Cushing Syndrome

A hormonal disorder characterized by prolonged exposure to excess cortisol

Table of Contents

Quick Facts

  • Type: Hormonal/Endocrine Disorder
  • ICD-10: E24
  • Prevalence: 40-70 per million
  • Peak Age: 25-40 years

Overview

Cushing syndrome is a hormonal disorder caused by prolonged exposure to high levels of the hormone cortisol. This condition can result from various causes, including the body producing too much cortisol or from taking corticosteroid medications. Named after Harvey Cushing, the neurosurgeon who first described it in 1912, this syndrome represents one of the most challenging endocrine disorders to diagnose and treat.

Cortisol, often called the "stress hormone," plays vital roles in the body, including regulating blood pressure, reducing inflammation, converting nutrients into energy, and helping the body respond to stress. However, when cortisol levels remain elevated for extended periods, it can lead to a wide array of symptoms and serious health complications. The syndrome affects approximately 40-70 people per million, with women being affected three times more often than men.

The condition can develop gradually, making early detection challenging. Without treatment, Cushing syndrome can lead to serious complications including hypertension, type 2 diabetes, osteoporosis, and increased susceptibility to infections. However, with proper diagnosis and treatment, most people with Cushing syndrome can achieve remission and significant improvement in their symptoms.

Symptoms

Cushing syndrome causes a distinctive set of signs and symptoms, though the presentation can vary significantly between individuals. The symptoms typically develop gradually over months or years, making early recognition challenging.

Common Physical Signs

Central Weight Gain

Fat accumulation around midsection and upper back

 Skin Changes

Purple stretch marks, easy bruising, slow healing

 Muscle Weakness

Particularly in proximal muscles (hips, shoulders)

 Moon Face

Rounded, fuller facial appearance

Characteristic Features

  • Buffalo hump: Fat deposit between shoulders
  • Purple striae: Wide (>1 cm) purple stretch marks on abdomen, thighs, breasts, and arms
  • Skin thinning: Fragile skin that bruises easily
  • Facial plethora: Reddish complexion of the face
  • Hirsutism: Excessive hair growth in women
  • Acne: Adult-onset or worsening acne

Metabolic and Systemic Symptoms

Psychological Symptoms

  • Depression (present in 50-80% of patients)
  • Anxiety and irritability
  • Cognitive difficulties and memory problems
  • Emotional lability (mood swings)
  • Psychosis (in severe cases)

Causes

Cushing syndrome results from prolonged exposure to high levels of cortisol. The causes can be categorized into two main groups: endogenous (originating within the body) and exogenous (from external sources).

Endogenous Causes

Pituitary Adenoma (Cushing Disease)

The most common endogenous cause (70% of cases) is a benign tumor of the pituitary gland that produces excess adrenocorticotropic hormone (ACTH). This stimulates the adrenal glands to produce too much cortisol. When caused by a pituitary adenoma, the condition is specifically called Cushing disease.

Adrenal Tumors

  • Adrenal adenomas: Benign tumors that produce cortisol independently
  • Adrenal carcinomas: Rare malignant tumors that overproduce cortisol
  • Bilateral adrenal hyperplasia: Enlargement of both adrenal glands

Ectopic ACTH Syndrome

Non-pituitary tumors that produce ACTH, including:

  • Small cell lung cancer
  • Carcinoid tumors
  • Medullary thyroid cancer
  • Pancreatic neuroendocrine tumors

Exogenous Causes

The most common overall cause of Cushing syndrome is the use of corticosteroid medications:

  • Oral corticosteroids: Prednisone, dexamethasone, hydrocortisone
  • Injectable steroids: For joint or back pain
  • Inhaled steroids: High doses for asthma or COPD
  • Topical steroids: Rarely, with extensive use

Rare Causes

  • Familial Cushing syndrome (genetic predisposition)
  • Primary pigmented nodular adrenocortical disease
  • McCune-Albright syndrome

Risk Factors

Several factors can increase the likelihood of developing Cushing syndrome:

