Cushing Syndrome: Low-Dose Dexamethasone Suppression Test
The next appropriate investigation is the low-dose dexamethasone suppression test (Option A), which is the recommended first-line confirmatory test for suspected Cushing syndrome in this patient presenting with classic features of hypercortisolism. 1
Clinical Presentation Analysis
This 40-year-old woman presents with a constellation of findings highly suggestive of Cushing syndrome:
- Weight gain with central distribution 1
- Amenorrhea (4 months without menses) 1
- Hirsutism (androgen excess manifestation) 1
- Striae (specifically the wide, violaceous striae characteristic of hypercortisolism) 1
These clinical features together create a high pretest probability for Cushing syndrome, warranting confirmatory biochemical testing rather than random screening tests. 1
Diagnostic Algorithm for Cushing Syndrome
Step 1: Confirm Hypercortisolism (Current Priority)
The diagnostic approach follows a two-step process: first confirm hypercortisolism, then determine its etiology. 1 For initial confirmation of Cushing syndrome, guidelines recommend one of three first-line tests:
- Low-dose dexamethasone suppression test (LDDST) - 95% sensitivity, 80% specificity 1
- 24-hour urinary free cortisol (requires 3 collections) 1
- Late-night salivary cortisol 1
The LDDST is preferred in this clinical scenario because it provides rapid, reliable confirmation with a single test, whereas random serum cortisol (Option B) has no diagnostic value due to the pulsatile nature of cortisol secretion and wide normal variation throughout the day. 1
Why Not the Other Options?
Option B (Random serum cortisol): This test is not recommended for Cushing syndrome diagnosis because cortisol levels vary significantly throughout the day and overlap between normal individuals and those with Cushing syndrome, making interpretation unreliable. 1
Option C (Serum testosterone): While this patient has hirsutism suggesting hyperandrogenism, the combination of weight gain, striae, and amenorrhea points more strongly toward Cushing syndrome than isolated androgen excess (such as PCOS). Testosterone testing would be appropriate if clinical features suggested primary hyperandrogenism without the cushingoid features. 1
Option D (ACTH stimulation test): This test evaluates adrenal insufficiency, not hypercortisolism, and is therefore completely inappropriate for this clinical presentation. 1
Step 2: Determine Etiology (After Confirmation)
Once hypercortisolism is confirmed, the next step involves measuring morning (09:00h) plasma ACTH to distinguish ACTH-dependent from ACTH-independent causes:
- ACTH normal or elevated (>5 ng/L): Suggests Cushing disease (pituitary) or ectopic ACTH production 1
- ACTH low or undetectable: Suggests adrenal source 1
Clinical Pitfalls to Avoid
Do not order multiple screening tests simultaneously - this increases false-positive rates and creates diagnostic confusion. Follow the algorithmic approach: confirm hypercortisolism first, then investigate etiology. 1
Do not rely on clinical features alone - while this patient's presentation is highly suggestive, biochemical confirmation is mandatory before proceeding to imaging or invasive testing. 1
Do not skip confirmatory testing - the prevalence of Cushing syndrome even in resistant hypertension populations is low (<0.1%), making false-positives common if screening is performed without strong clinical suspicion. 1 However, this patient's multiple classic features justify immediate confirmatory testing.
Practical Implementation
The standard LDDST protocol involves:
- Dose: 0.5 mg dexamethasone every 6 hours for 48 hours 1
- Timing: 09:00,15:00,21:00,03:00 hours 1
- Measurement: Serum cortisol at 0,24, and 48 hours 1
- Diagnostic threshold: Failure to suppress cortisol to <50 nmol/L (<1.8 μg/dL) indicates Cushing syndrome 1
An alternative overnight dexamethasone test (1 mg at midnight with morning cortisol) has lower sensitivity (75%) and is less reliable in this setting. 1