Cushing’s Disease

What is Cushing’s disease?

Cushing’s disease is a hormonal disorder caused by a pituitary tumour that produces excessive amounts of adrenocorticotropic hormone (ACTH). This overproduction of ACTH overstimulates the adrenal glands, leading to persistently high levels of cortisol, an essential-to-life stress hormone that affects metabolism, blood pressure and immune function.

Cushing’s disease is a specific cause of cushing’s syndrome. Cushing’s syndrome refers to an overall state of excess cortisol in the body, which can arise from various causes, including cushing’s disease, medications or adrenal tumours. Cushing’s disease, however, refers specifically to the form caused by an ACTH-secreting pituitary adenoma, a benign tumour located at the base of the brain at the pituitary.

Cortisol plays an essential role in regulating how the body responds to stress, maintains blood sugar and controls inflammation. It is essential to life. Without it, a drop of blood pressure and subsequently death occurs. Conversely when levels remain elevated for a long time, it can lead to a range of symptoms, including weight gain (particularly around the face and trunk), muscle weakness, high blood pressure and changes in mood or skin appearance.

Cushing’s disease is rare and occurs more often in women than in men, typically between the ages of 20 and 50. With accurate diagnosis and effective treatment, cortisol levels can be normalised, allowing recovery of hormonal balance and improved quality of life.

What causes Cushing’s disease?

Cushing’s disease develops when a benign (non-cancerous) tumour called a pituitary adenoma forms in the pituitary gland, located at the base of the brain. This tumour produces excessive amounts of adrenocorticotropic hormone (ACTH), which overstimulates the adrenal glands sitting atop the kidneys to release too much cortisol.

Cortisol is vital for maintaining blood pressure, regulating metabolism and managing the body’s response to stress. However, when ACTH secretion becomes uncontrolled, cortisol levels remain chronically elevated, disrupting many body systems.

• Pituitary adenoma — the most common cause, they are usually small (microadenomas less than 10 mm), though larger tumours (macroadenomas) can occur. These tumours are almost always benign but can affect surrounding structures if they grow large enough (macroadenomas).
• Genetic factors — in rare cases, Cushing’s disease may be associated with inherited conditions such as multiple endocrine neoplasia type 1 (MEN1), which predispose individuals to develop tumours in multiple endocrine glands.
• Other rare causes — very rarely, excess ACTH production can result from abnormal pituitary tissue or hormone-secreting tumours elsewhere in the brain, but these represent a small minority of cases.

Understanding the cause is crucial, as treatment aims to remove or suppress the ACTH-producing tumour and restore normal cortisol levels, reducing the risk of long-term complications.

What are the symptoms of Cushing’s disease?

The symptoms of Cushing’s disease develop gradually and may vary depending on how long cortisol levels have been elevated and the severity of hormone excess. Because cortisol affects many systems in the body, symptoms can be wide-ranging and often mistaken for other conditions such as obesity, depression or polycystic ovary syndrome (PCOS). 

Physical symptoms

• Weight gain, particularly around the abdomen, chest and face, leading to a characteristic “moon face” appearance
• Fat accumulation between the shoulders (previously called a “buffalo hump”)
• Thinning of the skin, which bruises easily and heals slowly
• Purple stretch marks (striae), especially on the abdomen, thighs, or arms
• Muscle weakness, particularly in the upper arms and thighs
• Loss of bone density (osteoporosis), increasing fracture risk

Metabolic and cardiovascular symptoms

• High blood pressure and increased risk of cardiovascular disease
• High blood sugar or diabetes mellitus due to insulin resistance
• Fluid retention and swelling (oedema)

Reproductive and hormonal changes

• In women: menstrual irregularities, infertility, or excess facial and body hair (hirsutism)
• In men: reduced libido, erectile dysfunction and sometimes infertility

Psychological and general symptoms

• Mood changes, including irritability, anxiety or depression
• Fatigue, poor concentration and sleep disturbance
• Cognitive difficulties or memory problems in advanced cases

Over time, untreated Cushing’s disease can lead to serious complications such as osteoporosis, cardiovascular disease and increased susceptibility to infections. Early recognition and proper treatment are essential to reverse hormonal imbalance and prevent long-term health effects.

Who is at risk of Cushing’s disease in Singapore?