Medical Conditions

  • Pituitary tumors: History of pituitary adenomas
  • Adrenal tumors: Previous adrenal gland disorders
  • Neuroendocrine tumors: Particularly lung, pancreas, or thyroid
  • Multiple endocrine neoplasia type 1 (MEN1): Genetic syndrome

Medication Use

Demographic Factors

  • Gender: Women are 3 times more likely to develop Cushing disease
  • Age: Most common between ages 25-40
  • Genetics: Rare familial forms exist

Other Risk Factors

  • History of depression or bipolar disorder (may be both cause and effect)
  • Obesity (can complicate diagnosis)
  • Poorly controlled diabetes
  • Chronic stress (though this alone doesn't cause Cushing syndrome)

Diagnosis

Diagnosing Cushing syndrome can be challenging due to its gradual onset and symptoms that overlap with other common conditions. A systematic approach involving multiple tests is typically required.

Initial Screening Tests

24-Hour Urinary Free Cortisol

Measures cortisol levels in urine collected over 24 hours. Values more than 3-4 times the upper normal limit are highly suggestive of Cushing syndrome.

Late-Night Salivary Cortisol

Cortisol normally drops to very low levels late at night. Elevated late-night salivary cortisol (collected at home) indicates loss of normal circadian rhythm.

Low-Dose Dexamethasone Suppression Test

  • Overnight test: 1 mg dexamethasone at 11 PM, cortisol measured at 8 AM
  • 48-hour test: 0.5 mg every 6 hours for 2 days
  • Failure to suppress cortisol suggests Cushing syndrome

Confirmatory Tests

If initial tests are abnormal, additional testing confirms the diagnosis:

  • Midnight plasma cortisol (requires hospitalization)
  • Combined dexamethasone-CRH test
  • Multiple collections of 24-hour urine or late-night saliva

Tests to Determine the Cause

ACTH Levels

  • Suppressed ACTH: Suggests adrenal tumor
  • Normal/Elevated ACTH: Indicates pituitary or ectopic source

High-Dose Dexamethasone Suppression Test

Helps differentiate between pituitary and ectopic ACTH production

Imaging Studies

  • Pituitary MRI: To detect pituitary adenomas
  • CT of adrenal glands: To identify adrenal tumors
  • CT of chest/abdomen: To search for ectopic ACTH sources

Inferior Petrosal Sinus Sampling

Gold standard for differentiating pituitary from ectopic ACTH production when imaging is inconclusive

Treatment Options

Treatment of Cushing syndrome depends on the underlying cause and aims to normalize cortisol levels, reverse symptoms, and treat any complications. The approach must be individualized based on the source of excess cortisol.

Surgical Treatment

Transsphenoidal Surgery

For pituitary adenomas (Cushing disease):

  • First-line treatment with 65-90% remission rate
  • Minimally invasive approach through the nose
  • Performed by experienced neurosurgeons
  • May require hormone replacement temporarily

Adrenalectomy

For adrenal tumors:

  • Unilateral adrenalectomy for single adenoma
  • Bilateral adrenalectomy for bilateral disease or failed pituitary surgery
  • Can be performed laparoscopically
  • Bilateral removal requires lifelong hormone replacement

Radiation Therapy

  • Stereotactic radiosurgery: For residual or recurrent pituitary tumors
  • Conventional radiation: Alternative when radiosurgery not available
  • Effects develop slowly over months to years
  • Often used as adjuvant therapy

Medical Therapy

Steroidogenesis Inhibitors

  • Ketoconazole: Blocks cortisol synthesis
  • Metyrapone: Inhibits 11-beta-hydroxylase
  • Mitotane: Adrenolytic agent for adrenal carcinoma
  • Etomidate: IV option for severe hypercortisolism

Pituitary-Directed Drugs

  • Pasireotide: Somatostatin analog for Cushing disease
  • Cabergoline: Dopamine agonist (limited efficacy)

Glucocorticoid Receptor Antagonist

  • Mifepristone: Blocks cortisol action at receptor level
  • Useful for diabetes control in Cushing syndrome

