Cushing's syndrome is a complex endocrine disorder characterized by excessive cortisol production resulting from prolonged corticosteroid use (exogenous) or the body's overproduction of cortisol (endogenous).
This excess cortisol disrupts many bodily functions, leading to symptoms such as muscle weakness, weight gain, and increased risk of cardiovascular disease. This can leave patients feeling overwhelmed and possibly challenged when describing their experience to their doctor.
In this article, we’ll dive into the symptoms that can indicate whether additional assessment for Cushing’s syndrome is appropriate, helping patients and practitioners close the gap between symptom onset and diagnosis.
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What is Cushing's Syndrome?
Cushing's syndrome is characterized by excess cortisol, often resulting from prolonged corticosteroid use (exogenous) or, less commonly, from the body's overproduction of cortisol (endogenous).
Cushing's disease, a subtype of endogenous Cushing's syndrome, is specifically caused by a benign pituitary tumor that overproduces adrenocorticotropic hormone (ACTH), leading to excessive cortisol production by the adrenal cortex.
While Cushing's disease accounts for 80% of endogenous cases, exogenous Cushing's syndrome, primarily caused by prolonged corticosteroid use, is now more common due to widespread glucocorticoid treatments.
Cortisol is a glucocorticoid hormone that regulates metabolism, modulates the immune response, directs the stress response, and is necessary for healthy fetal development.
However, excessive cortisol, as seen in Cushing's syndrome, disrupts these functions, leading to muscle weakness, osteoporosis, hyperglycemia, weight gain, hypertension, and increased risk of cardiovascular disease.
Prolonged high cortisol levels also contribute to neuropsychiatric issues, including emotional instability, depression, anxiety, and cognitive deficits.
Common Symptoms of Cushing's Syndrome
Cushing’s syndrome and Cushing’s disease cannot be differentiated by symptoms alone. Identifying patients with symptoms of excess cortisol requires additional diagnostic procedures to determine the root cause of high cortisol.
Common symptoms of Cushing’s syndrome include:
- Central Obesity: excess cortisol leads to fat accumulation in the abdomen, face ("moon face"), and upper back ("buffalo hump").
- Skin Changes: thinning skin, slow wound healing, and purple stretch marks (striae) on the abdomen and thighs are all due to disrupted collagen production.
- Acne and Hair Growth: acne and changes in hair growth patterns can occur, especially in women and prepubertal children.
- Muscle Weakness: muscle wasting, especially in the limbs, causes a contrast between a large belly and thin arms and legs.
- Mood Disturbances: elevated cortisol can lead to depression, anxiety, and cognitive impairment.
- High Blood Pressure: hypertension results from cortisol's effects on fluid retention and blood vessel function.
- Metabolic Issues: glucose and lipid metabolism abnormalities are common, with insulin resistance, hyperglycemia, and hyperlipidemia being associated with high cortisol levels.
- Bone Health Issues: osteoporosis due to increased bone resorption and decreased bone formation, leading to fragile bones and back pain.
- Reproductive Health: women may experience menstrual irregularities, while men may have decreased libido and erectile dysfunction.
- Other Symptoms: Increased thirst, urination, headaches, visual disturbances, and decreased immunity, which may be mistaken for other conditions like diabetes or cardiovascular disease.
Initial Consultation: Recognizing Symptoms and Taking a Medical History
Cushing’s syndrome is rare outside of excessive or chronic glucocorticoid use. However, symptom recognition and the diagnostic process can take years, so discussing concerns with your primary care provider is essential.
This timeline is often due to the variability and subtlety of symptoms, making diagnosis challenging.
Most often, patients will first discuss their health concerns with their primary care provider, who will ask additional questions about the individual’s current symptoms and medical history. A medical examination is also often performed.
Identifying Symptoms
Key symptoms that may indicate Cushing’s syndrome often include the characteristic central weight gain pattern, loss of muscle mass in limbs, muscle weakness, skin changes, loss of bone density, increased infections, hyperglycemia and hyperlipidemia, and hypertension.
