The effects of inhaled corticosteroids on cortisol production can be distorted by analytical methodology and clinical study design
RS Fink1, LN Pierre2, PT Daley-Yates2, DH Richards3 & JW Honour4
Measurement of urinary free cortisol (UFC) in overnight, early morning and 24h sample collections are often used to assess potential effects of inhaled or intranasal corticosteroids (ICS) on the HPA axis. In the present study the effects of single inhaled doses of fluticasone propionate (FP), Budesonide (Bud), Triamcinolone acetate (TAA)(molar equivalence; 1750, 1600 and 1600 micrograms respectively) and placebo on UFC excretion was investigated in 13 healthy male subjects. UFC was measured after solvent extraction using 4 different assay systems (Abbott TDX, Bayer ACS 180, DPC Immulite and ICN Corticote), cortisol production rate was assessed by gas chromatographic analysis of total cortisol metabolites (TCM). One assay (Abbott) showed an apparent 100% increase over placebo UFC levels, the other assays detected suppression although the degree of suppression for each ICS between all the methods was considerable (29-61% suppression , 25% suppression to +100% stimulation and 30-62% suppression respectively for the ICS). The numbers of subjects with UFC below a lower reference limit of 50nmol/24h depended on the assay used (FP - 1, 6 and 2 cases; Bud - 1, 3 and 2 cases and TAA - 1, 8 and 1 cases depending on the respective assays). Suppression was more pronounced in the first 12h after TAA and in the second 12hours after FP, similar suppression was found in each 12h period after BUD. UFC estimation based on immunoassays following ICS may be an unreliable surrogate marker for HPA axis suppression. Interferences in assays for UFC after BUD have not been previously reported. The similarity in structure of BUD and its metabolites with cortisol makes interference entirely feasible with any immunoassay. Based on these findings many published studies describing or comparing the systemic safety of ICS should be re-evaluated and some results treated with caution.