Dexamethasone Suppression Test and the Synacthen Test

Cushing’s Syndrome

• Relationship with ACTH:
  • Cushing’s syndrome is characterized by chronic excess cortisol production. Depending on the source of excess cortisol, ACTH levels can vary:
    • ACTH-dependent: Caused by an excess of ACTH, often from a pituitary adenoma (Cushing’s disease) or ectopic ACTH production by a tumor (e.g., small-cell lung cancer).
    • ACTH-independent: Caused by adrenal adenomas or carcinomas producing cortisol autonomously, leading to suppressed ACTH due to negative feedback.
• Investigation:
  • Dexamethasone Suppression Test: Low-dose and high-dose dexamethasone suppression tests help differentiate between pituitary-driven (ACTH-dependent) Cushing’s disease and ectopic or adrenal causes.
  • Serum ACTH Levels: High in ACTH-dependent cases (pituitary or ectopic sources), low in ACTH-independent (adrenal causes).
  • Imaging: MRI of the pituitary or CT scans for suspected adrenal or ectopic sources.
  • Inferior Petrosal Sinus Sampling (IPSS): Used to distinguish between pituitary and ectopic sources of ACTH in complex cases.

2. Addison’s Disease

• Relationship with ACTH:
  • Addison’s disease is a primary adrenal insufficiency where the adrenal glands fail to produce sufficient cortisol, leading to increased ACTH levels due to lack of negative feedback.
  • In primary adrenal insufficiency, ACTH levels are elevated, but cortisol is low.
  • In secondary or tertiary adrenal insufficiency, ACTH production is low due to pituitary or hypothalamic dysfunction, and adrenal glands are not adequately stimulated to produce cortisol.
• Investigation:
  • ACTH Stimulation Test (Synacthen Test): Evaluates adrenal response to ACTH; low cortisol response indicates adrenal insufficiency.
  • Baseline Serum ACTH and Cortisol: Elevated ACTH with low cortisol confirms primary adrenal insufficiency.
  • Plasma Renin and Aldosterone Levels: Useful in primary adrenal insufficiency to assess mineralocorticoid deficiency.
  • Autoantibody Testing: Detects autoimmune causes of adrenal failure, common in Addison’s disease.

Feature	Dexamethasone Suppression Test	Synacthen Test

Purpose

To assess adrenal suppression and identify causes of Cushing’s syndrome (e.g., pituitary vs. adrenal cause).

To evaluate adrenal gland function, specifically assessing adrenal response to ACTH to diagnose adrenal insufficiency.

Mechanism

Administers dexamethasone (a glucocorticoid) to suppress ACTH production and assess if cortisol levels drop accordingly.

Administers synthetic ACTH (Synacthen) to stimulate the adrenal glands and measure cortisol response.

Indications

Suspected Cushing’s syndrome, differentiating between Cushing’s disease and ectopic ACTH secretion.

Suspected adrenal insufficiency (e.g., Addison’s disease) or secondary/tertiary adrenal insufficiency.

Types of Tests

1. Low-dose (1 mg) 2. High-dose (8 mg)

1. Standard dose (250 mcg) 2. Low dose (1 mcg)

Procedure

– Low-dose: 1 mg dexamethasone orally at 11 p.m., cortisol measured next morning. – High-dose: 8 mg dexamethasone, cortisol measured after administration.

– Standard: 250 mcg Synacthen given IM or IV, cortisol measured at baseline, 30 min, and 60 min.\n – Low-dose: Similar measurements, using 1 mcg Synacthen.

Interpretation

– Normal: Cortisol suppression in response to dexamethasone. – Abnormal: Lack of suppression indicates possible Cushing’s syndrome.

– Normal: Adequate cortisol rise after ACTH. – Abnormal: Insufficient cortisol response suggests adrenal insufficiency.

Sensitivity/Specificity

High specificity for diagnosing Cushing’s syndrome, especially in high-dose test.

High sensitivity in diagnosing primary adrenal insufficiency but may need further testing for secondary causes.

Common Side Effects

Mild side effects due to dexamethasone (e.g., gastrointestinal upset, insomnia).

Rare side effects but may cause flushing or slight pain at injection site.

Contraindications

Severe liver disease, recent surgery, or significant stress (may affect cortisol levels).

Allergy to ACTH or Synacthen, or conditions like severe illness that may alter adrenal response.

Limitations

May not differentiate between all causes of Cushing’s if ectopic ACTH production is involved.

May not distinguish primary from secondary adrenal insufficiency in all cases.

Time Taken for Results

Overnight for low-dose, several hours for high-dose.

Approximately 1 hour for cortisol response assessment.

Cost & Accessibility

Generally affordable and widely available in most labs.

Readily available but may vary by healthcare setting.