Cushing's Syndrome

Introduction

Cushing’s syndrome is the medical name for the cluster of changes that happen in the body when there is too much cortisol over a long period of time. Cortisol is a hormone the body needs in normal amounts, but when levels stay high — whether because the body is making too much, or because cortisol-like medications are being taken — a recognisable pattern develops: weight gain in particular areas, changes to the skin, raised blood pressure, raised blood sugar, weakening of bones and muscles, mood changes, and several other features.

If you have been diagnosed with Cushing’s syndrome, or are being investigated for it, this article will help you understand what it is, what may be causing it in your case, how the diagnosis is confirmed, what treatments are used, and what to expect from recovery. The information here is built around the most common reasons people are referred for evaluation: persistent symptoms suggesting cortisol excess, an incidental finding on imaging, or being on long-term steroid medication.

Cushing’s syndrome is treatable. The treatment depends entirely on the underlying cause, and identifying that cause is the most important part of the work-up. Many patients who are treated successfully see their symptoms improve substantially over months, though full recovery can take a year or longer and some changes may not fully reverse. Specialist endocrinology care is central throughout.

What Is Cushing’s Syndrome?

Cortisol is a hormone produced by the adrenal glands, which sit on top of each kidney. Its production is normally controlled by a signal hormone called adrenocorticotropic hormone (ACTH), which is released by the pituitary gland at the base of the brain. The pituitary releases ACTH; ACTH tells the adrenal glands to make cortisol; cortisol then provides feedback to keep the system in balance. Cortisol does many important things in the body — regulating blood sugar, blood pressure, the immune response, and helping the body respond to physical or emotional stress.

Cushing’s syndrome occurs when the body is exposed to too much cortisol for too long. There are two broad ways this can happen:

• Taking cortisol-like medications (glucocorticoids) for a prolonged period — this is by far the most common cause overall. Medications such as prednisone, dexamethasone, prednisolone, and others used for asthma, autoimmune diseases, inflammatory bowel disease, transplants, and many other conditions can produce Cushing’s syndrome when taken at high doses or for extended periods. This is called exogenous (medication-induced or iatrogenic) Cushing’s syndrome.
• The body making too much cortisol on its own — this is called endogenous Cushing’s syndrome. It is much less common than the medication-induced form, but it is the form that requires investigation to identify a tumour or other underlying cause.

People often hear the terms “Cushing’s syndrome” and “Cushing’s disease” and assume they mean the same thing. They do not. Cushing’s syndrome is the general term for the clinical picture caused by high cortisol from any cause. Cushing’s disease is specifically the form caused by a tumour in the pituitary gland that produces excess ACTH. Cushing’s disease is the most common cause of endogenous Cushing’s syndrome but is only one of several possibilities. This distinction matters because treatments differ depending on the cause.

Causes and Risk Factors

Identifying the cause of Cushing’s syndrome is the central work of the endocrine evaluation, because the treatment depends entirely on where the excess cortisol is coming from.

Exogenous (medication-induced) Cushing’s syndrome

Cortisol-like medications, called glucocorticoids or corticosteroids, are widely used in medicine for their anti-inflammatory and immune-suppressing effects. When taken at significant doses for more than a few weeks, they can produce the same cluster of changes seen in Cushing’s syndrome from any other cause.

Common situations in which exogenous Cushing’s syndrome develops include long-term use of:

• Oral corticosteroids for asthma, COPD, rheumatoid arthritis, lupus, vasculitis, inflammatory bowel disease, or many other conditions
• Inhaled corticosteroids at high doses (less common but possible)
• Injected corticosteroids given frequently into joints or other areas
• Topical corticosteroid creams used over large body areas or for long periods, particularly potent formulations
• Steroids in some over-the-counter or traditional preparations — sometimes unrecognised by patients themselves
• Medications used after organ transplantation

Recognising exogenous Cushing’s syndrome is important because the underlying medication usually needs to continue for the condition it is treating. Treatment then involves careful balancing, dose reduction where possible, switching to different formulations or doses, and managing the side effects.

