tubes are passed through groin veins to the veins draining the pituitary. ACTH is measured there and in the arm after a stimulating injection. A high ratio confirms a pituitary source. This is used when MRI is unclear.
• CRH or desmopressin stimulation tests and CT scans may help rule out an ectopic tumor.

Treatment

Transsphenoidal surgery

A neurosurgeon removes the tumor through the nose or upper lip and sphenoid sinus, without opening the skull. In experienced centers, remission rates for microadenomas are around 70% to 90%. Success is lower for large tumors.

After successful surgery, cortisol drops to very low levels because the normal ACTH cells have been suppressed for a long time. You will need hydrocortisone replacement for months, sometimes a year or more, and must learn sick-day rules to avoid adrenal crisis. Many people feel worse for a while as the body adjusts, with aches, tiredness and low mood. Some people develop temporary diabetes insipidus (passing large volumes of urine).

If surgery does not cure it

• Repeat surgery in selected cases.
• Medicines: adrenal blockers (such as osilodrostat, metyrapone and ketoconazole), a pituitary-targeted drug (pasireotide), cabergoline, or a cortisol receptor blocker (mifepristone, used for high blood sugar in Cushing's). These control cortisol but do not remove the tumor.
• Radiation therapy: stereotactic radiosurgery or conventional radiotherapy. It works slowly, over months to years, and can cause other pituitary hormone deficiencies.
• Removal of both adrenal glands (bilateral adrenalectomy): cures the excess cortisol immediately but means lifelong steroid replacement. A small number develop Nelson syndrome, in which the pituitary tumor grows and causes skin darkening.

Blood pressure, diabetes, bone thinning and mood problems are treated alongside. Doctors also consider blood-thinning protection around surgery, because clotting risk is high.

Complications and outlook

Untreated Cushing's disease significantly shortens life, mostly from heart attacks, strokes, blood clots and infections. Once cortisol is normal, most features improve over 6 to 18 months: weight falls, stretch marks fade to silver, muscle strength returns and blood pressure and sugar improve. Some changes, such as bone loss, some heart risk and mood or memory symptoms, can persist. Recurrence occurs in roughly 10% to 25% over 10 years, so lifelong follow-up with periodic cortisol testing is needed.

Frequently asked questions

What is the difference between Cushing's disease and Cushing's syndrome?

Cushing's syndrome means any excess of cortisol, whatever the cause, including steroid medicines and adrenal tumors. Cushing's disease is the specific type caused by an ACTH-secreting pituitary tumor. All Cushing's disease is Cushing's syndrome, but not the other way round.

Is Cushing's disease cancer?

Almost never. The pituitary tumor is a benign adenoma that does not spread. The harm comes from the excess hormone it makes. Pituitary carcinomas that spread are extremely rare.

Can Cushing's disease be cured?

Yes, often. Transsphenoidal surgery by an experienced pituitary surgeon cures most people with small tumors. If it does not, medicines, radiation or removal of the adrenal glands can control cortisol. Lifelong check-ups are needed because it can come back.

How long does recovery take after pituitary surgery for Cushing's?

Most people need 6 to 12 months, sometimes longer, to recover. Steroid replacement is tapered slowly as the body's own ACTH returns. Weight, skin and muscle changes improve gradually, and tiredness and aches during steroid withdrawal are common.

Why is Cushing's disease hard to diagnose?

Its features, such as weight gain, high blood pressure, diabetes and low mood, are common in the general population, and cortisol tests can be falsely abnormal from stress, alcohol, depression or the pill. The tumor is often too small for MRI to see, so several tests are combined.