Management of Complications

  • Hypertension: ACE inhibitors, ARBs, calcium channel blockers
  • Diabetes: Metformin, insulin as needed
  • Osteoporosis: Bisphosphonates, vitamin D, calcium
  • Infections: Prophylactic antibiotics in severe cases
  • Depression: Antidepressants, counseling

Tapering Exogenous Steroids

For medication-induced Cushing syndrome:

  • Gradual dose reduction to avoid adrenal insufficiency
  • Switch to alternate-day therapy when possible
  • Use steroid-sparing agents for underlying condition
  • Monitor for adrenal recovery

Prevention

While endogenous Cushing syndrome cannot be prevented, several strategies can reduce the risk of developing exogenous Cushing syndrome and help with early detection:

Medication Management

  • Minimize corticosteroid use: Use lowest effective dose for shortest duration
  • Consider alternatives: Non-steroidal anti-inflammatory drugs when appropriate
  • Local administration: Prefer topical or inhaled steroids over systemic when possible
  • Regular monitoring: Check for side effects during long-term steroid use
  • Steroid-sparing agents: Use immunosuppressants or biologics for chronic conditions

Early Detection Strategies

  • Annual health screenings for those on chronic steroids
  • Monitor for characteristic signs (moon face, striae, central weight gain)
  • Regular blood pressure and glucose monitoring
  • Bone density testing for osteoporosis screening
  • Report unusual symptoms to healthcare providers promptly

Lifestyle Measures

For those at risk or with treated Cushing syndrome:

  • Maintain healthy weight through diet and exercise
  • Calcium and vitamin D supplementation for bone health
  • Regular cardiovascular exercise
  • Stress management techniques
  • Avoid excessive alcohol consumption

When to See a Doctor

Early recognition and treatment of Cushing syndrome is crucial for preventing complications. Seek medical evaluation in the following situations:

Concerning Symptoms

  • Unexplained weight gain, especially with central distribution
  • Development of purple stretch marks wider than 1 cm
  • Easy bruising without trauma
  • Facial rounding and redness
  • New or difficult-to-control high blood pressure
  • Unexplained muscle weakness
  • Mood changes including depression or anxiety

High-Risk Situations

  • Taking corticosteroids and developing suspicious symptoms
  • History of pituitary or adrenal problems
  • Multiple unexplained fractures suggesting osteoporosis
  • Children with slowed growth despite weight gain
  • Women with irregular periods and male-pattern hair growth

Emergency Situations

Seek immediate medical care for:

  • Severe muscle weakness preventing normal activities
  • Confusion or altered mental status
  • Severe infections or poor wound healing
  • Fractures from minimal trauma
  • Psychosis or suicidal thoughts

Follow-up Care

Regular monitoring is essential for:

  • Patients in remission (risk of recurrence)
  • Those on medical therapy
  • Post-surgical patients
  • Individuals with treated complications

Related Conditions

Cushing syndrome is associated with several endocrine disorders and can lead to various complications:

Addison's Disease

Opposite condition with cortisol deficiency

 Diabetes Mellitus

Common complication of Cushing syndrome

 Osteoporosis

Bone loss from excess cortisol

 Metabolic Syndrome

Often coexists with Cushing syndrome

Differential Diagnoses

  • Pseudo-Cushing states: Alcohol abuse, depression, obesity
  • Polycystic ovary syndrome (PCOS): Similar metabolic features
  • Metabolic syndrome: Overlapping symptoms
  • Simple obesity: Different fat distribution pattern

Complications

Medical Disclaimer: This information is for educational purposes only and should not replace professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment of Cushing syndrome or any medical condition. If you're experiencing symptoms suggestive of hormonal imbalance, seek prompt medical evaluation.

References

  1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.
  2. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet. 2015;386(9996):913-927.
  3. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing's Disease. Endocr Rev. 2015;36(4):385-486.
  4. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875.
  5. Sharma ST, Nieman LK, Feelders RA. Comorbidities in Cushing's disease. Pituitary. 2015;18(2):188-194.