Endogenous Cushing’s syndrome

When the body produces too much cortisol on its own, the cause is somewhere in the system that regulates cortisol. Endogenous Cushing’s syndrome is divided into two broad categories based on whether ACTH is driving the cortisol excess.

ACTH-dependent causes — cortisol is high because something is producing too much ACTH, which in turn drives the adrenal glands to overproduce cortisol:

• Cushing’s disease (pituitary adenoma) — a benign tumour in the pituitary gland produces excess ACTH. This accounts for roughly 70% of endogenous Cushing’s syndrome cases. The tumours are usually small (microadenomas, less than 1 cm) and may be difficult to see on standard MRI.
• Ectopic ACTH syndrome — a tumour elsewhere in the body, most commonly in the lung (small cell lung cancer or carcinoid tumour) but sometimes the pancreas, thymus, or other organs, produces ACTH abnormally. This accounts for roughly 10–15% of endogenous cases.
• Ectopic CRH syndrome — very rare; a tumour produces corticotropin-releasing hormone, which drives the pituitary to overproduce ACTH.

ACTH-independent causes — cortisol is high because of a problem in the adrenal glands themselves; ACTH is suppressed because of feedback from the high cortisol:

• Adrenal adenoma — a benign tumour of the adrenal gland producing excess cortisol. Around 10% of endogenous cases.
• Adrenal carcinoma — a malignant tumour of the adrenal gland; uncommon but important to identify because of the different treatment and prognosis.
• Bilateral adrenal hyperplasia — both adrenal glands are enlarged and produce excess cortisol. Includes specific rare conditions such as primary pigmented nodular adrenocortical disease (PPNAD) and bilateral macronodular adrenal hyperplasia.

Signs and Symptoms

The features of Cushing’s syndrome develop gradually and overlap with several common conditions, which is one reason the diagnosis is sometimes delayed. The pattern, taken together, is what raises suspicion and what continues to be monitored during treatment and follow-up.

Changes in body shape and skin

• Weight gain, particularly central (around the trunk), with relatively thinner arms and legs
• Rounding of the face (“moon face”)
• Accumulation of fat between the shoulders (sometimes called a “buffalo hump”)
• Thinning of the skin, easy bruising, and slow wound healing
• Wide purplish stretch marks (striae), often on the abdomen, thighs, breasts, or arms
• Acne
• In some patients, darkening of the skin (more typical of certain causes such as ectopic ACTH syndrome)

Metabolic and cardiovascular changes

• High blood pressure
• High blood sugar or new-onset diabetes
• Raised cholesterol
• Increased risk of blood clots

Bone, muscle, and joint changes

• Weakness, particularly in the muscles of the thighs and upper arms — difficulty climbing stairs or rising from a low chair is a common feature
• Reduced bone density (osteoporosis), with increased risk of fractures, including fractures from minor injury

Reproductive and hormonal changes

• In women: irregular or absent periods, increased facial or body hair, reduced fertility
• In men: reduced libido, erectile dysfunction

Psychological and cognitive changes

• Mood changes — depression, anxiety, irritability, occasionally more severe psychiatric symptoms
• Difficulty with concentration and memory
• Sleep disturbance
• Reduced overall quality of life

Other features

• Increased susceptibility to infections, sometimes with reduced typical signs because the immune response is dampened
• Fatigue
• In children: slowing of growth alongside weight gain — an important pattern that prompts evaluation in paediatric patients

Because many of these features (weight gain, high blood pressure, diabetes, depression, irregular periods) are also common in the general population without Cushing’s syndrome, the diagnosis depends on the overall pattern, the severity, and the rate of change, combined with the results of specific tests.

Diagnosis

Confirming Cushing’s syndrome involves two distinct steps: first, establishing that cortisol is genuinely elevated; and second, determining where the excess is coming from. Both steps are essential, and each can be done in different ways depending on the situation.

