Cortisol measurement in patients receiving metyrapone therapy

Abstract

Current guidance recommends titrating the dose of metyrapone against serum cortisol concentration, in patients under medical management of Cushing's syndrome. In the UK, this almost always involves measuring serum cortisol concentration by immunoassay, the performance of which is questionable in the presence of altered steroid metabolism. Sera from two patients receiving metyrapone were analysed using a liquid chromatography tandem mass spectrometry (MS) steroid assay to identify which steroids, if any, were elevated in these patients. In addition, control serum was spiked with a series of steroids to identify any potential positive interferences in a cortisol immunoassay. Serum 11-deoxycortisol concentration was elevated in both of the patients studied. One patient also had an elevated serum 17-hydroxyprogesterone concentration and the other an elevated androstenedione. In addition, the results of the interference studies indicated that the cortisol immunoassay was susceptible to interference from 11-deoxycortisol, 17-hydroxyprogesterone and 21-deoxycortisol. However, the magnitude of interference, in the serum cortisol immunoassay, due to these three steroids could not account for the discrepancy between the cortisol concentrations measured by immunoassay and those measured by MS. Both clinicians and laboratory staff should be aware of these interferences when monitoring patients undergoing treatment with metyrapone, and consequently serum should be measured in these patients by MS, not by immunoassay.

Serum Cortisol: An Up-To-Date Assessment of Routine Assay Performance

“…Our results indicate all 5 immunoassays over recover cortisol relative to the cRMP in the metyrapone cohort. Of these, the first generation Roche E170 and Siemens Centaur XP were particularly prone to over-estimation, likely secondary to antibody cross-reactivity with cortisol precursors (10,11 ). Our observations support recent Endocrine Society guidelines that advise serum cortisol is measured by LC-MS/MS in patients prescribed metyrapone (6 ).…”

“…Furthermore, mean cortisol concentrations at baseline and 30 min post-synacthen were found to be assay specific and exhibit a consistently negative bias in women taking the oral contraceptive pill (OCP) (9 ). Immunoassay cortisol measurements in patients taking metyrapone have also been reported to display a positive bias relative to a routine LC-MS/MS assay (10,11 ).…”

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

“…This is particularly important for metyrapone (and LCI699), which is a potent inhibitor of 11b-hydroxylase and is known to significantly increase 11-deoxycortisol. This cortisol precursor is structurally similar to cortisol and has been shown to interfere with many commercial cortisol immunoassays leading to the overestimation of cortisol levels and the risk of patient overtreatment (149,150). It is therefore important that patients on metyrapone have biochemical monitoring of the cortisol response using more specific laboratory methods such as mass spectrometry (151).…”

Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor metyrapone

“…8,11 Immunoassay of cortisol was performed on the Siemens ADVIA Centaur XP analyser (Siemens, Camberley, Surrey, UK).…”

“…6,7 A recent case report also highlighted the potential shortfalls in the measurement of serum cortisol by immunoassay in patients receiving metyrapone therapy. 8 Figure 1 The pathway of adrenal glucocorticoid and mineralocorticoid biosynthesis. Molecular structures of the adrenal steroids are presented to illustrate the close structural homology that elicits cross-reactivity in immunoassay.…”