High-resolution daily profiles of tissue adrenal steroids by portable automated collection

Abstract

Rhythms are intrinsic to endocrine systems, and disruption of these hormone oscillations occurs at very early stages of the disease. Because adrenal hormones are secreted with both circadian and ultradian periods, conventional single–time point measurements provide limited information about rhythmicity and, crucially, do not provide information during sleep, when many hormones fluctuate from nadir to peak concentrations. If blood sampling is attempted overnight, then this necessitates admission to a clinical research unit, can be stressful, and disturbs sleep. To overcome this problem and to measure free hormones within their target tissues, we used microdialysis, an ambulatory fraction collector, and liquid chromatography–tandem mass spectrometry to obtain high-resolution profiles of tissue adrenal steroids over 24 hours in 214 healthy volunteers. For validation, we compared tissue against plasma measurements in a further seven healthy volunteers. Sample collection from subcutaneous tissue was safe, well tolerated, and allowed most normal activities to continue. In addition to cortisol, we identified daily and ultradian variation in free cortisone, corticosterone, 18-hydroxycortisol, aldosterone, tetrahydrocortisol and allo-tetrahydrocortisol, and the presence of dehydroepiandrosterone sulfate. We used mathematical and computational methods to quantify the interindividual variability of hormones at different times of the day and develop “dynamic markers” of normality in healthy individuals stratified by sex, age, and body mass index. Our results provide insight into the dynamics of adrenal steroids in tissue in real-world settings and may serve as a normative reference for biomarkers of endocrine disorders (ULTRADIAN, NCT02934399).

HormoneBayes: A novel Bayesian framework for the analysis of pulsatile hormone dynamics

“…At least one other model used for the analysis of LH pulsatility has used more complex (multiple timescale) clearance dynamics, however we expect this assumption should have a minimal impact for the purpose of assessing LH pulsatility. Nevertheless, the modular design of HormoneBayes allows future extensions of the model with the scope of comparing how well different models capture LH dynamics as well as enabling the analysis of hormone dynamics beyond LH [ 22 , 23 ].…”

“…For instance, inferred posterior distributions can be used to evaluate the impact of hormonal interventions on LH secretion parameters, and crucially, this statistical evaluation can be conducted not only at the population level but also on an individual basis (see Fig E in S1 Text for an example of this type of personalised analysis). We expect these features of our method regarding personalized analysis will be crucial as measurement technologies mature enabling cheap sampling of hormone levels in real time [ 22 , 24 ].…”

Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial

“…In future studies, the pattern and dose of the cortisol infusions can be further improved, allowing individual fine‐tuning. This should be easier now with new methodologies such as ambulatory microdialysis, which can provide details of cortisol responses [ 33 ]. Finally, longer duration studies can now be designed, allowing sufficient time to account for central remodelling.…”

Advancements in Cortisol Detection: From Conventional Methods to Next-Generation Technologies for Enhanced Hormone Monitoring

“…Nowadays, the most common method of measuring cortisol levels is via immunoassay, with a wide range of kits available commercially for centralized diagnostic purposes. The current gold standard for cortisol measurement is mass spectroscopy (MS), a highly sensitive and precise technique for small molecule detection, which also has the advantage of being able to measure multiple compounds from the same sample . While both immunoassays and MS offer unique advantages and disadvantages, they are both difficult to adopt to point-of-care (PoC) detection, due to factors such as cost, requiring specialized personnel and overhead time loss.…”

“…The current gold standard for cortisol measurement is mass spectroscopy (MS), a highly sensitive and precise technique for small molecule detection, which also has the advantage of being able to measure multiple compounds from the same sample. 28 While both immunoassays and MS offer unique advantages and disadvantages, they are both difficult to adopt to point-of-care (PoC) detection, due to factors such as cost, requiring specialized personnel and overhead time loss. Additionally, neither of these modalities can be used for continuous monitoring of cortisol.…”