Providers should also question patients about changes in their mood or cognitive abilities.
The symptom picture for Cushing’s syndrome often mimics cardiometabolic conditions like diabetes or heart disease, so clinicians should keep Cushing’s syndrome in mind when any concern for this condition arises, especially in patients whose symptoms are progressive and/or are unusual for their age.
Detailed Medical History
A comprehensive medical evaluation will include the patient’s medication use. Clinicians concerned about Cushing’s syndrome should be on the lookout for chronic glucocorticoid use as well as other medications that can cause Cushing’s syndrome.
For example, megestrol acetate, a synthetic progesterone with glucocorticoid activity, has been associated with Cushing’s syndrome.
Clinicians should also ask about using specific herbs, including licorice, an 11β-HSD2 inhibitor, anti-inflammatory joint injections, and topical products that might contain glucocorticoids.
Additionally, the patient's medical and family history should be reviewed, particularly regarding previous endocrine issues.
Physical Examination
A physical exam will be performed to look for symptoms consistent with Cushing’s syndrome.
Doctors look for highly discriminatory signs of Cushing's syndrome, including easy bruising, facial redness, muscle weakness, and striae, mainly when they are reddish purple and greater than 1 cm wide.
In children, a notable sign is weight gain accompanied by a concurrent decrease in growth velocity.
Additionally, more common but less specific signs of the syndrome include the presence of a dorsocervical fat pad (also known as a "buffalo hump"), facial fullness (“moon facies”), obesity, supraclavicular fullness, thin skin, peripheral edema, acne, hirsutism or female-pattern balding, and poor skin healing.
Blood pressure should be measured, as Cushing's syndrome is often associated with hypertension, especially when it occurs at a younger-than-expected age.
Recent laboratory studies may also demonstrate hypokalemia (low potassium), impaired glucose tolerance or diabetes, and/or dyslipidemia (elevated cholesterol and triglycerides).
Laboratory Tests for Diagnosing Cushing's Syndrome
A doctor will begin by ordering initial screening tests and may order additional follow-up testing and imaging studies [29., 30., 32.].
Initial Screening Tests
- 24-Hour Urinary Free Cortisol Test
- This test measures cortisol levels in the urine over a 24-hour period to provide an integrated assessment of cortisol secretion uninfluenced by cortisol-binding globulin (CBG) levels.
- Elevated cortisol levels on this test indicate excessive cortisol with high sensitivity, especially when at least two collections are made to confirm the results.
- Late-Night Salivary Cortisol Test
- This test measures cortisol levels in saliva late at night, typically between 11:00 PM and midnight, when cortisol levels are generally at their lowest.
- It demonstrates the loss of the normal circadian rhythm of cortisol secretion, which is characteristic of Cushing's syndrome.
- Dexamethasone Suppression Test: this test can be done overnight or for up to 48 hours to determine the body’s response to dexamethasone, which will slow cortisol production in healthy people.
- Overnight Dexamethasone Suppression Test
- Involves administering 1 mg of dexamethasone orally at night and measuring serum cortisol the next morning. Inadequate suppression of cortisol suggests Cushing's syndrome.
- Cortisol levels less than 1.8 μg/dl are suppressed, indicating a normal response.
- 48-Hour Low-Dose Dexamethasone Suppression Test (2 mg/day)
- Administers 0.5 mg of dexamethasone every six hours for 48 hours, with serum cortisol measured six hours after the last dose.
- This test is considered more specific in excluding pseudo-Cushing's syndrome (PCS) and helps confirm Cushing's syndrome.
- Sensitivity is reported as 100%, and specificity as 88%.
Confirmatory Tests
- Midnight Serum Cortisol Test (Sleeping and Awake)
- Measures serum cortisol at midnight, either during sleep or while awake, to detect the absence of the normal midnight cortisol drop, a key sign of Cushing's syndrome.
- Blood draw requires specific procedures depending on whether the patient is asleep or awake.
- The loss of the normal cortisol drop at night confirms Cushing's syndrome, especially in cases with mild or cyclical disease.
