Cushing's Syndrome: Symptoms, Causes & Treatment

Cushing's Syndrome is a rare but serious disorder caused by prolonged exposure to high levels of the hormone cortisol. Cortisol is naturally produced by the adrenal glands (sitting above the kidneys) and regulates blood pressure, glucose, and stress response. However, when cortisol becomes excessively elevated, it causes significant health complications.

There are three main types: medication-induced Cushing's (most common), pituitary tumor-induced, and adrenal or ectopic tumor-induced Cushing's. In the Middle East and Jordan, medication-induced Cushing's is typically the most frequent due to long-term corticosteroid use for rheumatologic and allergic diseases. Cushing's Syndrome affects both sexes but is more common in women.

Early diagnosis and prompt treatment are crucial to prevent long-term complications such as osteoporosis, diabetes, and hypertension.

Symptoms of Cushing's Syndrome are diverse and develop gradually over months or years. Presentation varies based on cortisol elevation rate and duration. Women may notice additional hormonal symptoms like menstrual irregularities and hirsutism. Key symptoms include:

• Moon facies: Marked facial swelling and roundness due to fat redistribution.
• Central obesity: Fat accumulation in abdomen and upper back with relatively thin limbs.
• Purple/red stretch marks: Deep, prominent striae especially on thighs, breasts, and abdomen.
• Easy bruising: Skin breaks down easily even with light pressure.
• Muscle weakness: Particularly in thighs and shoulders; difficulty climbing stairs or standing.
• Osteoporosis: Bone pain and pathologic fractures.
• Acne and oily skin: Or recurrent skin/fungal infections.
• Hypertension: May require multiple medications for control.
• New-onset diabetes or glucose intolerance: Or worsening of pre-existing diabetes.
• Depression and anxiety: Mood swings, sometimes psychosis.
• Excessive sweating: Particularly at night.
• Hair loss or baldness: Especially in women.
• Menstrual irregularities: Or amenorrhea in women; erectile dysfunction in men.

• Long-term corticosteroid medications: Most common cause; used to treat inflammatory diseases like lupus, rheumatoid arthritis, and chronic asthma.
• Pituitary gland tumor (Cushing's Disease): A benign tumor producing ACTH hormone that overstimulates the adrenal glands to produce excess cortisol.
• Adrenal gland tumor: Cancer or benign tumor in the adrenal gland itself producing cortisol directly.
• Ectopic ACTH-secreting tumors: Tumors in other organs (commonly lungs) abnormally producing ACTH hormone.
• Pituitary overproduction: The pituitary gland releases excessive CRH hormone that overstimulates cortisol production.
• Familial tumors: Rare hereditary syndromes that increase susceptibility to multiple endocrine tumors.
• Unregulated cosmetic products: Some illegal skin-lightening creams contain potent steroids.

• Female sex: Women are three times more likely to develop Cushing's than men.
• Age: Most commonly occurs between ages 20-50, but can occur at any age.
• Chronic inflammatory diseases: Lupus, rheumatoid arthritis, severe asthma.
• Malignancies: Especially small-cell lung cancer (produces abnormal ACTH).
• Primary obesity: May predispose to cortisol dysregulation.
• Psychiatric conditions: Chronic depression and anxiety can elevate natural cortisol levels.
• Pre-existing diabetes and hypertension: Increases risk of complications.
• Concurrent use of multiple steroid medications: Particularly in patients receiving multidisciplinary treatment.
• Family history: Rare familial endocrine tumor syndromes.
• Occupational exposure: Healthcare workers handling topical steroids without proper protection.

Diagnosis requires a systematic approach combining clinical examination, laboratory tests, and imaging. Doctors typically begin with clinical suspicion based on characteristic symptoms.