Cushing’s disease is rare, but certain groups are more likely to develop it based on biological, genetic or medical factors. Recognising these risk factors can help with early detection and timely intervention.

• Sex and age — the condition is most common in women between the ages of 20 and 50, though it can occur in men and, very rarely, in children.
• Pituitary disorders — individuals with a history of pituitary adenomas or other pituitary abnormalities are at greater risk, as most cases of Cushing’s disease are caused by ACTH-secreting tumours within the pituitary gland.
• Genetic predisposition — a small number of cases are linked to inherited syndromes such as multiple endocrine neoplasia type 1 (MEN1), which increases the likelihood of developing hormone-producing tumours in the pituitary, pancreas and parathyroid glands.
• Other endocrine disorders — patients with adrenal or thyroid conditions are occasionally evaluated for secondary pituitary abnormalities, as these systems are closely interconnected through hormonal regulation.

While most people who develop Cushing’s disease do not have an identifiable risk factor, doctors need to be acutely aware of warning signs of possible cushing’s such as unexplained weight gain, rapidly progressive diabetes or high blood pressure, unusual infections and, easy bruising. Early medical assessment can improve outcomes.

What are the complications of Cushing’s disease? 

Persistent high levels of cortisol can affect nearly every organ system in the body, leading to serious complications if left untreated. These effects develop gradually but can become irreversible without timely diagnosis and management.

Cardiovascular and metabolic complications

• High blood pressure and atherosclerosis, increasing the risk of heart attack and stroke
• Type 2 diabetes mellitus, due to cortisol-induced insulin resistance
• High cholesterol and triglycerides, contributing to metabolic syndrome
• Weight gain and central obesity, which further exacerbate cardiovascular risk

Musculoskeletal complications 

• Osteoporosis, caused by cortisol increasing bone loss and affecting Vitamin D metabolism, increasing fracture risk
• Muscle wasting and weakness, particularly in the upper arms and thighs contributing to sarcopenia

Immune and infectious complications 

• Suppressed immune function, making patients more prone to infections
• Slow wound healing, due to impaired collagen synthesis

Psychological and neurological complications 

• Depression, anxiety and mood swings
• Memory and concentration difficulties, often linked to prolonged cortisol exposure

Reproductive and endocrine complications

• Menstrual irregularities and infertility in women
• Low testosterone and sexual dysfunction in men
• Hypopituitarism, if a large pituitary tumour compresses surrounding hormone-producing tissue

General and long-term risks

• Increased clotting tendency, which raises the risk of deep vein thrombosis or pulmonary embolism
• Higher overall mortality if untreated, mainly due to cardiovascular and infectious causes

Early treatment to normalise cortisol levels can reverse many of these complications and restore long-term health. Ongoing monitoring after therapy helps detect residual effects and prevent recurrence.

How is Cushing’s disease diagnosed?

Diagnosing Cushing’s disease requires a detailed assessment of symptoms, hormone levels, and imaging studies to confirm the source of excess cortisol. Because many of its features overlap with common conditions such as obesity, diabetes, or depression, a structured diagnostic approach is essential.

Hormone testing 

Initial tests focus on confirming high cortisol levels and determining whether the excess is ACTH-dependent (pituitary-related). Common investigations include:

• 24-hour urinary free cortisol test — measures total cortisol production over a full day; elevated levels suggest hypercortisolism.
• Late-night salivary cortisol test — cortisol should normally be low at night; persistently high levels indicate loss of normal hormonal rhythm.
• Low-dose dexamethasone suppression test — in healthy individuals, cortisol levels fall after taking dexamethasone. In Cushing’s disease, cortisol remains abnormally high.

ACTH measurement

Blood tests are performed to measure ACTH levels. Elevated ACTH points to a pituitary or ectopic (non-pituitary) source of cortisol overproduction.

Imaging studies

• Magnetic resonance imaging (MRI) of the pituitary gland is the preferred method for identifying ACTH-secreting adenomas.
• If the tumour is small or not clearly visible, inferior petrosal sinus sampling (IPSS) may be performed. This advanced test measures ACTH levels directly from veins draining the pituitary gland, confirming the diagnosis of Cushing’s disease and distinguishing it from other causes of Cushing’s syndrome.

Additional evaluations

Blood sugar, blood pressure, bone density and cholesterol levels are assessed to identify complications related to prolonged cortisol excess.

