Pseudo-Cushing's syndrome

Overview

Pseudo-Cushing's syndrome refers to a group of conditions that result in clinical and biochemical features similar to true Cushing’s syndrome—characterized by elevated cortisol levels—but without a true pathological overproduction of cortisol due to an endocrine tumor or disorder. These features may include central obesity, hypertension, glucose intolerance, and a rounded face, among others. Unlike true Cushing’s syndrome, pseudo-Cushing’s is typically caused by external factors such as chronic alcoholism, severe stress, depression, or certain medications, and the abnormalities usually resolve when the underlying cause is treated or removed.

Causes

Pseudo-Cushing’s syndrome is not caused by a tumor or intrinsic disorder of the hypothalamic-pituitary-adrenal (HPA) axis, but rather by external or functional factors that stimulate cortisol production or affect its metabolism. Common causes include:

• Chronic alcoholism: Alcohol affects cortisol metabolism and can lead to elevated levels resembling Cushing's

• Major depressive disorder: Severe depression is associated with HPA axis hyperactivity and increased cortisol secretion

• Severe obesity: Adipose tissue can alter cortisol clearance and contribute to elevated free cortisol levels

• Poorly controlled diabetes mellitus: Can be associated with elevated cortisol and mimic Cushingoid features

• Polycystic ovary syndrome (PCOS): May share overlapping symptoms such as hirsutism and menstrual irregularities

• Stress and malnutrition: Physical and psychological stressors can transiently increase cortisol levels

• Certain medications: Use of oral contraceptives, anticonvulsants, or psychotropic medications may influence cortisol levels or assays

Symptoms

The symptoms of pseudo-Cushing’s syndrome closely mimic those of true Cushing’s syndrome but are often less severe and more reversible. Common features include:

Physical Signs

• Central (truncal) obesity

• Facial rounding (moon face)

• Fat accumulation over the upper back (buffalo hump)

• Thin skin and easy bruising

• Facial plethora (redness of the face)

• Hirsutism (in women)

Metabolic and Psychological Symptoms

• Hypertension

• Glucose intolerance or type 2 diabetes

• Menstrual irregularities in women

• Mood disturbances such as anxiety or depression

• Muscle weakness or fatigue

Unlike true Cushing’s syndrome, the symptoms of pseudo-Cushing’s may fluctuate and are often reversible once the underlying cause is addressed.

Diagnosis

Diagnosing pseudo-Cushing's syndrome involves differentiating it from true Cushing’s syndrome, which can be challenging due to overlapping symptoms and hormonal findings. The diagnostic process includes:

Initial Screening

• 24-hour urinary free cortisol: May be elevated in both true and pseudo-Cushing’s

• Late-night salivary cortisol: Elevated levels suggest loss of normal diurnal rhythm, common in both conditions

• Low-dose dexamethasone suppression test (DST): In pseudo-Cushing’s, cortisol may not suppress normally, mimicking true Cushing’s

Differentiation Tests

• Dexamethasone-CRH test: Combines low-dose dexamethasone followed by corticotropin-releasing hormone (CRH) stimulation. True Cushing’s syndrome shows a significant cortisol response to CRH, while pseudo-Cushing’s does not

• Normalization after treating underlying cause: If cortisol levels normalize after addressing depression, stopping alcohol, or correcting other triggers, pseudo-Cushing’s is likely

Additional Evaluation

• Thorough patient history to identify potential stressors, substance use, or medication effects

• Assessment of psychiatric conditions, especially depression or anxiety disorders

Treatment

Treatment of pseudo-Cushing’s syndrome focuses on identifying and managing the underlying cause of the cortisol elevation. Unlike true Cushing’s, surgery or specific endocrine therapy is not needed.

Management Strategies

• Treating underlying psychiatric disorders: Appropriate use of antidepressants and psychotherapy for depression or anxiety

• Alcohol cessation: Discontinuing alcohol use in patients with alcohol-related pseudo-Cushing’s often leads to resolution of symptoms and hormonal abnormalities

• Weight loss: For obesity-related cases, lifestyle changes, diet, and exercise may reduce cortisol levels and reverse Cushingoid features

• Optimizing diabetes control: Helps reduce stress-related cortisol production

• Medication review: Discontinuing or adjusting medications that may interfere with cortisol metabolism or testing

Monitoring

• Regular follow-up with endocrine testing to confirm normalization of cortisol levels

• Monitoring for recurrence of symptoms if the underlying cause is not fully resolved

Prognosis

The prognosis for pseudo-Cushing’s syndrome is generally favorable when the underlying cause is correctly identified and effectively treated. Hormonal abnormalities and physical symptoms often resolve over weeks to months once the triggering factor is eliminated. Early recognition and targeted intervention are key to preventing unnecessary investigations or treatments for true Cushing’s syndrome.

Unlike true Cushing’s syndrome, pseudo-Cushing’s does not lead to permanent adrenal or pituitary dysfunction and does not require surgical intervention. Long-term outcomes depend on the successful management of the root cause, whether psychological, metabolic, or behavioral in nature.