• 24-hour urinary cortisol: Highly sensitive initial test. Normal value <50 µg/24h. Markedly elevated in true Cushing's.
• Overnight dexamethasone suppression test (DST): Patient takes 1 mg dexamethasone before sleep; cortisol measured next morning. Normal <5 µg/dL. In Cushing's, cortisol doesn't suppress adequately.
• Plasma ACTH measurement: Helps determine Cushing's type. (High ACTH = pituitary or ectopic; Low ACTH = adrenal).
• MRI of pituitary gland: Searches for pituitary tumor if ACTH is elevated.
• CT imaging of adrenal glands: Searches for adrenal tumor if ACTH is suppressed.
• High-dose dexamethasone suppression test: Higher dose (8 mg) distinguishes pituitary from ectopic Cushing's.
• Inferior petrosal sinus sampling: Specialized test used in select cases to precisely localize tumor source.

Medications

• Stopping corticosteroids (first step): If medication-induced, dosage is tapered gradually under medical supervision (never abruptly). May take weeks to months.
• Metyrapone: Inhibits the final enzyme in cortisol production. Used pre-surgery or short-term therapy.
• Ketoconazole: Antifungal that reduces cortisol synthesis. Used for resistant cases but has hepatotoxic side effects.
• Mitotane: Destroys adrenal cortex cells. Used in adrenocortical carcinoma producing cortisol.
• Pasireotide: Somatostatin analog reducing ACTH. Useful in resistant pituitary Cushing's.

Surgical Procedures

• Pituitary tumor resection: Transsphenoidal endoscopic removal of pituitary adenoma. Often curative in pituitary Cushing's.
• Adrenalectomy: Partial or total removal of adrenal gland in cases of adrenal tumor. Laparoscopic or open depending on size.
• Resection of ectopic tumor: Removal of source tumor (e.g., small-cell lung cancer).
• Radiation therapy: Used if surgery fails or as adjunctive therapy (especially pituitary radiotherapy in pituitary Cushing's).

Lifestyle Modifications

• Stress reduction: Psychological stress elevates natural cortisol; yoga and meditation beneficial.
• Regular physical activity: Light-to-moderate exercise (walking, swimming) helps restore muscle and bone strength.
• Healthy diet: Rich in calcium and vitamin D to prevent osteoporosis; low sodium to reduce hypertension.
• Regular monitoring: Periodic cortisol measurements and treatment efficacy assessments.
• Psychological support: Depression and anxiety are common; may require psychiatric consultation or medication.

• Osteoporosis: High cortisol reduces calcium absorption and increases bone loss. Pathologic fractures can occur from minor trauma. One of the most common and disabling complications.
• Hyperglycemia/Diabetes Mellitus: Cortisol increases insulin resistance. New-onset diabetes or worsening of pre-existing diabetes is common and requires ongoing management.
• Hypertension: Cortisol increases sodium and fluid retention. Blood pressure can become dangerously elevated requiring multiple medications.
• Cardiovascular disease: Hypertension, diabetes, and obesity increase risk of myocardial infarction and stroke. Potentially life-threatening.
• Recurrent and serious infections: Cortisol weakens immune function. Bacterial, fungal, or viral infections become recurrent and can become severe.
• Severe depression and psychiatric disorders: May progress to psychosis or suicidal ideation, requiring urgent psychiatric intervention.
• Proximal muscle weakness: Can severely limit mobility, work capacity, and independence.
• Chronic renal insufficiency: Chronic hypertension and diabetes may lead to progressive kidney failure.

• Judicious corticosteroid use: Use the lowest effective dose for the shortest duration. Consult your doctor before starting or stopping any steroid medication.
• Avoid unlicensed cosmetic products: Particularly skin-lightening creams from unreliable sources; may contain potent steroids.
• Regular monitoring for long-term steroid users: If taking steroids for more than 3 weeks, request periodic medical surveillance for symptoms.
• Maintain healthy weight: Obesity exacerbates metabolic problems and complicates disease management.
• Regular physical activity: Strengthens bones and muscles; reduces diabetes and hypertension risk.
• Balanced nutrition: Rich in calcium, vitamin D, and protein.
• Stress management: Practice yoga, meditation, or relaxation activities.
• Do not exceed prescribed doses: Some patients self-escalate doses; this is extremely dangerous.
• Report suspicious symptoms: If unusual signs appear during steroid use, inform your doctor immediately.
• Routine screening: Regular glucose, blood pressure, and bone density checks, especially in elderly patients.