Context The adrenal cortex produces specific steroid hormones including steroid sulfates such as dehydroepiandrosterone sulfate (DHEAS), the most abundant steroid hormone in the human circulation. Steroid sulfation involves a multi-step enzyme machinery that may be impaired by inborn errors of steroid metabolism. Emerging data suggest a role of steroid sulfates in the pathophysiology of adrenal tumors and as potential biomarkers. Evidence Acquisition Selective literature search using “steroid”, “sulfat*”, “adrenal”, “transport”, “mass spectrometry” and related terms in different combinations. Evidence Synthesis A recent study highlighted the tissue abundance of estrogen sulfates to be of prognostic impact in adrenocortical carcinoma tissue samples using MALDI mass spectrometry imaging. General mechanisms of sulfate uptake, activation and transfer to substrate steroids are reasonably well understood. Key aspects of this pathway however have not been investigated in detail in the adrenal; these include the regulation of substrate specificity and the secretion of sulfated steroids. Both for the adrenal and targeted peripheral tissues, steroid sulfates may have relevant biological actions beyond their cognate nuclear receptors after desulfation. Impaired steroid sulfation such as low DHEAS in Cushing adenomas is of diagnostic utility, but more comprehensive studies are lacking. In bioanalytics, the requirement of deconjugation for gas-chromatography/mass-spectrometry has precluded the study of steroid sulfates for a long time. This limitation may be overcome by liquid-chromatography/tandem-mass-spectrometry. Conclusions A role of steroid sulfation in the pathophysiology of adrenal tumors has been suggested and a diagnostic utility of steroid sulfates as biomarkers is likely. Recent analytical developments may target sulfated steroids specifically.
Background The dexamethasone suppression test (DST) is the recommended first-tier test for suspected Cushing syndrome (CS). Missed dexamethasone intake or insufficient dexamethasone serum exposure may yield false positive results. Quantification of serum dexamethasone in DST samples may therefore improve test performance. Methods Simultaneous quantification of dexamethasone and cortisol by liquid chromatography-tandem mass spectrometry in 400 DST serum samples (100 overt CS, 200 excluded CS, 100 adrenal incidentalomas with (possible) autonomous cortisol secretion, AI-ACS) randomly selected within the indication groups. The 2.5th percentile of dexamethasone in patients with excluded CS was considered the lower limit of normal (LLN). Results Serum dexamethasone varied from undetectable to 20.2 ng/mL with a median of 4.8 ng/mL (95% CI 4.5-5.1 ng/mL). Dexamethasone was undetectable in only 16 patients (4%), suggesting non-compliance. The dexamethasone LLN was 1.8 ng/mL (4.6 nmol/L). Decreased glomerular filtration rate and diabetes mellitus were associated with higher serum dexamethasone concentration, while body mass index, sex, age, nicotine, and oral contraceptives had no significant effect. By excluding the 27 samples with dexamethasone <LLN and applying the method-specific cortisol cutoff of 2.4 µg/dL (66 nmol/L) to samples with suspected CS, the clinical specificity for CS increased from 67.5% to 92.4% while preserving 100% clinical sensitivity. Among 100 AI-ACS samples (defined by immunoassay), 4 samples had dexamethasone <1.8 ng/mL and 14 samples had cortisol <2.4 µg/dL, which excluded autonomous cortisol secretion. Conclusions Quantification of dexamethasone and method-specific cortisol cutoffs in DST samples may reduce the false positive rate and lower the proportion of patients requiring further workup.
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