Cushing's disease is a specific form of Cushing's syndrome caused by a pituitary tumor that overproduces ACTH, causing excessive cortisol levels. Chronically elevated cortisol levels can have widespread adverse health effects; unfortunately, as a rare disease, it can be missed by clinicians.
Common symptoms often include central obesity, skin changes, muscle weakness, hypertension, and mood disturbances, which can be mistaken for other conditions such as diabetes or cardiovascular disease.
Accurate diagnosis is essential to avoid the severe health risks associated with prolonged high cortisol exposure. With appropriate treatment, regular monitoring, and the implementation of healthy lifestyle measures, patients can enjoy sustained recovery and quality of life.
This article examines the differences between exogenous and endogenous Cushing's syndrome to help readers better understand the causes of this condition.
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What is Cushing's Disease?
Cushing's disease is the second most common cause of Cushing's syndrome. Cushing's disease is an endocrine disorder characterized by the overproduction of adrenocorticotropic hormone (ACTH), typically due to a benign pituitary tumor, often a small pituitary microadenoma (less than 10 mm in size).
This excess ACTH disrupts the normal circadian rhythm of cortisol production, leading to excessive cortisol output from the adrenal cortex. The resulting glucocorticoid and mineralocorticoid effects can cause serious complications often overlooked in the early stages.
As the most common form of endogenous Cushing's syndrome, Cushing's disease often goes undiagnosed for 3 to 6 years, primarily diagnosed in women and adults between 30 and 40. With a mortality rate of 10-11%, untreated Cushing's disease significantly increases the risk of cardiovascular complications, infections, and mental health issues.
Managing Cushing's disease requires a multidisciplinary approach involving surgery, medication, and continuous monitoring to address its complex symptoms.
Cushing's Disease vs. Cushing's Syndrome
Cushing's disease and Cushing's syndrome are conditions characterized by excess cortisol. Cushing's syndrome is the broad term for hypercortisolism, while Cushing's disease is a subtype of this.
Cushing's syndrome results from prolonged exposure to elevated cortisol levels, most often due to iatrogenic (caused by a treatment or medication) corticosteroid use or certain herbal preparations.
In contrast, Cushing's disease refers specifically to the ACTH-dependent cortisol excess caused by a pituitary adenoma, accounting for 80% of endogenous Cushing syndrome cases.
History of Cushing's Disease
Cushing's disease is a subtype of Cushing's syndrome.
Cushing's disease was first identified in 1932 by Harvey W. Cushing, who noted a condition caused by high cortisol levels, manifesting in symptoms including muscular weakness, obesity, abdominal striae, diabetes, and arterial hypertension. He believed this condition originated in the pituitary gland, now known as Cushing's disease.
Then, in the early 1950s, glucocorticoids became commonly used to treat rheumatoid arthritis. This led to the emergence of iatrogenic, or medication-caused, Cushing's syndrome.
Now, with the widespread use of glucocorticoids, exogenous Cushing's syndrome is more common than Cushing's disease.
Symptoms of Cushing's Disease
While the variability and subtlety of symptoms can make diagnosis challenging, Cushing's disease has several hallmark symptoms.
Weight Gain and Fat Distribution
Excess cortisol leads to central obesity, characterized by fat accumulation in the abdomen, face ("moon face"), and upper back ("buffalo hump"). This is due to cortisol's role in fat storage, particularly in these areas.
Skin Changes
Excess cortisol causes thinning skin, slow wound healing, and the appearance of purple stretch marks (striae) on areas like the abdomen and thighs due to the disruption of collagen production and skin structure. Acne and changes in hair growth patterns can also be seen.
Muscle Weakness and Fatigue
Muscle wasting and weakness, particularly in the limbs, occur as cortisol disrupts the balance between muscle protein synthesis and breakdown, leading to a noticeable contrast between a large belly and thin arms and legs.
Mood Changes
Cushing's disease often results in mood disturbances such as depression, anxiety, and cognitive impairment, as elevated cortisol negatively impacts brain regions like the hippocampus.
High Blood Pressure
Hypertension in Cushing's disease is caused by cortisol's effects on fluid retention, vascular responsiveness, and inhibition of nitric oxide, all contributing to elevated blood pressure.
Bone Health Issues
Osteoporosis is a common consequence of hypercortisolism. Cortisol increases bone resorption, decreases bone formation, and disrupts calcium balance, leading to fragile bones and back pain from vertebral fractures.
Reproductive and Sexual Health Symptoms
Women with Cushing's disease may experience menstrual irregularities due to cortisol's interference with the hypothalamic-pituitary-gonadal axis, while men may suffer from decreased libido and erectile dysfunction.
Other Important Symptoms
Patients might also experience increased thirst and urination, headaches, visual disturbances, and decreased immunity, all linked to cortisol's widespread effects on various body systems.
These symptoms may be mistaken for other conditions, such as diabetes or cardiovascular disease, which can miss the root cause of the individual's illness.
It is also important to note that headaches and visual disturbances are rare findings in Cushing's disease, so other causes, such as intracranial hypertension, should also be ruled out.
