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Clinical Subject Page

Cushing Disease

Cushing Disease is a form of endogenous Cushing syndrome caused by an adrenocorticotropic
hormone (ACTH)-secreting pituitary adenoma. Excess ACTH stimulates the adrenal glands to produce excessive cortisol

Also called

ACTH-secreting pituitary adenoma

ICD-10

E24.0

Specialty

Endocrine

Onset

Chronic

Reviewed

August 2026

On This Page

Overview

–Cushing Disease is caused by excessive ACTH secretion from a pituitary corticotroph
adenoma, resulting in :


• chronic cortisol excess. It commonly presents with central obesity, moon face, proximal muscle weakness,


• hypertension, glucose intolerance, and purple striae.


• Cushing Disease is a specific cause of Cushing syndrome.

Etiology & Risk Factors

-The primary cause is:


• ACTH-Secreting Pituitary Adenoma
• Usually a small pituitary microadenoma.
• Excess ACTH stimulates the adrenal cortex.
• Increased adrenal cortisol production develops.

-Risk Factors:

• Female sex
• Middle adulthood
• Previous pituitary disease
• Family history of pituitary tumors

Pathophysiology

Pituitary corticotroph adenoma
→ ↑ ACTH secretion
→ ↑ Adrenal cortisol production
→ Chronic hypercortisolism
→ Increased gluconeogenesis + insulin resistance
→ Hyperglycemia
→ Protein catabolism
→ Muscle wasting + thin skin
→ Altered fat distribution
→ Central obesity + moon face + dorsocervical fat accumulation
→ Cortisol-mediated mineralocorticoid and cardiovascular effects
→ Hypertension + metabolic complications

Clinical Presentation

-Symptoms

• Weight gain, especially central weight gain
• Facial rounding
• Increased abdominal fat
• Muscle weakness
• Fatigue
• Easy bruising
• Skin changes
• Purple stretch marks
• Headache
• Mood changes

-Signs

• Central obesity
• Moon facies
• Dorsocervical fat pad
• Thin skin
• Easy bruising
• Wide violaceous striae
• Proximal muscle weakness
• Hypertension
• Acne
• Hirsutism

History Taking

-Ask about:

• Weight gain and distribution
• Facial changes
• Muscle weakness
• Easy bruising
• Skin changes
• Purple stretch marks
• Headaches
• Menstrual irregularities
• Reduced libido
• Erectile dysfunction
• Mood changes
• Depression or anxiety

Physical Examination

-General Examination:
• Measure weight and BMI
• Assess body fat distribution
• Measure blood pressure
• Look for skin changes


-System-Specific Examination


-Skin:
• Thin skin
• Easy bruising
• Wide violaceous striae
• Acne
• Increased pigmentation if ACTH is markedly elevated


-Musculoskeletal:
• Proximal muscle weakness
• Osteoporosis-related deformities

Investigations

-Initial Screening for Hypercortisolism:


-Recommended tests include:


• 24-hour urinary free cortisol
• Late-night salivary cortisol
• 1-mg overnight dexamethasone suppression test
• Cushing syndrome is suggested by failure to appropriately suppress cortisol.


-Plasma ACTH
• Used after confirming hypercortisolism.
Low ACTH → ACTH-independent Cushing syndrome
Normal or high ACTH → ACTH-dependent Cushing syndrome


-Other Laboratory Findings
May include:
• Hyperglycemia
• Hypokalemia
• Dyslipidemia

-Imaging
Pituitary Magnetic Resonance Imaging (MRI)
• Used after biochemical confirmation of ACTH-dependent Cushing Disease.
May demonstrate:
• Pituitary microadenoma
• Pituitary macroadenoma
• Tumor location and size

-Inferior Petrosal Sinus Sampling (IPSS)


Used when the source of ACTH is unclear, particularly when:
• Pituitary MRI is negative or equivocal
• A small pituitary lesion is found but the diagnosis remains uncertain

Diagnosis

-Diagnosis involves several steps:


1. Confirm endogenous hypercortisolism using an appropriate screening test.
2. Measure plasma ACTH.
3. If ACTH is normal or elevated, evaluate for an ACTH-dependent source.
4. Pituitary MRI is used to identify a pituitary adenoma.
5. Inferior petrosal sinus sampling may be required when the source remains
uncertain

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Management

1. Definitive Treatment


–Transsphenoidal Pituitary Surgery


• First-line definitive treatment for most patients with confirmed Cushing Disease.
Goals:
• Remove the ACTH-secreting pituitary adenoma
• Normalize cortisol production


2. Medical Treatment
Medical therapy may be used:
• Before surgery in selected patients
• When surgery is unsuccessful
• In recurrent disease
• When surgery is contraindicated


-Examples include:
• Steroidogenesis Inhibitors
• Ketoconazole
• Metyrapone
• Osilodrostat

3. Supportive Management
Treat associated complications:
• Hypertension
• Diabetes mellitus
• Hypokalemia
• Osteoporosis
• Dyslipidemia

Complications

• Diabetes mellitus
• Insulin resistance
• Dyslipidemia
• Obesity
• Hypertension
• Cardiovascular disease
• Heart failure
• Increased thromboembolic risk
• Osteoporosis
• Vertebral fractures
• Proximal muscle weakness
• Easy bruising
• Thin skin

Prognosis

• Cushing Disease is potentially curable with successful treatment of the pituitary tumor.

–Untreated prolonged hypercortisolism significantly increases morbidity and mortality, particularly through :
• cardiovascular, metabolic, infectious, and thromboembolic complications

Key Points / Clinical Pearls

  • • Cushing Disease is caused by an ACTH-secreting pituitary adenoma.
    • It is a specific cause of Cushing syndrome.
    • Excess ACTH stimulates excessive adrenal cortisol production.
    • Common features include central obesity, moon face, and proximal muscle weakness.
    • Wide violaceous striae and easy bruising are characteristic findings.
    • Hypertension and glucose intolerance are common complications.
    • Endogenous hypercortisolism must be confirmed biochemically.
    • Initial tests include late-night salivary cortisol, urinary free cortisol, or dexamethasone
    suppression testing.
    • ACTH determines whether hypercortisolism is ACTH-dependent.
    • Pituitary MRI is used to identify the source in ACTH-dependent disease.
  • Nieman LK, Biller BMK, 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. Journal of Clinical Endocrinology & Metabolism .
  • Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. Journal of Clinical Endocrinology & Metabolism .
  • Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet. 2015;386(9996):913-927.
  • 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.
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Cushing's Syndrome . National Institutes of Health.