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Stafford L. Lightman - One of the best experts on this subject based on the ideXlab platform.
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circadian and Ultradian glucocorticoid Rhythmicity implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis
Frontiers in Neuroendocrinology, 2016Co-Authors: Carlos P Fitzsimons, M Schouten, Onno C Meijer, J Herbert, Paul J. Lucassen, Stafford L. LightmanAbstract:Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian Rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free hormone. Although only the free fraction is biologically active, surprisingly little is known about the Rhythms of free glucocorticoid hormones. We used single-probe microdialysis to measure directly the free corticosterone levels in the blood of freely behaving rats. Free corticosterone in the blood shows a distinct circadian and Ultradian Rhythm with a pulse frequency of approximately one pulse per hour together with an increase in hormone levels and pulse height toward the active phase of the light/dark cycle. Similar Rhythms were also evident in the subcutaneous tissue, demonstrating that free corticosterone Rhythms are transferred from the blood into peripheral target tissues. Furthermore, in a dual-probe microdialysis study, we demonstrated that the circadian and Ultradian Rhythms of free corticosterone in the blood and the subcutaneous tissue were highly synchronized. Moreover, free corticosterone Rhythms were also synchronous between the blood and the hippocampus. These data demonstrate for the first time an Ultradian Rhythm of free corticosterone in the blood that translates into synchronized Rhythms of free glucocorticoid hormone in peripheral and central tissues. The maintenance of Ultradian Rhythms across tissue barriers in both the periphery and the brain has important implications for research into aberrant biological Rhythms in disease and for the development of improved protocols for glucocorticoid therapy.
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role of cortisol Ultradian pulsatility in human pregnancy a case control study
The Lancet, 2016Co-Authors: Laura I Stirrat, Stafford L. Lightman, Jamie J Walker, Jane E Norman, Brian R Walker, Rebecca M ReynoldsAbstract:Abstract Background Cortisol concentrations follow an Ultradian Rhythm, and these hormone pulses are an important factor governing gene transcription in target tissue. The maternal hypothalamic–pituitary–adrenal axis undergoes dramatic activation during pregnancy with resultant increased circulating cortisol. However, little is known about changes that might occur in pulsatility during this period. We tested our hypothesis that pulse frequency and amplitude are altered during pregnancy. Methods Study visits were at the Edinburgh Royal Infirmary. We recruited eligible women aged 16–45 years with body-mass index of less than 25 kg/m 2 . Exclusion criteria were diabetes, smoking, and use of glucocorticoid therapy or hormonal contraception. Cortisol was measured by ELISA in serum obtained every 10 min for 6 h from five healthy pregnant women (16–24 weeks' gestation [P1] and 30–36 weeks' [P2]), and from three non-pregnant controls [NP]) during the luteal phase of the menstrual cycle. Women gave written, informed consent, and ethics approval was given by the local research ethics committee. Data are given as mean (SD). Findings Fasting serum cortisol, pulse frequency, and pulse amplitude were all significantly higher in pregnancy than in non-pregnancy (all p Interpretation We show that in normal human pregnancy, increased frequency and amplitude of cortisol pulsatility might be a novel mechanism underlying pregnancy complications related to cortisol exposure such as intrauterine growth restriction. Future studies will investigate whether the pulsatility of bioavailable cortisol in peripheral tissue is altered, and characterise the Ultradian Rhythm of cortisol in high-risk pregnancy groups. Funding Tommy's.
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dynamics of adrenal glucocorticoid steroidogenesis in health and disease
Molecular and Cellular Endocrinology, 2015Co-Authors: Francesca Spiga, Stafford L. LightmanAbstract:The activity of the hypothalamic–pituitary–adrenal (HPA) axis is characterized by an Ultradian (pulsatile) pattern of hormone secretion. Pulsatility of glucocorticoids has been found critical for optimal transcriptional, neuroendocrine and behavioral responses. This review will focus on the mechanisms underlying the origin of the glucocorticoid Ultradian Rhythm. Our recent research shows that the Ultradian Rhythm of glucocorticoids depends on highly dynamic processes within adrenocortical steroidogenic cells. Furthermore, we have evidence that disruption of these dynamics leads to abnormal glucocorticoid secretion observed in disease and critical illness in both humans and rats.
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Subcutaneous pulsatile glucocorticoid replacement therapy
Clinical Endocrinology, 2014Co-Authors: Georgina M Russell, C. Durant, Alia F. Ataya, Chrysoula Papastathi, Ragini Bhake, Wolfram Woltersdorf, Stafford L. LightmanAbstract:The 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.
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cardio metabolic consequences of glucocorticoid replacement relevance of Ultradian signalling
Clinical Endocrinology, 2014Co-Authors: David Henley, Stafford L. LightmanAbstract: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.
