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Background: Twenty-four hour urinary free cortisol (UFC) determination can be used for screening and follow-up of Cushing syndrome (CS). As immunoassay methods lack specificity for UFC measurement, the use of high-performance liquid chromatography coupled to mass spectrometer (LC-MSMS) is recommended. The aim of our study was to compare UFC results using four LC-MSMS methods performed in four independent laboratories in order to evaluate interlaboratory agreement., Methods: Frozen aliquots of 24-h urine samples (78 healthy volunteers and 20 patients with CS) were sent to four different laboratories for analysis. Following liquid-liquid or solid-liquid extraction, UFC were determined using four different LC-MSMS assay., Results: UFC intra- and interassays variation coefficients were lower than 10% for each centre. External quality control results were not significantly different. UFC normal ranges (established from healthy volunteers) were 17-126, 15-134, 12-118 and 27-157 nmol/day, respectively. Classification of UFC from healthy volunteers and patients with CS using a 95th percentile threshold was similar. However, for extreme UFC values (<50 or >270 nmol/day), negative or positive bias was noted., Conclusions: Even for highly specific methods such as LC-MSMS, variations of results can be found depending on analytical process. Validation of LC-MSMS methods including determination of the reference range is essential.

Purpose: Some adrenal incidentalomas produce cortisol in mild excess ('subclinical' Cushing's adenomas) and can potentially induce osteopenia. Their diagnosis is usually based on exclusive tumour uptake on adrenal scintigraphy using 131I-6 beta-methyl-iodo-19-norcholesterol and on inadequate cortisol response to dexamethasone (DXM) suppression tests. The aims of the present study were to evaluate bone mineral density (BMD) and metabolic markers of bone turnover in patients with incidentalomas and to test the effect of mild hypercortisolism on bone parameters., Methods: Thirty-five patients (13 men, 22 postmenopausal women, 49-76 years) with unilateral incidentaloma were studied. BMD was measured by dual X-ray absorptiometry. Two biochemical markers of bone formation, serum osteocalcin (BGP) and bone alkaline phosphatase (bALP), and two markers of bone resorption, urinary free deoxypyridinoline (D-Pyr) and urinary carboxy-telopeptide of bone type 1 collagen (CTX), were measured by radioimmunoassay. D-Pyr and CTX were corrected for creatinine excretion., Results: Median values of lumbar and femoral T-score were -1.125 and -0.920, respectively, whereas corresponding Z-score values where normal (0.105 and 0.120, respectively). Thirty-nine percent of patients had low serum BGP values and 3% had low bALP values; 16% showed elevated D-Pyr/creatinine values and 23% increased CTX/creatinine values. Patients both with suppression of the contralateral adrenal on scintigraphy and with an inadequate cortisol response to 1 mg DXM (> 50 nmol/L) (n = 14) presented a lower femoral T-score (P < 0.02) and, to a lesser extent, a lower femoral Z-score (P = 0.11) than other patients (n = 21). The proportion of increased values of CTX/creatinine (42% versus 11%, P = 0.08) also tended to be higher in the first than in the second group of patients. These two groups of patients were similar in terms of age, but tumour size was larger (P < 0.04) and plasma ACTH value was lower (P < 0.02) in patients with scintigraphic and endocrine abnormalities., Conclusion: Subclinical hypercortisolism defined on the basis of scintigraphic and hormonal criteria seems to contribute to bone loss in patients with adrenal incidentaloma. As other possible side effects of mild hypercortisolism, these findings have to be taken into account in the therapeutic management of these patients.