Which collection would give an accurate assessment of potential excess cortisol production?

• A. Collect a plasma sample as a baseline, and another one 1 hour after administration of metyrapone
• B. Collect a plasma sample at 8 a.m. only
• C. Collect a 24-hour urine free cortisol
• D. Collect a plasma sample at 8 a.m. and at 8 a.m. the next day

Answer: (C)

Cortisol levels vary throughout the day and with various stresses, so a single time-point measurement can miss ongoing overproduction. A 24-hour urine free cortisol collection sums up all cortisol excreted over a full day, providing an integrated view of total daily production and reducing the impact of normal diurnal fluctuations. This makes it the most reliable way to detect excess cortisol production in suspected Cushing’s syndrome.

A dynamic test involving metyrapone is used to evaluate how the HPA axis responds to pharmacologic inhibition, giving information about axis function rather than a direct measure of how much cortisol is being produced overall. A single morning plasma sample, or two morning samples a day apart, can still miss or misrepresent hypercortisolism due to diurnal variation or transient fluctuations.