Astrid C E Linthorst - One of the best experts on this subject based on the ideXlab platform.
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automated 24 hours sampling of subcutaneous tissue free cortisol in humans
Journal of Medical Engineering & Technology, 2013Co-Authors: Ragini Bhake, Astrid C E Linthorst, J A Leendertz, Stafford L. LightmanAbstract:AbstractHormonal systems are major regulators of metabolic and cognitive function and many of these, including the critical stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, release their constituent hormones in a circadian manner. This circadian Rhythmicity is made up from an underlying approximate hourly Ultradian Rhythm. In order to understand the importance of both circadian and Ultradian Rhythms in man it is important to be able to carry out multiple sampling studies over extended periods in a subject’s home setting, which is the most meaningful physiological setting for homeostatically important hormones. This study has developed a novel automated sampling system that, when used in combination with a microdialysis system, collects timed samples of microdialysis fluid over a full 24 h in individuals going about their normal everyday activity. The apparatus has the capacity to provide sufficient sample volumes to measure changes in hormone concentration over 24 h, including the important pe...
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the Ultradian and circadian Rhythms of free corticosterone in the brain are not affected by gender an in vivo microdialysis study in wistar rats
Journal of Neuroendocrinology, 2009Co-Authors: Sk Droste, Liesbeth De Groote, Johannes M. H. M. Reul, Stafford L. Lightman, Astrid C E LinthorstAbstract:: Recently, we described that free corticosterone levels in the brain of male Wistar rats, as assessed by in vivo microdialysis, show an Ultradian Rhythm with a pulse frequency of 1.2 pulses/h. To establish whether gender influences brain free corticosterone Rhythms, we studied free corticosterone levels in the female Wistar rat under baseline and stressful conditions using microdialysis in the hippocampus. Analysis of the data with the PULSAR algorithm revealed that hippocampal free corticosterone levels show a clear Ultradian pattern in female rats with a pulse frequency of 1.16+/-0.05 pulses/h between 09.00 h and 21.00 h. Further analysis showed that the pulse amplitude is significantly higher during the late afternoon/early night (15.00-21.00 h) than during the morning/early afternoon (09.00-15.00 h) phase (0.13+/-0.03 versus 0.07+/-0.01 microg/dl, respectively, P 0.05]. Both exposure to a novel environment and forced swim stress increased hippocampal free corticosterone levels. However, the stress-induced rise reached higher levels and was more prolonged after forced swimming (area under the curve: 46.84+/-9.25 and 12.08+/-1.69 arbitrary units for forced swimming and novelty stress respectively, P = 0.01). Importantly, the Ultradian Rhythm was rapidly restored after termination of the stress response. This is the first demonstration that the female rat brain is exposed to free corticosterone levels that follow a circadian as well as an Ultradian pattern and show almost identical pulse characteristics as recently reported in male animals. These observations are of significance for further investigations into the dynamics of glucocorticoid action in the brain of both genders.
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corticosterone levels in the brain show a distinct Ultradian Rhythm but a delayed response to forced swim stress
Endocrinology, 2008Co-Authors: Susanne K. Droste, Stafford L. Lightman, Lotte De Groote, Helen C. Atkinson, J M H M Reul, Astrid C E LinthorstAbstract:Circulating corticosterone levels show an Ultradian Rhythm resulting from the pulsatile release of glucocorticoid hormone by the adrenal cortex. Because the pattern of hormone availability to corticosteroid receptors is of functional significance, it is important to determine whether there is also a pulsatile pattern of corticosterone concentration within target tissues such as the brain. Furthermore, it is unclear whether measurements of plasma corticosterone levels accurately reflect corticosterone levels in the brain. Given that the hippocampus is a principal site of glucocorticoid action, we investigated in male rats hippocampal extracellular corticosterone concentrations under baseline and stress conditions using rapid-sampling in vivo microdialysis. We found that hippocampal extracellular corticosterone concentrations show a distinct circadian and Ultradian Rhythm. The PULSAR algorithm revealed that the pulse frequency of hippocampal corticosterone is 1.03 +/- 0.07 pulses/h between 0900 and 1500 h and is significantly higher between 1500 and 2100 h (1.31 +/- 0.05). The hippocampal corticosterone response to stress is stressor dependent but resumes a normal Ultradian pattern rapidly after the termination of the stress response. Similar observations were made in the caudate putamen. Importantly, simultaneous measurements of plasma and hippocampal glucocorticoid levels showed that under stress conditions corticosterone in the brain peaks 20 min later than in plasma but clears concurrently, resulting in a smaller exposure of the brain to stress-induced hormone than would be predicted by plasma hormone concentrations. These data are the first to demonstrate that the Ultradian Rhythm of corticosterone is maintained over the blood-brain barrier and that tissue responses cannot be reliably predicted from the measurement of plasma corticosterone levels.
