Automated 24-hours sampling of subcutaneous tissue free cortisol in humans

Summary Chronic exposure to elevated glucocorticoid levels is associated with obesity, insulin resistance, impaired glucose tolerance, hypertension and dyslipidaemia, manifest classically in Cushing's syndrome and with high‐dose glucocorticoid therapy. However, cardiovascular events are also reportedly higher in patients with primary and secondary hypoadrenalism receiving ‘replacement’ glucocorticoid doses. This has been attributed to an inability to mimic accurately the diurnal rhythm of cortisol with current oral replacement therapy and subsequent glucocorticoid excess. Although development of delayed release oral preparations has sought to overcome this problem, there has been little attention on the ultradian rhythm of glucocorticoids and its relevance for replacement therapy and associated cardio‐metabolic comorbidity. Endogenous glucocorticoids are released in a pulsatile manner, and this ultradian rhythm is important in maintaining homeostatic control through glucocorticoid‐receptor (GR)‐dependent transcription regulation that rapidly responds to circulating hormone levels. Constant glucocorticoid exposure can result in continuous transcription, aberrant mRNA accumulation and abnormal protein levels. GR regulation of transcription programmes is highly cell and tissue specific, binding to distinct genomic loci in different cellular contexts. GR also interacts with a large cohort of DNA‐binding factors with cell‐specific interactions. The relevance of kinetic patterns of GR‐dependent gene expression in vivo is not yet fully elucidated. However, given that GR gene variants are associated with cardiovascular disease, it is possible that ultradian delivery of glucocorticoid replacement may become important, at least in selected patients.

Section: Glucocorticoid Access To Target Tissuessupporting

confidence: 56%

Section: Hpa Axis Physiologymentioning

confidence: 61%

Cardio‐metabolic consequences of glucocorticoid replacement: relevance of ultradian signalling

Henley

Lightman

2014

“…In man, deconvolution analysis has revealed secretory pulses of cortisol every 80-110 min, [1][2][3][4] which are reflected in the plasma with cortisol peaks approximately every 3 h. 5 This HPA activity is tightly controlled via a feedforward/ feedback system with natural inbuilt delays via signalling within the pituitary and adrenal glands 6 with ACTH pulsatility being absolutely critical for normal adrenal function. 7 Individual pulses of glucocorticoid are transmitted to the tissues 8 and provide an oscillating signal at the cellular level. 9 Pulses of corticosterone/ cortisol induce a pulse of glucocorticoid receptor (GR) binding that then triggers cyclic GR-mediated transcriptional regulation or gene pulsing.…”

Section: Introductionmentioning

confidence: 99%

Subcutaneous pulsatile glucocorticoid replacement therapy

Russell

Durant

Ataya

et al. 2014

SummaryThe glucocorticoid hormone cortisol is released in pulses resulting in a complex and dynamic ultradian rhythm of plasma cortisol that underlies the classical circadian rhythm. These oscillating levels are also seen at the level of tissues such as the brain and trigger pulses of gene activation and downstream signalling. Different patterns of glucocorticoid presentation (constant vs pulsatile) result not only in different patterns of gene regulation but also in different neuroendocrine and behavioural responses. Current ‘optimal’ glucocorticoid replacement therapy results in smooth hormone blood levels and does not replicate physiological pulsatile cortisol secretion. Validation of a novel portable pulsatile continuous subcutaneous delivery system in healthy volunteers under dexamethasone and metyrapone suppression. Pulsatile subcutaneous hydrocortisone more closely replicates physiological circadian and ultradian rhythmicity.

“…Subcutaneous interstitial fluid samples for measurement of free cortisol 28 were obtained at 20-minute intervals over 24 hours by microdialysis. A linear microdialysis catheter (Linton, Norfolk, UK) was inserted subcutaneously into the interstitial compartment of the anterior abdominal wall and collected via a novel, miniaturized, portable collection device as described by Bhake et al 15 Serum was separated immediately and stored at −80°C for later laboratory analysis. Clinical outcomes including maternal booking BMI, gestation at delivery, birthweight and offspring gender were extracted from medical records.…”

Section: Participants Attended Study Visits At the Edinburgh Clinicalmentioning

confidence: 99%

Pulsatility of glucocorticoid hormones in pregnancy: Changes with gestation and obesity

Stirrat

Walker

Stryjakowska

et al. 2018

SummaryObjectiveHypothalamic‐pituitary‐adrenal axis (HPA) activity is decreased in obese pregnancy and associates with increased foetal size. Pulsatile release of glucocorticoid hormones regulates their action in target tissues. Glucocorticoids are essential for normal foetal growth, but little is known about glucocorticoid pulsatility in pregnancy. We aimed to investigate the ultradian rhythm of glucocorticoid secretion during obese and lean pregnancy and nonpregnancy.DesignSerum cortisol, cortisone, corticosterone and 11‐dehydrocorticosterone were measured by LC‐MS/MS from samples obtained at 10‐minute intervals between 08.00‐11.00 hours and 16.00‐19.00 hours, from 8 lean (BMI <25 kg/m2) and 7 obese (BMI > 35 kg/m2) pregnant women between 16‐24 weeks gestation and again at 30‐36 weeks), and nonpregnant controls (lean n = 3, obese n = 4) during the luteal phase of their menstrual cycle. Interstitial fluid cortisol was measured by ELISA, from samples obtained using a portable microdialysis and automated collection device at 20‐minute intervals over 24 hours.ResultsSerum cortisol AUC, highest peak and lowest trough increased significantly with gestation in lean and obese pregnant compared with nonpregnant subjects. Pulsatility of cortisol was detected in interstitial fluid. In pregnant subjects, interstitial fluid pulse frequency was significantly lower with advancing gestation in obese, but not in lean.ConclusionsWe demonstrate cortisol pulsatility in interstitial fluid. Pulse frequency is altered with increased gestation and BMI. This may be a novel mechanism to explain decreased HPA activity in obese pregnancy.