Step 1: Confirming cortisol excess

Several screening tests are used to demonstrate cortisol excess. The Endocrine Society’s clinical practice guideline recommends starting with one of the following tests, each with high diagnostic accuracy:

• 24-hour urinary free cortisol — a 24-hour collection of urine measured for total cortisol output. Sustained elevation supports the diagnosis.
• Late-night salivary cortisol — cortisol normally drops to its lowest level around midnight. A high salivary cortisol at this time suggests loss of the normal day-night rhythm, which is characteristic of Cushing’s syndrome.
• Low-dose dexamethasone suppression test — dexamethasone, a synthetic cortisol-like medication, is given at night, and cortisol is measured the next morning. In a healthy person, dexamethasone suppresses cortisol production; in Cushing’s syndrome, it does not.

Because each test has potential for false positive or false negative results — influenced by factors such as obesity, depression, alcohol use, oral contraceptive use, shift work, and other conditions — abnormal results are usually confirmed with a second different test. Once cortisol excess is confirmed, the work moves to identifying the cause.

Step 2: Identifying the source of excess cortisol

The next step is measuring ACTH in the blood. The result divides the work-up into two paths:

• ACTH is low — the problem is in the adrenal glands themselves (ACTH-independent cause). Imaging of the adrenals (usually a CT scan or MRI) is the next step, looking for an adenoma, a carcinoma, or bilateral adrenal disease.
• ACTH is normal or high — the problem is from ACTH overproduction (ACTH-dependent cause). The next question is whether the source is the pituitary (Cushing’s disease) or somewhere else in the body (ectopic ACTH).

Distinguishing Cushing’s disease from ectopic ACTH can be challenging and may require additional tests:

• MRI of the pituitary gland — looking for a pituitary adenoma. Small adenomas may not be visible.
• High-dose dexamethasone suppression test — pituitary adenomas typically retain partial response to dexamethasone, while ectopic sources usually do not.
• CRH stimulation test — another biochemical test to distinguish pituitary from ectopic sources.
• Inferior petrosal sinus sampling (IPSS) — a specialised invasive test in which blood is sampled from the veins draining the pituitary gland and compared with peripheral blood for ACTH levels. It is the most accurate test for confirming or excluding a pituitary source when imaging is inconclusive, but requires significant expertise and is available only at specialised centres.
• Imaging for ectopic ACTH sources — CT scans of the chest, abdomen, and pelvis; sometimes nuclear medicine scans such as somatostatin receptor imaging or FDG-PET, looking for an ACTH-producing tumour elsewhere in the body.

The work-up is sometimes straightforward; sometimes it takes weeks of careful evaluation. Patients are best evaluated by an experienced endocrinologist with access to the necessary tests, ideally at a centre that sees Cushing’s syndrome regularly. The diagnostic pathway is one of the most subspecialised in endocrinology, and patients often benefit from a second opinion at a specialised pituitary or adrenal centre.

Treatment and Management

The treatment of Cushing’s syndrome depends on the cause. Each major type has its own approach, and current Endocrine Society guidance describes a cause-specific framework rather than a single pathway.

Treatment of exogenous (medication-induced) Cushing’s syndrome

When Cushing’s syndrome is caused by long-term corticosteroid medication, the goal is to reduce or eliminate the cortisol excess while continuing to treat the underlying condition that required the steroid in the first place. The approach typically involves:

• Reviewing whether the steroid is still necessary — in some cases the original indication has resolved or alternative treatments are now available.
• Gradual dose reduction — steroids cannot be stopped abruptly after long-term use because the body’s own cortisol production is suppressed and needs time to recover. A carefully managed taper, usually over months, is needed.
• Switching to alternative medications — for some conditions, steroid-sparing medications can substitute fully or partly for steroid use.
• Switching formulations — in some cases changing from oral to inhaled or topical steroids, or to a different specific drug, reduces systemic exposure.
• Managing the consequences — bone protection (such as calcium, vitamin D, and bone-protecting medications), blood pressure and blood sugar management, and other supportive measures.

Steroid dose changes must be supervised by the prescribing doctor. Abruptly stopping long-term steroids can cause an adrenal crisis, which is a medical emergency.

Treatment of Cushing’s disease (pituitary cause)

For Cushing’s disease, current guidelines describe surgery to remove the pituitary adenoma as the first-line treatment. The standard approach is transsphenoidal surgery — the surgeon reaches the pituitary gland through the nose and the sphenoid sinus at the base of the skull, without any external incision. The procedure is performed by an experienced pituitary neurosurgeon, typically using endoscopic or microscopic techniques.

