Cushing Syndrome

A 45 year old female presents to her primary care physician with complaints of irregular menstruation, weight gain, and fatigue over the past 8 months. On examination, she has central obesity, abdominal striae, hirsutism, and thin extremities. Blood pressure is 150/90 mmHg. Laboratory studies reveal hyperglycemia, elevated 24 hour urinary free cortisol, elevated ACTH, and failure of suppression with low dose dexamethasone. High dose dexamethasone test shows suppression of cortisol. MRI reveals a pituitary mass. Diagnosis?

Diagnosis is Cushing disease.

1. Definition

Cushing disease is a form of ACTH dependent Cushing syndrome caused by a pituitary adenoma secreting excess ACTH, leading to hypercortisolism.

2. Etiology of Cushing Syndrome

1. Exogenous glucocorticoid use is the most common cause overall
• Low ACTH, high cortisol, bilateral adrenal atrophy
2. Pituitary adenoma (Cushing disease) is the most common endogenous cause
• High ACTH, high cortisol, bilateral adrenal hyperplasia
3. Ectopic ACTH secretion
• High ACTH, high cortisol, typically no suppression with high dose dexamethasone
4. Adrenal tumors
• Low ACTH, high cortisol, unilateral adrenal mass

3. Pathophysiology

1. Excess ACTH causes bilateral adrenal hyperplasia
2. Leads to excessive cortisol production
3. Loss of normal diurnal variation of cortisol
4. Cortisol effects include:
• Protein catabolism leading to muscle wasting
• Gluconeogenesis causing hyperglycemia
• Mineralocorticoid effects causing hypertension
5. Hypokalemia may occur, but is more prominent in ectopic ACTH syndrome

4. Clinical Features

4.1 Fat Redistribution

1. Central obesity
2. Moon facies
3. Buffalo hump
4. Supraclavicular fat pads
5. Thin extremities due to muscle wasting

4.2 Skin Changes

1. Purple striae
2. Easy bruising
3. Skin thinning

4.3 Metabolic Features

1. Hypertension
2. Hyperglycemia

4.4 Endocrine Features

1. Hirsutism
2. Acne
3. Amenorrhea or oligomenorrhea

4.5 Neuropsychiatric Features

1. Depression
2. Insomnia
3. Cognitive changes

5. Diagnosis

5.1 Screening for Hypercortisolism

1. Elevated 24 hour urinary free cortisol
2. Elevated late night salivary cortisol
3. Low dose dexamethasone suppression test showing no suppression
4. At least two abnormal tests are required

5.2 Determining ACTH Dependence

1. Elevated ACTH indicates ACTH dependent disease

5.3 Differentiation of Cause

1. High dose dexamethasone suppression test
• Suppression present in Cushing disease
• No suppression in ectopic ACTH secretion
2. CRH stimulation test
• Increased ACTH and cortisol in pituitary disease
3. Inferior petrosal sinus sampling
• Gold standard
• Central to peripheral ACTH ratio greater than 3 confirms pituitary source

5.4 Imaging

1. Pituitary MRI
2. Most lesions are microadenomas less than 10 mm

6. Management

6.1 First Line

1. Transsphenoidal surgical resection

6.2 Persistent or Recurrent Disease

1. Repeat surgery or radiotherapy

6.3 Medical Therapy

1. Pituitary directed therapy
• Pasireotide
• Cabergoline
2. Adrenal steroidogenesis inhibitors
• Ketoconazole
• Metyrapone
• Osilodrostat
3. Glucocorticoid receptor antagonist
• Mifepristone

7. Complications

1. Hypertension
2. Diabetes mellitus
3. Osteoporosis
4. Infections
5. Muscle wasting
6. Psychiatric disorders

8. Prognosis and Follow Up

1. Untreated disease increases mortality
2. Recurrence can occur
3. Requires lifelong follow up

9. Key Clinical Insight

Central obesity + striae + hypertension + hyperglycemia + elevated ACTH + suppression with high dose dexamethasone + pituitary mass = Cushing disease

10. Exam Level Pearls

1. Cushing disease is the most common endogenous cause
2. High dose dexamethasone suppression distinguishes pituitary from ectopic ACTH
3. Inferior petrosal sinus sampling is the gold standard
4. Transsphenoidal surgery is first line treatment
5. Always confirm hypercortisolism before localization