High variability in baseline urinary free cortisol values in patients with Cushing's disease

Abstract

Objective: Twenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing's syndrome. Because there are few data on UFC variability in patients with active Cushing's disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing's disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data.

Design: Observational study (enrolment phase of Phase III study).

Methods: Patients (n = 152) with persistent/recurrent or de novo Cushing's disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30-145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks.

Results: Over 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48-56). The intrapatient CV was 51% (95% CI: 44-58) for samples 1 and 2, 49% (95% CI: 43-56) for samples 3 and 4 and 54% (95% CI: 49-59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism.

Conclusions: There is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity.

Trial registration: ClinicalTrials.gov NCT00434148.

Figure 1

Distribution of baseline mean urinary free cortisol (UFC) values expressed as a percentage of the upper limit of normal (ULN), calculated from the mean of four UFC values for each patient.

Figure 2

Mean + SD (bars) and median (dashed lines) UFC levels. Samples 1 and 2: mean = 1000 ± 1872 nmol/24 h (362 ± 679 μg/24 h); median = 610 nmol/24 h (221 μg/24 h). Samples 3 and 4: mean = 940± 2148 nmol/24 h (341 ± 779 μg/24 h); median = 527 nmol/24 h (191 μg/24 h). SD, standard deviation; UFC, urinary free cortisol.

Figure 3

(a) Variability of urinary free cortisol (UFC) levels in relation to the mean UFC for individual patients (mUFC); (b) Correlation between UFC samples 1 and 2 from individual patients; (c) UFC levels from the first, second, third and fourth collections. Note: The inserts in (a) and (b) show the same figure but with the extreme outliers removed and the axis scales expanded. Twelve patients had at least one UFC value >2500 nmol/24 h. Each data point in (a), (b) and each line in (c) represents an individual patient (N = 152).

Figure 4

Correlation between the mean UFC for individual patients (mUFC) and clinical features of Cushing’s disease: (a) fasting glucose; (b) HbA_1C; (c) fasting insulin; (d) insulin resistance (HOMA IR); (e) β-cell function (HOMA β); (f) body mass index (BMI); (g) sitting systolic blood pressure; and (h) sitting diastolic blood pressure. Note: The shaded areas represent the normal ranges for UFC (x-axis) and each individual clinical feature (y-axis).