Cushing Syndrome

A 45-year-old woman 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 mm Hg. Laboratory studies reveal hyperglycemia, elevated 24-hour urinary free cortisol, elevated ACTH, and failure of suppression with low-dose dexamethasone. High-dose dexamethasone testing 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 an ACTH-secreting pituitary corticotroph adenoma, leading to hypercortisolism.

2. Etiology of Cushing Syndrome

1.      Exogenous glucocorticoid use is the most common cause overall

o    Suppresses endogenous ACTH and cortisol production

o    Prolonged use may cause bilateral adrenal atrophy

2.      Pituitary adenoma (Cushing disease) is the most common endogenous cause

o    Inappropriately non-suppressed or elevated ACTH

o    Elevated cortisol

o    May cause bilateral adrenal hyperplasia

3.      Ectopic ACTH secretion

o    Elevated ACTH

o    Elevated cortisol

o    Usually does not suppress with high-dose dexamethasone

4.      Adrenal causes

o    Low or suppressed ACTH

o    Elevated cortisol

o    Causes include adrenal adenoma, adrenal carcinoma, and primary bilateral adrenal nodular disease

3. Pathophysiology

1.      Excess ACTH stimulates the adrenal cortex and may cause bilateral adrenal hyperplasia

2.      Leads to excessive cortisol production

3.      Causes loss of the normal circadian rhythm of cortisol secretion

4.      Cortisol effects include:

o    Protein catabolism causing proximal muscle weakness and thin extremities

o    Increased gluconeogenesis and insulin resistance causing hyperglycemia

o    Increased vascular reactivity and mineralocorticoid receptor activation contributing to hypertension

o    Bone loss causing osteopenia or osteoporosis

o    Immunosuppression increasing susceptibility to infection

5.      Hypokalemia may occur in severe hypercortisolism and is more prominent in ectopic ACTH syndrome

4. Clinical Features

4.1 Fat Redistribution

1.      Central obesity

2.      Facial rounding

3.      Dorsocervical fat pad

4.      Supraclavicular fat pads

5.      Thin extremities due to muscle wasting

4.2 Skin Changes

1.      Wide reddish-purple striae

2.      Easy bruising

3.      Skin thinning

4.      Poor wound healing

4.3 Metabolic Features

1.      Hypertension

2.      Hyperglycemia or diabetes mellitus

3.      Dyslipidemia

4.4 Endocrine Features

1.      Hirsutism

2.      Acne

3.      Amenorrhea or oligomenorrhea

4.      Reduced libido

4.5 Neuropsychiatric Features

1.      Depression

2.      Anxiety or irritability

3.      Insomnia

4.      Cognitive changes

5. Diagnosis

5.1 Screening for Hypercortisolism

1.      24-hour urinary free cortisol, preferably at least two collections

2.      Late-night salivary cortisol, preferably at least two measurements

3.      1 mg overnight dexamethasone suppression test

o    Serum cortisol greater than 1.8 micrograms/dL, or 50 nmol/L, after dexamethasone is abnormal

4.      An abnormal initial test should generally be confirmed with another appropriate test before determining the cause

5.2 Determining ACTH Dependence

1.      Low or suppressed ACTH

o    Suggests ACTH-independent Cushing syndrome, usually of adrenal origin

2.      Inappropriately non-suppressed or elevated ACTH

o    Suggests ACTH-dependent Cushing syndrome

o    Main causes are Cushing disease and ectopic ACTH secretion

5.3 Differentiation of Cause

1.      High-dose dexamethasone suppression test

o    Approximately 50% or greater suppression of cortisol from baseline supports a pituitary source

o    Lack of suppression favors ectopic ACTH secretion

o    The test is supportive but not diagnostic

2.      CRH or desmopressin stimulation test

o    Increased ACTH and cortisol responses support a pituitary source

o    These tests are not definitive when used alone

3.      Inferior petrosal sinus sampling

o    Gold-standard invasive test for distinguishing pituitary from ectopic ACTH secretion when localization remains uncertain

o    Central-to-peripheral ACTH ratio ≥2 before stimulation supports a pituitary source

o    Central-to-peripheral ACTH ratio ≥3 after CRH or desmopressin stimulation supports a pituitary source

o    Should be performed during biochemically active hypercortisolism

5.4 Imaging

1.      Pituitary MRI

2.      Most corticotroph adenomas are microadenomas less than 10 mm

3.      A pituitary lesion alone does not establish Cushing disease because incidental pituitary lesions can occur

4.      Current consensus suggests:

o    Lesion <6 mm: IPSS is generally recommended

o    Lesion 6 to 9 mm: most experts recommend IPSS

o    Lesion ≥10 mm with concordant clinical and biochemical findings: IPSS is generally unnecessary

6. Management

6.1 First Line

1.      Transsphenoidal surgical resection of the pituitary adenoma by an experienced pituitary surgeon

6.2 Persistent or Recurrent Disease

1.      Repeat transsphenoidal surgery in selected patients

2.      Medical therapy

3.      Pituitary radiotherapy or stereotactic radiosurgery

4.      Bilateral adrenalectomy in selected severe or refractory cases

6.3 Medical Therapy

1.      Pituitary-directed therapy

o    Pasireotide

o    Cabergoline

2.      Adrenal steroidogenesis inhibitors

o    Ketoconazole

o    Metyrapone

o    Osilodrostat

3.      Glucocorticoid receptor antagonist

o    Mifepristone

7. Complications

1.      Hypertension

2.      Diabetes mellitus

3.      Dyslipidemia

4.      Osteoporosis and fractures

5.      Cardiovascular disease

6.      Venous thromboembolism

7.      Infections

8.      Muscle wasting

9.      Psychiatric disorders

10.  Reproductive dysfunction

8. Prognosis and Follow Up

1.      Untreated Cushing disease is associated with increased morbidity and mortality

2.      Recurrence may occur years after successful treatment

3.      Requires long-term clinical and biochemical follow-up

9. Key Clinical Insight

Central obesity + wide reddish-purple striae + hypertension + hyperglycemia + confirmed hypercortisolism + inappropriately non-suppressed or elevated ACTH + suppression with high-dose dexamethasone + compatible pituitary lesion = Cushing disease strongly suspected

High-dose dexamethasone suppression supports a pituitary source but is not diagnostic. When biochemical findings and pituitary imaging are inconclusive, IPSS is used to distinguish a pituitary from an ectopic ACTH source.

References

1.      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. doi:10.1016/S2213-8587(21)00235-7. PMID: 34687601.

2.      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. doi:10.1210/jc.2008-0125. PMID: 18334580.

3.      Siddiq F, Brooks H, Demirtas E, et al. Consensus Guidelines on Inferior Petrosal Sinus Sampling: A Guideline From the Society of Vascular and Interventional Neurology Guidelines and Practice Standards Committee. Stroke Vasc Interv Neurol. 2026;6(3):e002309. doi:10.1161/SVIN.125.002309. PMID: 42088331.