- Plasma ACTH Levels
- Plasma ACTH levels differentiate between ACTH-dependent and ACTH-independent forms of Cushing's syndrome.
- Elevated ACTH levels (>4.4 pmol/L) typically indicate an ACTH-dependent source such as Cushing's disease (CD) caused by a pituitary adenoma or ectopic ACTH production from non-pituitary tumors.
- Suppressed ACTH levels (<2.2 pmol/L) suggest an ACTH-independent form of Cushing's syndrome, such as an adrenal adenoma or carcinoma, which autonomously produces cortisol and suppresses ACTH secretion.
- Low-Dose Dexamethasone Suppression Test (LDDST) with CRH Stimulation
- Combines dexamethasone suppression with CRH stimulation to assess cortisol and ACTH response.
- This test differentiates between Cushing’s disease and other causes of Cushing's syndrome by assessing the response to CRH after dexamethasone suppression. It’s particularly useful in patients with equivocal results from other tests.
- CRH is administered after completing a 48-hour dexamethasone suppression test, and cortisol and ACTH levels are measured 15 minutes later.
- Desmopressin (dDAVP) Test
- Involves administering desmopressin intravenously and measuring the subsequent rise in ACTH and cortisol levels to differentiate between Cushing's disease (CD) and pseudo-Cushing's syndrome (PCS).
Imaging Studies to Identify the Source of Excess Cortisol
Guidelines for diagnosis of Cushing's syndrome emphasize that imaging, such as pituitary or adrenal imaging, is not recommended for initial testing to diagnose Cushing's syndrome. Instead, the diagnosis should start with biochemical tests to assess cortisol levels.
Imaging tests are typically reserved for later stages in the diagnostic process, specifically after biochemical confirmation of hypercortisolism.
The following imaging studies are used to identify the source of excess cortisol production:
MRI (Magnetic Resonance Imaging)
Pituitary MRI is recommended for detecting microadenomas (often <10 mm) in suspected Cushing's disease (ACTH-dependent). MRI is highly sensitive to small tumors. Further tests may be needed to confirm the diagnosis if no tumor is found.
CT Scans (Computed Tomography)
Adrenal CT scans are suggested for ACTH-independent Cushing's to detect adrenal adenomas, carcinomas, or hyperplasia. CT can also help locate small ectopic ACTH-producing tumors in the chest, abdomen, or pelvis.
PET Scans (Positron Emission Tomography)
PET scans are used when ectopic ACTH production is suspected but not detected by CT or MRI.
PET effectively identifies small neuroendocrine tumors with specific tracers, especially when biochemical tests indicate ectopic ACTH production, but conventional imaging (CT or MRI) fails to find a source.
Bilateral Inferior Petrosal Sinus Sampling (BIPSS)
BIPSS differentiates between pituitary and ectopic ACTH sources when imaging is inconclusive.
It measures ACTH levels from the petrosal sinuses and peripheral blood, with a higher gradient indicating a pituitary source (Cushing's disease). This test is highly sensitive and specific, especially when MRI does not clearly show a tumor.
Differential Diagnosis: Ruling Out Other Conditions
Ruling out conditions with a similar symptom picture is important to arrive at the correct diagnosis.
Conditions with Similar Symptoms
Cushing’s Syndrome from Excessive Corticosteroid or Medication Use
Before running laboratory assessments, a thorough medication and health history assessment should be done to rule this out.
Pseudo-Cushing's Syndrome (PCS) and Subclinical Cushing's Syndrome (SCS)
Pseudo-Cushing’s Syndrome mimics Cushing’s Syndrome but is caused by chronic stress conditions like alcoholism or severe obesity. Differentiating from true Cushing’s requires tests like the desmopressin test or midnight serum cortisol.
Subclinical Cushing’s Syndrome involves excess cortisol without obvious clinical signs. It is often associated with adrenal incidentalomas and is difficult to diagnose.
Cyclical Cushing's Syndrome
Characterized by fluctuating cortisol levels and intermittent symptoms, cyclical Cushing’s syndrome can be difficult to diagnose. Prolonged testing over a 28-day period or more is often necessary.