Outcomes depend significantly on surgical expertise and on the size and visibility of the tumour. Initial remission rates after surgery for microadenomas in experienced centres are commonly reported in the range of 70–90%, with lower rates for larger or less visible tumours. Recurrence can occur years later, so long-term follow-up is essential.

When initial surgery does not achieve remission, when the disease recurs, or when surgery is not possible, additional treatments are considered:

• Repeat pituitary surgery in selected cases
• Radiation therapy to the pituitary — conventional fractionated radiation or stereotactic radiosurgery. Effective but slow to act; cortisol normalisation may take months to years, and the patient often needs medical therapy in the interim. Risk of damaging other pituitary hormone functions is a consideration.
• Medical therapy — medications that block cortisol production or action (see below)
• Bilateral adrenalectomy — removal of both adrenal glands. This produces immediate cure of the cortisol excess but creates permanent adrenal insufficiency, requiring lifelong hormone replacement. It is considered when other treatments have failed or are not suitable.

Treatment of adrenal Cushing’s syndrome

When the cause is an adenoma or carcinoma in the adrenal gland, treatment is surgical removal of the affected adrenal gland (adrenalectomy). For a benign single-side adenoma, this is usually performed laparoscopically (minimally invasive) by an experienced adrenal surgeon and is generally curative. For adrenal carcinoma, more extensive surgery is required, and additional treatments such as the medication mitotane and chemotherapy may follow. For bilateral disease, both adrenal glands are removed and lifelong hormone replacement is required.

After one-sided adrenal surgery for a cortisol-producing adenoma, the other adrenal gland has typically been suppressed by the prolonged high cortisol and takes months to recover. Patients usually need hydrocortisone replacement after surgery, with gradual reduction as the remaining adrenal recovers. This recovery period can take six to twelve months or longer and requires careful endocrine follow-up.

Treatment of ectopic ACTH syndrome

The treatment of ectopic ACTH syndrome is treatment of the underlying tumour — surgical removal where possible, and chemotherapy or other cancer treatments as appropriate for the specific tumour. When the tumour cannot be located or fully removed, medical therapy to block cortisol production is used to manage the cortisol excess.

Medical therapy

Several medications can reduce cortisol production or its action. These are used in specific situations: as a bridge to surgery, after unsuccessful surgery, when surgery is not possible, while waiting for radiation to take effect, or as long-term treatment in some patients. The main classes include:

• Steroidogenesis inhibitors — medications such as ketoconazole, metyrapone, osilodrostat, and levoketoconazole that block one or more enzymes involved in cortisol production. Each has a different side-effect profile and monitoring requirements.
• Pituitary-targeted medication — pasireotide, a somatostatin analogue, which acts on the pituitary tumour to reduce ACTH secretion. Used specifically for Cushing’s disease.
• Adrenolytic medication — mitotane, which has a direct toxic effect on adrenal cortex cells. Used particularly in adrenal carcinoma and selected other situations.
• Glucocorticoid receptor blocker — mifepristone, which blocks the effect of cortisol at its receptor rather than reducing cortisol levels. Used in specific situations, particularly when blood sugar control is the main goal.

Recovery after treatment of Cushing’s syndrome unfolds over months and sometimes years. Understanding the pace and the typical phases helps set realistic expectations.

Immediate post-treatment phase

After successful surgery (whether pituitary or adrenal), cortisol levels often drop quickly, sometimes precipitously. The body, which has been adapted to high cortisol for months or years, then experiences a relative deficiency. This produces symptoms of cortisol withdrawal: fatigue, muscle aches, joint pains, nausea, mood changes, and a general feeling of being unwell. Hydrocortisone replacement is typically given during this period to bridge the gap until the body’s own production recovers. The patient is closely monitored to ensure adequate replacement, which may need adjustment over weeks to months.

