Hypothalamic-Pituitary-Adrenal Axis Function after Inhaled Corticosteroids: Unreliability of Urinary Free Cortisol Estimation

Chemical Pathology Department, West Middlesex University Hospital/Quest Diagnostics, Inc., Isleworth, Middlesex, United Kingdom TW7 6AF.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.21). 11/2002; 87(10):4541-6. DOI: 10.1210/jc.2002-020287
Source: PubMed

ABSTRACT Free cortisol in the urine (UFC) is frequently measured in clinical research to assess whether inhaled corticosteroids (ICS) cause suppression of the hypothalamic-pituitary-adrenal axis. Thirteen healthy male subjects received single inhaled doses (of molar equivalence) of fluticasone propionate (FP), triamcinolone acetonide (TAA), budesonide (BUD), and placebo in this single blind, randomized, cross-over study. UFC output was measured using four commercial immunoassays in samples collected in 12-h aliquots over 24 h. The cortisol production rate was assessed from the outputs of cortisol metabolites. UFC showed a 100% increase over placebo levels in the Abbott TDX assay after the administration of BUD. The other assays detected variable suppression (ranging from 29-61% suppression for FP, 30-62% suppression for TAA, and 25% suppression to 100% stimulation for BUD). Suppression was more pronounced in the first 12 h after TAA and in the second 12 h after FP. Similar suppression was found in each 12-h period after BUD. UFC estimation based on immunoassays after ICS may be an unreliable surrogate marker of adrenal suppression. Many of the published studies describing or comparing the safety of different ICS should be reevaluated, and some should be interpreted with caution.

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    • "Since cortisol levels decrease throughout the day, a random cortisol measurement is not an adequate measure of AS in children. Other measures of adrenal insufficiency are available, such as the assessment of urinary or salivary cortisol levels; however, these tests have not been well-studied in children with AS [50-52]. "
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    ABSTRACT: Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory agents available for the treatment of asthma and represent the mainstay of therapy for most patients with the disease. Although these medications are considered safe at low-to-moderate doses, safety concerns with prolonged use of high ICS doses remain; among these concerns is the risk of adrenal suppression (AS). AS is a condition characterized by the inability to produce adequate amounts of the glucocorticoid, cortisol, which is critical during periods of physiological stress. It is a proven, yet under-recognized, complication of most forms of glucocorticoid therapy that can persist for up to 1 year after cessation of corticosteroid treatment. If left unnoticed, AS can lead to significant morbidity and even mortality. More than 60 recent cases of AS have been described in the literature and almost all cases have involved children being treated with ≥500 μg/day of fluticasone. The risk for AS can be minimized through increased awareness and early recognition of at-risk patients, regular patient follow-up to ensure that the lowest effective ICS doses are being utilized to control asthma symptoms, and by choosing an ICS medication with minimal adrenal effects. Screening for AS should be considered in any child with symptoms of AS, children using high ICS doses, or those with a history of prolonged oral corticosteroid use. Cases of AS should be managed in consultation with a pediatric endocrinologist whenever possible. In patients with proven AS, stress steroid dosing during times of illness or surgery is needed to simulate the protective endogenous elevations in cortisol levels that occur with physiological stress. This article provides an overview of current literature on AS as well as practical recommendations for the prevention, screening and management of this serious complication of ICS therapy.
    Allergy Asthma and Clinical Immunology 08/2011; 7(1):13. DOI:10.1186/1710-1492-7-13 · 2.03 Impact Factor
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    • "The sum of glucocorticoid metabolites in urine (TCM) collected for 24h approximates the daily production rate of (105, 106) and is an excellent test for adrenal suppression (107). The improved sensitivity of LC-MS-MS methods shown for androgens and oestrogens (to<10 pmol.L) will now allow earlier and more accurate assessments of pubertal development (108). Even before signs of puberty, girls had higher androgen and oestrogen levels than boys. "
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    ABSTRACT: Most steroid disorders of the adrenal cortex come to clinical attention in childhood and in order to investigate these problems, there are many challenges to the laboratory which need to be appreciated to a certain extent by clinicians. The analysis of sex steroids in biological fluids from neonates, over adrenarche and puberty present challenges of specificities and concentrations often in small sample sizes. Different reference ranges are also needed for interpretations. For around 40 years, quantitative assays for the steroids and their regulatory peptide hormones have been possible using immunoassay techniques. Problems are recognised and this review aims to summarise the benefits and failings of immunoassays and introduce where tandem mass spectrometry is anticipated to meet the clinical needs for steroid analysis in paediatric endocrine investigations. It is important to keep a dialogue between clinicians and the laboratory, especially when any laboratory result does not make sense in the clinical investigation. Conflict of interest:None declared.
    Journal of Clinical Research in Pediatric Endocrinology 03/2010; 2(1):1-16. DOI:10.4274/jcrpe.v2i1.1
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    • "Commercially available RIA kits for measuring UFC may yield falsely high values, as results can be influenced by the presence of cortisol metabolites as well as other interfering substances; UFC values obtained with these assays are potentially two to four times higher than the true values established with chromatography (Murphy, 2002). Immunoassays have been reported to show particularly low specificity and poor precision at low cortisol concentrations, leading to widely discrepant results in studies of adrenal suppression (Fink et al., 2002). In choosing a laboratory, it is therefore important to make sure that the assay has been validated and is monitored according to established standards for UFC; details concerning the assay (accuracy, recovery , precision, antibody used, crossreactivity, extraction method) should also be reported in publications. "
    01/2008: pages 37-74; Sage Publications.
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