Why Cortisol Levels Matter
Cortisol plays a role in regulating metabolism, immune response, and stress management under normal conditions. It is also essential in fetal development.
However, in Cushing's disease, chronically elevated cortisol levels disrupt these functions, leading to a range of symptoms.
Excess cortisol primarily exerts glucocorticoid effects, causing muscle weakness, osteoporosis, hyperglycemia, insulin resistance, weight gain, and an increased risk of cardiovascular disease. It also has mineralocorticoid effects, contributing to hypertension, sodium retention, and potassium depletion.
Prolonged exposure to high cortisol levels in Cushing's disease is also linked to neuropsychiatric and cognitive issues such as emotional instability, depression, anxiety, impulsivity, and cognitive deficits.
Endogenous Causes of Cushing's Disease
Endogenous Cushing's syndrome is always associated with excessive cortisol production from the adrenal cortex. It can be ACTH-dependent or ACTH-independent.
Pituitary Adenomas
Pituitary adenomas, primarily pituitary microadenomas (tumors < 10 mm), are the most common endogenous cause of Cushing's disease. They are responsible for 80% of all diagnoses of Cushing's syndrome, making them the second most common cause of this syndrome.
These pituitary adenomas secrete ACTH, leading to excessive cortisol output from the adrenal cortex, which in turn causes the symptoms associated with Cushing's disease.
While this condition is rare overall, early diagnosis and treatment are essential to improve prognosis and reduce the risk of complications from hypercortisolism, which increases the risk of many health complications.
Ectopic ACTH Syndrome
Ectopic ACTH syndrome is a rare form of Cushing's syndrome caused by non-pituitary neuroendocrine tumors producing ACTH, often lung and GI tract cancers. This accounts for approximately 10% of diagnoses of ACTH-dependent Cushing's syndrome.
These neuroendocrine tumors produce adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH), which leads to hypercortisolemia and the typical Cushing's manifestation.
Unfortunately, these tumors can be challenging to identify as well as aggressive, leading to rapid progression of symptoms, complications including infections and excessive blood clots, and poor prognosis.
Adrenal Adenomas or Hyperplasia
Adrenal adenomas are benign, encapsulated cortical tumors, while adrenal hyperplasia involves diffuse or nodular enlargement of the gland. Either of these conditions can cause hypercortisolism by directly increasing cortisol output.
In these settings, the adrenal gland is directly responsible for hypercortisolism; therefore, this is considered an ACTH-independent cause of Cushing's syndrome.
In contrast, Cushing's disease is ACTH-dependent due to a pituitary tumor over-secreting ACTH, which then overstimulates adrenal production of cortisol.
Adrenal adenomas are typically unilateral (affecting one adrenal gland), while hyperplasia can be bilateral (affecting both glands).
The condition can be identified through imaging, where unilateral masses in the adrenal glands indicate adenomas. Surgical removal is often curative.
Some genetic mutations in cortisol-producing adrenal adenomas and unilateral hyperplasia have been linked to more severe Cushing's syndrome, suggesting that genetic testing should also be considered.
Exogenous Causes of Cushing's Syndrome
Exogenous causes of Cushing's syndrome refer to the condition resulting from external sources:
Long-Term Use of Corticosteroid Medications
Glucocorticoids are widely used to treat autoimmune diseases, hematological disorders, and inflammatory conditions like rheumatoid arthritis and psoriasis.
While short-term use rarely causes withdrawal issues, prolonged use, especially in children under 5, can lead to adrenal lesions, hyperplasia, and significant challenges.
Extended use overstimulates body-wide glucocorticoid receptors and suppresses the HPA axis, reducing CRH and ACTH secretion.
These effects increase the risk of complications such as hypertension, dyslipidemia, cardiovascular disease, and infections, contributing to the morbidity and mortality associated with Cushing's syndrome.
Diagnosing Cushing's Disease: Endogenous vs. Exogenous
The symptoms of exogenous and endogenous Cushing's syndrome, including Cushing's disease, can mirror each other. If Cushing's syndrome is suspected, an appropriate diagnostic workup is necessary to determine the cause of excess cortisol.
Diagnostic Tests
- 24-Hour Urinary Free Cortisol (UFC) Test: The Endocrine Society recommends this key screening tool to assess elevated daily cortisol production, a hallmark of Cushing's syndrome.
- Dexamethasone Suppression Test: also recommended by the Endocrine Society, this test involves taking dexamethasone at night and measuring cortisol the following morning. Elevated cortisol indicates excessive production and loss of negative feedback.
- Blood and Saliva Tests: Measuring cortisol levels at different times of the day
- Late-Night Salivary Cortisol: a noninvasive test measuring cortisol at bedtime to detect circadian rhythm loss; requires two measurements.
- Midnight Serum Cortisol: Measures cortisol at its lowest point (midnight) but may need inpatient admission to avoid stress-induced false positives.
Imaging Studies
- MRI and CT Scans: MRI is preferred for detecting pituitary microadenomas, while CT is typically used for identifying adrenal tumors or hyperplasia.
- PET Scans: PET scans are used as a complementary tool when MRI or CT results are inconclusive. They help identify ectopic ACTH sources or clarify adrenal findings.