Months following treatment

As cortisol returns toward normal and stays there, the body begins to reverse the changes of Cushing’s syndrome. Improvements typically include:

• Gradual weight loss, with redistribution of fat away from central areas
• Improvement in blood pressure
• Improvement in blood sugar control; in some patients with steroid-induced diabetes, diabetes may resolve
• Improvement in skin thinning and bruising over time, although stretch marks usually remain (they may fade)
• Gradual return of muscle strength
• Slow improvement in bone density; specific bone-protective treatments are often used
• Mood and cognitive function typically improve, though slowly
• Periods often return to normal in women; fertility can be restored in many patients

This recovery is gradual. Patients sometimes feel that the improvement is slower than they had hoped, particularly in the first months. Counselling about the realistic pace helps.

Living with Cushing’s Syndrome

For most patients treated successfully, the long-term outlook is good, but several long-term considerations apply and shape ongoing care.

• Lifelong follow-up with an endocrinologist, to monitor for recurrence and to manage long-term consequences. Cushing’s disease can recur years after apparently successful pituitary surgery.
• Bone health monitoring — osteoporosis can persist for years even after cortisol normalises, and ongoing assessment is part of routine care.
• Cardiovascular risk — the increased cardiovascular risk associated with long-standing Cushing’s syndrome reduces with treatment but may not return fully to baseline. Ongoing attention to blood pressure, lipids, and glucose is important.
• Mental health — psychiatric and cognitive features may persist or take longest to recover. Support and continued attention to mental health is part of comprehensive follow-up.
• Adrenal insufficiency — patients who have had bilateral adrenalectomy or whose remaining adrenal function has not fully recovered need long-term hydrocortisone replacement and the knowledge of how to manage stress doses and sick day rules. A medical alert bracelet or card is generally recommended for these patients.
• Replacement of other pituitary hormones — some patients who have had pituitary surgery or radiation may need replacement of other pituitary hormones (thyroid, growth hormone, sex hormones, antidiuretic hormone).

Complications

When Cushing’s syndrome is not recognised or not adequately treated, the long-term consequences of high cortisol can be serious. Major complications include:

• Cardiovascular disease — high blood pressure, raised cholesterol, and a higher risk of heart attack and stroke
• Diabetes — sometimes severe and difficult to control while cortisol remains high
• Osteoporosis and fractures — including fragility fractures of the spine, hip, and ribs from minor injuries
• Blood clots — deep vein thrombosis and pulmonary embolism are more common in people with active Cushing’s syndrome and around the time of surgery
• Serious infections — the immune system is suppressed, and infections may present with reduced typical signs
• Psychiatric complications — severe depression, anxiety, and occasionally psychotic features
• Muscle wasting — significant weakness that affects daily activity

Untreated endogenous Cushing’s syndrome carries a meaningfully increased mortality risk over time, which is why timely diagnosis and effective treatment matter.

Cushing’s Syndrome in Children

Cushing’s syndrome in children is rare but important to recognise. The combination of weight gain with slowing of growth (rather than continued normal growth) is the classic pattern that raises suspicion in paediatric patients — healthy weight gain in children is normally accompanied by increased height, so the combination of weight gain plus reduced growth velocity is a meaningful signal.

Causes of Cushing’s syndrome in children differ somewhat from adults. Cushing’s disease (pituitary adenoma) is again the most common endogenous cause, but rarer specific conditions of the adrenal gland — including some genetic conditions such as Carney complex and primary pigmented nodular adrenocortical disease — are seen more frequently in paediatric populations than in adults. Exogenous (medication-induced) Cushing’s remains common when children are on long-term steroid treatment for asthma, autoimmune disease, or after transplantation.

Investigation and treatment in children involve specialist paediatric endocrinologists, and care is best provided at centres with experience in paediatric Cushing’s. Long-term follow-up extends into adulthood, given the implications for growth, puberty, bone health, and the risk of recurrence.

When to Seek Urgent Care

If you are being treated for Cushing’s syndrome, or are taking hydrocortisone replacement after surgery, certain situations need urgent medical attention rather than waiting for a routine appointment. These include:

• Severe fatigue, dizziness, vomiting, abdominal pain, low blood pressure, or confusion — these can be signs of adrenal crisis, a medical emergency that needs immediate treatment with injected hydrocortisone and fluids
• A serious infection, major illness, severe injury, or surgery while on hydrocortisone replacement — doses usually need to be temporarily increased (“stress dosing”), and your endocrinologist will have given you a plan for this
• Severe headache, sudden visual changes, or new neurological symptoms after pituitary surgery
• Sudden, severe leg swelling or chest pain and breathlessness — possible signs of blood clots
• Severe mood changes or thoughts of self-harm

Patients on long-term hydrocortisone replacement should carry a medical alert card or bracelet noting that they have adrenal insufficiency and may need emergency steroids.

