Cushing syndrome

Cushing syndrome is a clinical disorder caused by prolonged exposure to excess glucocorticoids, leading to a wide range of metabolic, cardiovascular, musculoskeletal, and neuropsychiatric abnormalities. It can result from endogenous overproduction of cortisol or exogenous administration of corticosteroids. Early recognition and management are critical to prevent long-term complications and improve patient outcomes.

Etiology

Endogenous Causes

Endogenous Cushing syndrome arises from the body’s overproduction of cortisol due to various pathologies in the adrenal glands or pituitary gland.

• ACTH-Dependent: Conditions in which excess adrenocorticotropic hormone (ACTH) stimulates cortisol production, including:
  • Pituitary adenomas (Cushing disease)
  • Ectopic ACTH secretion from tumors such as small cell lung carcinoma
• ACTH-Independent: Conditions in which cortisol is produced independently of ACTH, such as:
  • Primary adrenal tumors (adenomas or carcinomas)
  • Adrenal hyperplasia

Exogenous Causes

Exogenous or iatrogenic Cushing syndrome occurs due to prolonged administration of glucocorticoids for medical conditions.

• Chronic systemic corticosteroid therapy
• Long-term topical, inhaled, or intra-articular glucocorticoid use in susceptible patients

Pathophysiology

The pathophysiology of Cushing syndrome revolves around chronic exposure to elevated cortisol levels, which affect multiple organ systems and metabolic pathways.

• Metabolic Effects: Cortisol excess increases gluconeogenesis, protein catabolism, and lipolysis, leading to hyperglycemia, muscle wasting, and fat redistribution.
• Cardiovascular Effects: Cortisol promotes sodium retention, hypertension, and increased risk of atherosclerosis and cardiovascular disease.
• Musculoskeletal Effects: Cortisol decreases bone formation and increases resorption, causing osteoporosis and increased fracture risk.
• Immune System Effects: Chronic glucocorticoid excess suppresses immune responses, increasing susceptibility to infections.
• Neuropsychiatric Effects: Cortisol influences mood, cognition, and behavior, contributing to depression, anxiety, and cognitive dysfunction.

Clinical Features

General Symptoms

Cushing syndrome presents with a characteristic set of systemic and physical manifestations due to prolonged cortisol excess.

• Weight Gain and Central Obesity: Fat accumulates in the face, trunk, and upper back, while limbs remain relatively thin.
• Fat Redistribution: Moon face, buffalo hump, and truncal obesity are hallmark features.
• Skin Changes: Purple striae on the abdomen, easy bruising, acne, and skin thinning are common findings.

Endocrine and Metabolic Manifestations

• Hyperglycemia and diabetes mellitus
• Hypertension
• Electrolyte disturbances such as hypokalemia

Musculoskeletal Manifestations

• Osteoporosis and increased risk of fractures
• Proximal muscle weakness (myopathy), leading to difficulty rising from chairs or climbing stairs

Neuropsychiatric Manifestations

• Mood disorders including depression, anxiety, and irritability
• Cognitive dysfunction and impaired memory

Reproductive Manifestations

• Menstrual irregularities and amenorrhea in women
• Infertility due to hormonal imbalances
• Hirsutism in females due to androgen excess

Diagnostic Evaluation

Screening Tests

Initial evaluation of suspected Cushing syndrome involves non-invasive tests to detect cortisol excess.

• 24-hour urinary free cortisol measurement
• Late-night salivary cortisol test
• Low-dose dexamethasone suppression test

Confirmatory Tests

Once screening suggests hypercortisolism, confirmatory testing is performed to establish the diagnosis and determine the etiology.

• ACTH measurement to differentiate ACTH-dependent from ACTH-independent causes
• High-dose dexamethasone suppression test to distinguish pituitary from ectopic ACTH sources

Imaging Studies

Imaging is used to locate tumors or abnormal tissue responsible for excess cortisol production.

• Pituitary MRI to identify adenomas
• Adrenal CT or MRI for adrenal adenomas, carcinomas, or hyperplasia
• Chest imaging for ectopic ACTH-producing tumors, such as small cell lung carcinoma

Management and Treatment

Medical Therapy

Medical management is often used to control cortisol levels in patients who are not surgical candidates or while awaiting surgery.

• Adrenal Enzyme Inhibitors: Drugs such as ketoconazole, metyrapone, and etomidate reduce cortisol synthesis.
• Glucocorticoid Receptor Antagonists: Mifepristone blocks cortisol activity at target tissues.
• Other Pharmacologic Agents: Mitotane may be used in adrenal carcinoma cases to suppress cortisol production.

Surgical Management

Surgery is the definitive treatment for most cases of Cushing syndrome caused by tumors or hyperplasia.

• Pituitary Surgery: Transsphenoidal resection of pituitary adenomas in Cushing disease.
• Adrenalectomy: Unilateral or bilateral removal of adrenal tumors or hyperplastic glands.
• Resection of Ectopic ACTH-Producing Tumors: Surgical removal of tumors such as small cell lung carcinoma or neuroendocrine tumors.

Radiation Therapy

Radiotherapy may be indicated in patients with residual pituitary tumors or recurrent disease.

• Pituitary radiotherapy to control tumor growth and cortisol production.
• Targeted radiation for ectopic or unresectable tumors in select cases.

Lifestyle and Supportive Measures

• Dietary modifications to manage weight, blood sugar, and hypertension.
• Management of comorbidities including diabetes, osteoporosis, and cardiovascular disease.
• Psychological support to address mood disorders and cognitive effects.

Complications

Cushing syndrome is associated with multiple complications due to chronic cortisol excess affecting various organ systems.

• Cardiovascular Complications: Hypertension, atherosclerosis, heart failure, and increased risk of cardiovascular events.
• Metabolic Complications: Hyperglycemia, diabetes mellitus, dyslipidemia, and obesity-related disorders.
• Musculoskeletal Complications: Osteoporosis, vertebral and long bone fractures, and proximal muscle weakness.
• Infections: Increased susceptibility due to immunosuppression caused by cortisol excess.
• Psychiatric Complications: Depression, anxiety, cognitive impairment, and mood disorders.

Prognosis

The prognosis of Cushing syndrome varies depending on the underlying cause, timeliness of diagnosis, and effectiveness of treatment. With appropriate intervention, many patients can achieve remission, though long-term monitoring is essential.

• Outcomes After Treatment: Successful surgery or medical therapy often normalizes cortisol levels and improves symptoms over months to years.
• Factors Affecting Prognosis: Age, comorbid conditions, duration of cortisol excess, and tumor characteristics influence recovery and long-term outcomes.
• Recurrence Risk: Patients with pituitary adenomas or adrenal tumors require ongoing surveillance for potential relapse.

Prevention and Monitoring

Prevention focuses primarily on iatrogenic Cushing syndrome, while monitoring is critical for detecting recurrence and managing comorbidities.

• Prevention of Iatrogenic Cushing Syndrome: Use the lowest effective dose of glucocorticoids for the shortest duration possible and monitor for early signs of cortisol excess.
• Monitoring for Recurrence or Relapse: Periodic clinical assessment, cortisol measurements, and imaging studies as indicated.
• Evaluation of Comorbidities: Regular assessment and management of hypertension, diabetes, osteoporosis, and cardiovascular risk factors.

References

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