Medical History and Medication Review
Obtaining a thorough drug history before testing for Cushing's syndrome to exclude exogenous glucocorticoid exposure, which can lead to iatrogenic Cushing's syndrome, is necessary.
Clinicians should carefully review current or recent use of medications, including oral, rectal, inhaled, topical, or injected glucocorticoids, as well as herbal medicines and "tonics" that may contain glucocorticoids.
This includes assessing the use of certain medications that can cause Cushing's syndrome at high doses, like megestrol acetate (a synthetic progesterone with glucocorticoid activity), to cause Cushing's syndrome at high doses.
Treatment Options Based on the Cause
Treatment options for Cushing's syndrome depend on the underlying cause.
Treatment for Endogenous Cushing's Syndrome
The following treatments are focused on treating endogenous causes:
Surgery
Surgical removal of the primary lesion is the preferred initial treatment for Cushing's syndrome. This includes transsphenoidal selective adenomectomy (TSS) for pituitary tumors, adrenalectomy for adrenal lesions, and resection of ectopic ACTH-secreting tumors.
Bilateral adrenalectomy is recommended for patients with severe, life-threatening ACTH-dependent disease unresponsive to medical therapy or occult/metastatic ectopic ACTH secretion (EAS). It is also a second-line option if other treatments fail.
Radiation Therapy
Radiation therapy (RT) or radiosurgery is recommended for patients with Cushing's disease who have failed transsphenoidal surgery or have recurrent disease and when mass effects or invasion from corticotroph adenomas are a concern.
Medications
Pharmaceutical drugs are prescribed on an individualized basis.
- Steroidogenesis Inhibitors: Ketoconazole, metyrapone, and mitotane are recommended for hypercortisolism in patients unable to undergo or who failed surgery or while awaiting radiation.
- Pituitary-Directed Treatments: Cabergoline and pasireotide are suggested for non-surgical candidates or those with persistent disease.
- Glucocorticoid Antagonists: Mifepristone is recommended for patients with diabetes or persistent disease post-surgery.
- Combination therapy may improve efficacy, especially in severe cases.
Treatment for Exogenous Cushing's Syndrome
The following treatments focus on treating the exogenous causes:
Gradual Reduction of Corticosteroids
While discontinuation after a short course (weeks to a few months) usually doesn't pose significant issues, withdrawal after prolonged use (months to years) is more complex and requires a gradual taper. Alternate-day dosing and hydrocortisone replacement may be considered.
Alternative Treatments
Glucocorticoids should be discontinued only when the underlying disease is in long-term remission. If the disease is still active, alternative treatments should be considered.
Ongoing monitoring for persistent issues like hypertension, diabetes, and cardiovascular problems is necessary even after hypercortisolism is controlled.
Monitoring and Support
Appropriate long-term care and regular follow-ups are necessary to ensure cortisol levels return to normal.
Long-Term Outlook and Management
The long-term outlook and management of Cushing's syndrome focus on controlling the cause, monitoring for complications, and making lifestyle adjustments to improve overall health.
Recovery and Monitoring
- Ongoing Management of Comorbidities: Patients need lifelong management of Cushing-associated comorbidities, such as cardiovascular risk factors, osteoporosis, and psychiatric symptoms, as these issues may persist or recur.
- Recurrence Monitoring: Regular testing for Cushing disease recurrence is generally recommended throughout the patient's life.
- Medical Monitoring: Ongoing medical support is essential for early detection and management of complications like hypertension, diabetes, osteoporosis, and psychological issues.
- Regular Follow-Ups: Ensure prompt treatment of emerging problems, supporting long-term health and quality of life.
Lifestyle Adjustments
These are foundational for recovery. Focus on a healthy diet, regular exercise, good sleep, and stress management to support HPA axis function and overall well-being.
- Balanced diet: Helps manage weight, blood sugar, and bone health.
- Regular exercise: Improves cardiovascular health, muscle strength, and mood.
- Stress management: Prevents cortisol fluctuations, aiding recovery.
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Key Takeaways
- Cushing's disease is a specific type of Cushing's syndrome caused by a pituitary tumor that overproduces ACTH, leading to excessive cortisol. It accounts for 80% of endogenous Cushing's syndrome cases, while the broader term includes both endogenous and exogenous causes.
- Accurate diagnosis is critical due to the harmful effects of high cortisol, which leads to central obesity, skin changes, muscle weakness, hypertension, and mood disturbances.
- Treatment typically involves surgical removal of the pituitary tumor, with radiation or medication, if surgery is not effective. Exogenous Cushing's syndrome, often due to prolonged corticosteroid use, requires careful tapering of the drug. Long-term care includes maintaining a healthy diet and lifestyle.
- Patients recovering from Cushing's disease require lifelong monitoring to watch for recurrence and manage comorbidities like cardiovascular issues, osteoporosis, and psychiatric symptoms. Regular follow-ups, a healthy lifestyle, and stress management are vital for long-term recovery and quality of life.
- Recovery is possible with proper treatment and support, offering a path to a healthier, more fulfilling life. Resources like your doctor and the Cushing's Support and Research Foundation can aid your journey.
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