Accurate diagnosis is crucial before initiating treatment, as managing Cushing’s disease differs from treating other forms of cortisol excess.

What are the treatment options for Cushing’s disease in Singapore?

The goal of treatment is to normalise cortisol levels, remove or control the ACTH-secreting pituitary tumour and reverse the effects of prolonged hormone excess. Treatment is tailored to the tumour’s size, location and the patient’s overall health.

Surgery 

• Transsphenoidal surgery is the primary treatment for most patients. The pituitary tumour is accessed through the nasal passage and carefully removed without external incisions.
• This procedure can restore normal ACTH production and reduce cortisol levels to normal within days.
• Success rates are highest when the tumour is small (microadenoma). Larger tumours (macroadenomas) may be more difficult to remove completely and sometimes require additional therapy.

Medical therapy 

When surgery is not possible, unsuccessful or while awaiting its effects, medications can help control cortisol levels. Common options include:

• Adrenal-blocking agents such as ketoconazole, metyrapone or osilodrostat, which reduce cortisol production by the adrenal glands.
• Pituitary-directed drugs such as pasireotide, which suppress ACTH secretion.
• Glucocorticoid receptor antagonists like mifepristone, used in selected cases to block cortisol’s effects on body tissues.

Radiotherapy 

• Radiotherapy may be recommended if surgery cannot fully remove the tumour or if it recurs.
• Modern stereotactic techniques deliver precise doses to the pituitary gland while sparing surrounding structures.
• The effects of radiotherapy develop gradually over several months or years, so interim medical therapy is often needed.

Bilateral adrenalectomy 

• In rare cases where cortisol levels remain uncontrolled after other treatments, removal of both adrenal glands may be considered to eliminate cortisol production entirely.
• Lifelong hormone replacement is then required to maintain essential adrenal function.

Ongoing care and monitoring

Regular follow-up is crucial, including blood tests to monitor cortisol levels, MRI scans to check for recurrence and assessment of bone, cardiovascular and metabolic health. Early detection of recurrence allows prompt re-treatment and prevents complications.

With timely and effective management, most patients achieve long-term hormonal control and significant improvement in symptoms and quality of life.

Prognosis and long-term outlook for Cushing’s disease

With appropriate treatment, most patients with Cushing’s disease can achieve normal or near-normal cortisol levels and experience significant improvement in symptoms. However, recovery may take time, as the body adjusts after prolonged exposure to high cortisol levels.

• After successful treatment — when the ACTH-producing tumour is fully removed, cortisol levels often return to normal within days or weeks. Some patients may temporarily require cortisol replacement therapy until normal adrenal function resumes. Physical symptoms such as facial rounding, muscle weakness and high blood pressure gradually improve, while emotional well-being and energy levels also recover over time.
• Recurrence and ongoing monitoring — even after successful surgery, recurrence can occur, sometimes years later. Lifelong follow-up with regular hormone testing and MRI scans is therefore essential. Early detection of relapse allows timely intervention and prevents complications.
• Long-term health considerations —some effects of prolonged cortisol exposure, such as osteoporosis, diabetes or cardiovascular disease may persist despite hormonal recovery. Targeted management of these conditions is an important part of ongoing care. Psychological support may also be beneficial, as mood and cognitive symptoms can take longer to resolve.
• Outlook and quality of life — with early diagnosis, effective treatment and consistent follow-up, most patients can expect a good long-term prognosis. Advances in surgical techniques, medical therapy and imaging have significantly improved recovery rates and reduced the risk of complications.

Summary 

Cushing’s disease is a rare but serious hormonal disorder caused by an ACTH-producing tumour of the pituitary gland, leading to excessive cortisol production. The resulting hormonal imbalance affects nearly every system in the body, causing weight gain, muscle weakness, high blood pressure, mood changes and other complications that can significantly impact long-term health and quality of life.

Advances in diagnostic testing and imaging allow for accurate identification of the underlying cause, while modern surgical and medical treatments can effectively restore normal cortisol levels and reverse many of the physical and metabolic effects. With proper management, most patients achieve long-term hormonal control, improved energy and a return to normal daily functioning.

If you are experiencing symptoms that may suggest hormonal imbalance or have been diagnosed with elevated cortisol levels, schedule a consultation with The Metabolic Clinic for a comprehensive evaluation and subsequen treatment aimed at reversing the condition and correcting metabolic abnormalities.

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