What is the appropriate diagnostic approach for a 19-year-old female with significant weight gain and no past medical history, considering Yaz (drospirenone and ethinyl estradiol) as a contraceptive option, to rule out Cushing's syndrome?

Diagnostic Approach for Cushing's Syndrome in a 19-Year-Old Female with Weight Gain

Begin screening with late-night salivary cortisol as the first-line test, which has 95% sensitivity and 100% specificity, making it the most accurate single screening test for this young patient with unexplained weight gain. 1

Initial Screening Strategy

Choose one of three first-line screening tests based on practical considerations for this 19-year-old patient:

• Late-night salivary cortisol (preferred): Sensitivity 95%, specificity 100% 1. This is the easiest test for a young outpatient—she collects saliva at home around 11 PM, and the sample is stable at room temperature for mailing to the laboratory 2, 3

• 24-hour urinary free cortisol (UFC): Diagnostic cut-off >193 nmol/24h with sensitivity 89% and specificity 100% 1. This requires complete urine collection with appropriate total volume to avoid false results 2

• 1-mg overnight dexamethasone suppression test: Morning serum cortisol <50 nmol/L excludes Cushing's syndrome 4, 2. The patient takes 1 mg dexamethasone at 11 PM and has blood drawn the next morning 2. This test has only 1.9% false-negative rate among 154 patients with confirmed Cushing's syndrome 5

Key Clinical Features to Assess

Look specifically for these physical findings during examination:

• Central obesity with "moon" face, dorsal and supraclavicular fat pads 4, 6
• Wide (≥1 cm) violaceous (purple) striae on abdomen 4, 7
• Proximal muscle weakness (difficulty rising from chair without using arms) 4, 6
• Fragile, thin skin with easy bruising 6
• Hirsutism and menstrual irregularities 6
• Hypertension (present in 70-90% of cases) 6

Important caveat: The absence of purple striae does not exclude Cushing's syndrome, as no single clinical feature has 100% sensitivity 7. Biochemical testing remains essential regardless of physical findings 7.

If Screening Test is Positive

Confirm the diagnosis with a second different screening test from the list above, as recommended by the Endocrine Society 1, 8. If both tests are positive, proceed to determine the etiology:

1. Measure morning plasma ACTH level to distinguish ACTH-dependent from ACTH-independent disease 1, 8

   • ACTH >1.1 pmol/L indicates ACTH-dependent disease (pituitary adenoma or ectopic ACTH source) 1
   • Low ACTH indicates primary adrenal disease 8, 9

2. For ACTH-dependent disease, obtain pituitary MRI (sensitivity 63%, specificity 92%) 1

3. If imaging is equivocal, bilateral inferior petrosal sinus sampling is the gold standard to differentiate pituitary from ectopic ACTH sources 1, 8

Critical Pitfalls to Avoid

• Drug interference: Oral contraceptives like Yaz can cause false-positive results on dexamethasone suppression testing 4. Consider stopping the contraceptive for 6 weeks before testing if clinically feasible, or use salivary cortisol or UFC instead 2

• Inadequate saliva collection: Ensure the collection device is properly soaked to avoid false results 2

• Incomplete urine collection: Verify 24-hour urine volume is appropriate (typically 1-2 liters) to ensure complete collection 2

• Assay cross-reactivity: Antibody-based immunoassays can generate false-positives due to cross-reactivity with cortisone and other metabolites; liquid chromatography with tandem mass spectrometry is more specific 2

Why This Matters for This Patient

The average diagnostic delay in Cushing's syndrome is 3 years from initial symptoms to diagnosis, resulting in increased mortality from cardiovascular events 6. In this 19-year-old with significant weight gain, timely diagnosis is critical because:

• Hypertension and glucose abnormalities occur in >80% of Cushing's patients, mimicking metabolic syndrome 6
• Chronic hypercortisolism causes severe multisystem morbidity affecting quality of life 6
• Early treatment prevents progression of comorbidities 8