Frequently Asked Questions

I have been on long-term steroids and I have weight gain and other features. Do I have Cushing’s syndrome?

If you have been taking significant doses of glucocorticoid medication for a prolonged period and are developing the features described in this article, you may have what is called exogenous or iatrogenic Cushing’s syndrome. Investigation for an underlying tumour is not usually needed in this situation — the medication is the cause. Treatment involves working with your doctor on the safest possible reduction of steroid dose, switching medications where possible, and managing the consequences. Do not stop your steroids on your own; abrupt withdrawal after long-term use can cause a dangerous adrenal crisis.

How long does it take to recover after treatment?

Substantial improvement is often seen within weeks to months after successful treatment, but full recovery can take a year or longer. The body has been adapted to high cortisol over months or years and needs time to readjust. Some features — muscle strength, weight distribution, bone density, mood — recover gradually; some, such as stretch marks, may not fully resolve. Patience and persistent follow-up matter.

Can Cushing’s syndrome come back after treatment?

Yes. Cushing’s disease (from a pituitary adenoma) in particular can recur years after apparently successful surgery, which is why lifelong endocrine follow-up is needed. Recurrence is generally detected by monitoring for the same biochemical and clinical features that prompted the original diagnosis. Early detection of recurrence allows earlier treatment.

Will I be able to have children after Cushing’s syndrome treatment?

For most women treated successfully, fertility is often restored over time as cortisol normalises and periods return to normal. Pregnancy is generally safer after Cushing’s syndrome has been treated and cortisol levels are stable. For men, sexual function and fertility likewise typically improve. Specific advice depends on the type of Cushing’s, the treatment received, and whether other pituitary hormones are affected.

Why is the work-up taking so long?

The diagnostic work-up of Cushing’s syndrome can take weeks because multiple tests are usually required, results need to be confirmed, and the source of the cortisol excess must be localised before treatment can be planned. Small pituitary adenomas can be difficult to see on imaging, and sometimes specialised invasive tests such as inferior petrosal sinus sampling are needed. The patience involved in a thorough work-up is well spent — treating the wrong cause is worse than waiting to identify the right one.

Are there alternative or natural treatments for Cushing’s syndrome?

There are no proven natural or alternative treatments for Cushing’s syndrome from any cause. The condition arises from a specific biochemical problem — either a tumour producing excess hormones or the effect of medications — and addressing the cause is the only effective approach. Lifestyle measures (healthy diet, exercise as tolerated, mental health support) are important alongside medical treatment but do not substitute for it.

What happens if Cushing’s syndrome is left untreated?

Untreated Cushing’s syndrome carries significant long-term risks, including cardiovascular disease (heart attack, stroke), severe osteoporosis with fractures, uncontrolled diabetes, serious infections, blood clots, and significant psychiatric problems. The mortality risk of untreated endogenous Cushing’s syndrome is meaningfully elevated. This is why establishing the diagnosis and getting to effective treatment matters.

Conclusion

Cushing’s syndrome is treatable, and most patients who are diagnosed and treated effectively see substantial improvement in their symptoms and their quality of life. The work-up is sometimes long because identifying the exact cause — whether medication, a pituitary tumour, an adrenal tumour, or an ectopic source — is what determines the right treatment. Specialist endocrinology care, often at a centre that sees Cushing’s regularly, makes a real difference both to getting the diagnosis right and to choosing the most appropriate treatment.

Recovery is gradual and takes patience. Most features of Cushing’s syndrome reverse over months to a year or more after successful treatment, though some may not fully resolve. Long-term follow-up is essential to monitor for recurrence, to manage the lasting effects on bones, blood pressure, and metabolism, and to support the patient through what is for many people a multi-year recovery and adjustment.