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Corticosterone levels in the brain show a distinct Ultradian Rhythm but a delayed response to forced swim stress.
Endocrinology, 2008Co-Authors: Susanne K. Droste, Johannes M. H. M. Reul, Stafford L. Lightman, Lotte De Groote, Helen C. Atkinson, Astrid C E LinthorstAbstract:Circulating corticosterone levels show an Ultradian Rhythm resulting from the pulsatile release of glucocorticoid hormone by the adrenal cortex. Because the pattern of hormone availability to corticosteroid receptors is of functional significance, it is important to determine whether there is also a pulsatile pattern of corticosterone concentration within target tissues such as the brain. Furthermore, it is unclear whether measurements of plasma corticosterone levels accurately reflect corticosterone levels in the brain. Given that the hippocampus is a principal site of glucocorticoid action, we investigated in male rats hippocampal extracellular corticosterone concentrations under baseline and stress conditions using rapid-sampling in vivo microdialysis. We found that hippocampal extracellular corticosterone concentrations show a distinct circadian and Ultradian Rhythm. The PULSAR algorithm revealed that the pulse frequency of hippocampal corticosterone is 1.03 ± 0.07 pulses/h between 0900 and 1500 h and...
Elizabeth B. Klerman - One of the best experts on this subject based on the ideXlab platform.
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arousal state feedback as a potential physiological generator of the Ultradian rem nrem sleep cycle
Journal of Theoretical Biology, 2013Co-Authors: Andrew J. K. Phillips, P.a. Robinson, Elizabeth B. KlermanAbstract:Abstract Human sleep episodes are characterized by an approximately 90-min Ultradian oscillation between rapid eye movement (REM) and non-REM (NREM) sleep stages. The source of this oscillation is not known. Pacemaker mechanisms for this Rhythm have been proposed, such as a reciprocal interaction network, but these fail to account for documented homeostatic regulation of both sleep stages. Here, two candidate mechanisms are investigated using a simple model that has stable states corresponding to Wake, REM sleep, and NREM sleep. Unlike other models of the Ultradian Rhythm, this model of sleep dynamics does not include an Ultradian pacemaker, nor does it invoke a hypothetical homeostatic process that exists purely to drive Ultradian Rhythms. Instead, only two inputs are included: the homeostatic drive for Sleep and the circadian drive for Wake. These two inputs have been the basis for the most influential Sleep/Wake models, but have not previously been identified as possible Ultradian Rhythm generators. Using the model, realistic Ultradian Rhythms are generated by arousal state feedback to either the homeostatic or circadian drive. For the proposed ‘homeostatic mechanism’, homeostatic pressure increases in Wake and REM sleep, and decreases in NREM sleep. For the proposed ‘circadian mechanism’, the circadian drive is up-regulated in Wake and REM sleep, and is down-regulated in NREM sleep. The two mechanisms are complementary in the features they capture. The homeostatic mechanism reproduces experimentally observed rebounds in NREM sleep duration and intensity following total sleep deprivation, and rebounds in both NREM sleep intensity and REM sleep duration following selective REM sleep deprivation. The circadian mechanism does not reproduce sleep state rebounds, but more accurately reproduces the temporal patterns observed in a normal night of sleep. These findings have important implications in terms of sleep physiology and they provide a parsimonious explanation for the observed Ultradian Rhythm of REM/NREM sleep.
David Henley - One of the best experts on this subject based on the ideXlab platform.
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cardio metabolic consequences of glucocorticoid replacement relevance of Ultradian signalling
Clinical Endocrinology, 2014Co-Authors: David Henley, Stafford L. LightmanAbstract: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.
F Kippert - One of the best experts on this subject based on the ideXlab platform.
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Intracellular coordination by the Ultradian clock.
Cell Biology International, 1993Co-Authors: F KippertAbstract:The time structure of a biological system is at least as intricate as its spatial structure. Whereas we have detailed information about the latter, our understanding of the former is still rudimentary. As techniques for monitoring intracellular processes continuously in single cells become more refined, it becomes increasingly evident that periodic behaviour abounds in all time domains. Timekeeping is essential for synchronization and coordination of intracellular processes. The presence of a temperature-compensated oscillator provides such a timer. The coupled outputs (epigenetic oscillations) of this Ultradian clock constitute a special class of Ultradian Rhythm. These are undamped and endogenously driven by a device which shows biochemical properties characteristic of transcriptional and translational elements. Energy-yielding processes, protein turnover, motility, and the timing of the cell division cycle processes, are all controlled by the Ultradian clock. Different periods 30 min-4h characterize different species.
