BACKGROUND:Accurate serum cortisol quantification is required for the correct diagnosis and management of adrenal pathologies. Presently, most laboratories use immunoassay to measure serum cortisol with proficiency schemes demonstrating a wide dispersion of results. Here, we investigate the effects of sex, matrix, and antibody specificity on serum cortisol quantification in 6 routine assays.
Background Monitoring of hormonal control represents a key part of the management of congenital adrenal hyperplasia (CAH). Monitoring strategies remain suboptimal because they rely on frequent blood tests and are not specific for adrenal-derived hormones. Recent evidence suggests the crucial role of adrenal-specific 11-oxygenated-C19 androgens in the pathogenesis of CAH. Objective To establish a correlation between plasma and salivary adrenal-specific androgens in CAH as a noninvasive monitoring strategy. Design This prospective cross-sectional study recruited patients between 2015 and 2018. Setting Multicenter study including 13 tertiary centers in the United Kingdom. Participants Seventy-eight children with CAH and 62 matched healthy controls. Methods Using liquid chromatography–tandem mass spectrometry, plasma and salivary concentrations of five steroids were measured: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11-hydroxyandrostenedione (11OHA4), and 11-ketotestosterone (11KT). The correlation between plasma and salivary steroids was analyzed to assess their use in clinical practice. Results Strong correlations between plasma and salivary steroid concentrations in patients with CAH were detected: 17OHP (rs = 0.871; P < 0.001), A4 (rs = 0.931; P < 0.001), T (rs = 0.867; P < 0.001), 11OH4A (rs = 0.876; P < 0.001), and 11KT (rs = 0.944; P < 0.001). These results were consistent for patient subgroups based on sex and age. Analysis of patient subgroups based on 17OHP concentrations established clear correlations between plasma and salivary concentrations of the adrenal-specific androgen 11KT. Conclusions The current study identified tight correlations between plasma and saliva for the adrenal-derived 11-oxygenated C19 androgen 11KT, as well as 17OHP and A4, which are widely used for monitoring treatment in CAH. This combination of steroid hormones will serve as an improved noninvasive salivary test for disease monitoring in patients with CAH.
Background: Symptoms of hyperandrogenism are common in patients with Cushing’s disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD. Methods: We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (T), 11-ketotestosterone (11KT) as well as metabolites of classic and 11oxygenated androgens in 24-hour urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotropic hormone in plasma in patients and controls were investigated. Results: Treatment naïve females with CD showed significantly elevated area under the curve (AUC) of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, p = 0.0002; 11KT mrd 17.42; p = 0.0005) whereas A4, T and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transphenoidal surgery 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 p < 0.0001; 11KT p = 0.0010) and urine (11-O-An p = 0.0011; 11-OH-AN p < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis. Conclusion Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.
Objective 11-oxygenated androgens significantly contribute to the circulating androgen pool. Understanding the physiological variation of 11-oxygenated androgens and their determinants is essential for clinical interpretation, e.g. in androgen excess conditions. We quantified classic and 11-oxygenated androgens in serum and saliva across the adult age and BMI range, also analysing diurnal and menstrual cycle-dependent variation. Design Cross-sectional. Morning serum samples were collected from 290 healthy volunteers (125 men, 22-95 years; 165 women, 21-91 years). Morning saliva samples were collected by a sub-group (51 women and 32 men). Diurnal saliva profiles were collected by 13 men. Twelve women collected diurnal saliva profiles and morning saliva samples on seven consecutive days during both follicular and luteal menstrual cycle phases. Methods Serum and salivary steroids were quantified by liquid chromatography-tandem mass spectrometry profiling assays. Results Serum classic androgens decreased with age-adjusted BMI, e.g. %change per kg/m2 for 5α-dihydrotestosterone: men -5.54% (-8.10, -2.98), women -1.62% (95%CI -3.16, -0.08). By contrast, 11-oxygenated androgens increased with BMI, e.g. %change per kg/m2 for 11-ketotestosterone: men 3.05% (0.08, 6.03), women 1.68% (95%CI -0.44, 3.79). Conversely, classic androgens decreased with age in both men and women, while 11-oxygenated androgens did not. Salivary androgens showed a diurnal pattern in men and in the follicular phase in women; in the luteal phase only 11-oxygenated androgens showed diurnal variation. Conclusions Classic androgens decrease while active 11-oxygenated androgens increase with increasing BMI, pointing towards the importance of adipose tissue mass for the activation of 11-oxygenated androgens. Classic but not 11-oxygenated androgens decline with age.
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