Cyclical Cushing's syndrome can be ACTH-dependent or independent, with varying symptom presentations depending on cycle duration and timing. Diagnosis requires at least three hypercortisolism episodes alternating with two normal cortisol periods.
Differentiating Between Cushing's Syndrome and Cushing's Disease
Cushing's syndrome is caused by prolonged high cortisol levels from either endogenous sources (like an adrenal tumor or ACTH-secreting pituitary adenoma) or exogenous sources (such as prolonged corticosteroid use).
Cushing's disease is a specific form of Cushing's syndrome caused by an ACTH-secreting pituitary adenoma. This pituitary adenoma is typically discovered on MRI.
Importance of Accurate Diagnosis
Correct identification of the cause of Cushing's syndrome is necessary because treatment varies based on the source of excess cortisol.
- If the syndrome is due to an ACTH-secreting pituitary adenoma (Cushing's disease), the primary treatment is usually surgical removal of the adenoma. For adrenal tumors, adrenalectomy is often required.
- If the cause is ectopic ACTH secretion from non-pituitary tumors, treatment focuses on locating and medically managing the tumor.
Misidentification of the cause could lead to ineffective or harmful treatments, so accurate diagnosis is essential for effective management and improved patient outcomes.
Next Steps After Diagnosis
After diagnosis, treatment and monitoring come next:
Treatment Options
Treatment for endogenous Cushing's syndrome typically involves surgical removal of the cause: transsphenoidal adenomectomy for pituitary tumors, adrenalectomy for adrenal lesions, and tumor resection for ectopic ACTH-secretion.
Bilateral adrenalectomy is reserved for severe cases or treatment failures.
Radiation therapy is considered for patients unresponsive to surgery or with recurrent disease.
Medical options include steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane) for those who can't undergo surgery or while awaiting radiation. Pituitary-directed drugs (cabergoline, pasireotide) and glucocorticoid antagonists (mifepristone) are alternatives for persistent disease. Combination therapy may be needed in severe cases.
For exogenous Cushing's syndrome, gradually reducing corticosteroids, especially after prolonged use. Alternate-day dosing and hydrocortisone replacement may also be considered.
Glucocorticoids should only be discontinued when the underlying disease is in long-term remission; otherwise, alternative treatments are necessary.
Monitoring and Follow-Up
Even after hypercortisolism is controlled, ongoing monitoring is crucial for persistent issues like hypertension, diabetes, and cardiovascular problems.
Long-term care and regular follow-ups are needed to ensure cortisol levels normalize and to manage Cushing-associated comorbidities, including cardiovascular problems, osteoporosis, and psychiatric symptoms.
Lifelong monitoring for disease recurrence is recommended to ensure early detection and intervention.
Preparing for Treatment
Preparation and recovery from Cushing's treatment require careful planning and ongoing management.
Unfortunately, patients can feel unprepared for the lengthy recovery, often citing inadequate information and support from healthcare providers.
Effective recovery involves not only stopping cortisol replacement medication (CRM) when adrenal function normalizes but also managing persistent symptoms like pain, fatigue, and neuropsychiatric issues.
Support systems, including family, friends, and support groups, are essential, and patients are encouraged to prioritize rest over physically demanding activities.
Organizations like the Cushing’s Support and Research Foundation can aid your journey.
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Key Takeaways
- Diagnosing Cushing's syndrome requires a thorough evaluation, including medical history, physical exams, specific biochemical tests, and imaging studies to identify the source of excess cortisol.
- Early detection of Cushing's syndrome can be life-changing; if you notice symptoms like central weight gain, skin changes, or mood disturbances, consult your healthcare provider promptly, especially if you have a history of prolonged corticosteroid use. Timely intervention can prevent complications and improve health outcomes.
- Effective treatments for Cushing’s Syndrome, including surgery, medical therapy, and radiation, can lead to remission and significant improvement in quality of life; with proper care and support, many patients successfully recover and regain their health.
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