Cushing’s syndrome

Cushing’s syndrome is a disorder caused by prolonged exposure to excessive levels of cortisol. It can arise from either endogenous overproduction or exogenous administration of glucocorticoids, leading to a wide range of metabolic, cardiovascular, and musculoskeletal complications.

Etiology

Endogenous Causes

Endogenous Cushing’s syndrome results from abnormal cortisol production within the body:

• Pituitary-dependent (Cushing’s disease): Excess adrenocorticotropic hormone (ACTH) secretion from a pituitary adenoma stimulates adrenal cortisol production.
• Adrenal tumors: Adenomas or carcinomas of the adrenal cortex autonomously produce cortisol independent of ACTH regulation.
• Ectopic ACTH secretion: Certain malignancies, such as small cell lung carcinoma or neuroendocrine tumors, secrete ACTH, leading to cortisol excess.

Exogenous Causes

Exogenous Cushing’s syndrome is caused by prolonged administration of corticosteroid medications:

• Chronic systemic glucocorticoid therapy for conditions such as asthma, rheumatoid arthritis, or organ transplantation.
• Excessive use of topical, inhaled, or intra-articular steroids that are absorbed systemically over time.

Pathophysiology

Cushing’s syndrome results from sustained hypercortisolemia, which affects multiple organ systems:

• Hypothalamic-Pituitary-Adrenal Axis Dysregulation: Endogenous causes disrupt normal feedback inhibition, leading to uncontrolled cortisol secretion.
• Metabolic Effects: Cortisol excess promotes gluconeogenesis, lipolysis, and protein catabolism, contributing to hyperglycemia, central obesity, and muscle wasting.
• Cardiovascular and Immunologic Effects: Elevated cortisol increases blood pressure, alters lipid metabolism, and suppresses immune function, increasing susceptibility to infections.
• Bone and Connective Tissue: Chronic hypercortisolemia leads to osteoporosis, impaired wound healing, and skin fragility.

Clinical Features

General Signs and Symptoms

• Weight Gain and Central Obesity: Fat accumulation predominantly in the trunk, face, and neck.
• Moon Face and Buffalo Hump: Rounded facial appearance and dorsal cervical fat pad.
• Skin Changes: Purple striae on the abdomen, easy bruising, thinning of the skin, and acne.

Metabolic and Cardiovascular Manifestations

• Hypertension: Common due to cortisol-induced sodium retention and increased vascular sensitivity to catecholamines.
• Hyperglycemia and Insulin Resistance: Cortisol promotes gluconeogenesis and impairs peripheral glucose uptake.
• Dyslipidemia: Altered lipid metabolism can increase cardiovascular risk.

Musculoskeletal and Neuropsychiatric Features

• Proximal Muscle Weakness: Atrophy of the shoulder and pelvic girdle muscles.
• Osteoporosis and Fractures: Cortisol impairs bone formation and increases bone resorption.
• Mood Disturbances: Depression, anxiety, irritability, and cognitive impairment are common.

Diagnosis

Screening Tests

• 24-hour Urinary Free Cortisol: Measures cortisol excretion over 24 hours to assess hypercortisolemia.
• Late-night Salivary Cortisol: Detects loss of normal circadian rhythm in cortisol secretion.
• Low-dose Dexamethasone Suppression Test: Evaluates cortisol suppression in response to exogenous glucocorticoid.

Confirmatory and Localization Tests

• High-dose Dexamethasone Suppression Test: Differentiates pituitary-dependent from ectopic ACTH secretion.
• Plasma ACTH Measurement: Helps determine whether the source of cortisol excess is ACTH-dependent or ACTH-independent.
• Imaging Studies: MRI of the pituitary, CT of the adrenal glands, or PET scans to localize ectopic ACTH-producing tumors.

Complications

• Cardiovascular Complications: Increased risk of myocardial infarction, stroke, and heart failure due to hypertension and dyslipidemia.
• Metabolic Complications: Development of type 2 diabetes mellitus, insulin resistance, and obesity-related conditions.
• Infections: Immunosuppression caused by cortisol excess increases susceptibility to bacterial, viral, and fungal infections.
• Osteoporosis and Fractures: Reduced bone density leads to increased risk of vertebral and long bone fractures.

Treatment

Surgical Management

• Transsphenoidal Pituitary Surgery: First-line treatment for Cushing’s disease caused by pituitary adenomas.
• Adrenalectomy: Indicated for cortisol-producing adrenal adenomas or carcinomas.
• Resection of Ectopic ACTH-producing Tumors: Surgical removal of ectopic sources is preferred when feasible.

Medical Therapy

• Adrenal Enzyme Inhibitors: Ketoconazole, metyrapone, and etomidate reduce cortisol synthesis in patients who are not surgical candidates or awaiting surgery.
• Glucocorticoid Receptor Antagonists: Mifepristone blocks the effects of cortisol at the receptor level.
• Other Steroidogenesis Inhibitors: Mitotane may be used in adrenal carcinoma or refractory cases.

Radiation Therapy

• Pituitary Irradiation: Considered in patients with persistent or recurrent pituitary adenomas after surgery.
• Techniques and Outcomes: Stereotactic radiosurgery provides targeted treatment while minimizing damage to surrounding tissues.

Prognosis

• Outcomes Based on Etiology and Treatment: Surgical removal of the causative tumor generally offers the best prognosis, with potential for full remission if detected early.
• Long-term Morbidity and Mortality Risks: Persistent hypercortisolemia increases the risk of cardiovascular disease, infections, metabolic disorders, and osteoporosis, which can affect long-term survival even after treatment.

References

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3. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. Williams Textbook of Endocrinology. 14th ed. Philadelphia: Elsevier; 2020.
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