Cortisol Circadian Rhythm Research Articles

Circadian rhythm of glucocorticoid administration entrains clock genes in immune cells: A DREAM trial ancillary study

Conventional glucocorticoid (GC) therapy in adrenal insufficiency (AI) does not fully mimic the endogenous cortisol circadian rhythm, and this may adversely affect long-term health. In the recent DREAM trial (Dual Release Hydrocortisone vs. Conventional Glucocorticoid Replacement in Hypocortisolism) patients with AI showed an atypical inflammation, with more classic monocytes and impaired innate immune responses. Treatment with once-daily modified-release hydrocortisone improved circulating immune cell profiles and reduced infections compared to standard GC replacement therapy.

Circadian Rhythm Disruption and Sepsis in Severe Trauma Patients.

Circadian rhythms are important regulators of immune functions. Admission to an intensive care unit may impact molecular clock activity and host response. Our objective was to assess and compare the immune circadian rhythms in trauma patients who develop and in those who do not develop sepsis. Blood samples were collected from severe trauma patients within 4 days after admission, with collections taking place every 4 h over a 24-h period. Cortisol and cytokines were measured with immunoassays. Whole-blood expression of 3 clock genes (Bmal1, Per2, and Per3) was studied by reverse transcription quantitative polymerase chain reaction. Neutrophils, monocytes, and lymphocytes were analyzed by flow cytometry. Patients with and without sepsis were compared with the cosinor mixed model to estimate mesors, amplitudes, and acrophases. Thirty-eight patients were enrolled in the study, and 13 developed at least 1 septic episode. The septic patients had higher levels of cortisol than the nonseptic patients (mesor at 489 nmol/L vs. 405 nmol/L, P < 0.05) and delayed acrophases (22 h vs. 15 h, P < 0.05). They also had lower lymphocyte counts (mesor at 785 vs. 1,012 cells/μL, P < 0.05), higher neutrophil counts (mesor at 7,648 vs. 7,001 cells/μL, P < 0.05), and monocyte counts (mesor at 579 vs. 473 cells/μL, P < 0.05) than the nonseptic patients. Although no amplitude difference was identified, the acrophases were significantly different between the 2 groups for lymphocytes, interleukin 10 and tumor necrosis factor. We demonstrated that all trauma patients had impaired circadian rhythms of cortisol, cytokines, leukocytes, and clock genes. Early circadian disruption was associated with the occurrence of sepsis and might be a marker of sepsis severity.

The Biochemical Fundamental Biomarkers of The Status of Health Against Cancer and Cardiovascular Diseases: Presence of Cortisol and Melatonin Circadian Rhythms, Normal Blood Levels of Fatty Acid Amide Hydrolase (FAAH) and Transforming Growth Factor-Beta (TGF-Beta), and Normal Values of Lymphocyte-to-Monocyte Ratio (LMR) and Atrial Natriuretic Peptide (ANP)-to-Endothelin-1 (Et-1) Ratio

The future of laboratory analyses would require the identification of clinical parameters involving the main integrative biological functions including neuroendocrine, immune and cardiovascular systems, and capable of predicting the evidence of metabolic alterations and the possible occurrence of systemic diseases

SUN-LB063 Peripheral Clock System Circadian Imbalance in Cushing's Disease

Context: Glucocorticoid circulating levels in healthy individuals oscillate according to a circadian rhythm, influenced by the molecular system of clock genes. In Cushing's syndrome, there is an altered cortisol daily rhythm, which can be associated to disruption of clock genes rhythmic expression. Objective: Evaluate the expression of clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1, PER2, PER3) in leukocytes of healthy individuals and in patients with Cushing's disease (CD). Design and Participants: Case-control study with female Cushing’s disease patients (n=12) and controls (n=13). Main Outcome Measures: Participants underwent salivary cortisol measurement at 0900h and 2300h. Peripheral blood samples were obtained at 0900h, 1300h, 1700h and 2300h for assessing clock genes expression by qPCR. Gene expression profiles were evaluated by Cosinor analysis method. Results: In healthy controls, there was a circadian variation of the mRNA expression of CLOCK (p<0.01), BMAL1 (p=0.02), CRY1 (p=0.02), PER2 (p<0.01), and PER3 (p<0.01), while no circadian rhythm of PER1, and CRY2 was observed. The expression of PER2 and PER3 genes in control leukocytes showed a late afternoon acrophase at 17.5h (14.9-20.1) and 19.5h (17.9-21.0), respectively, similar to CLOCK gene acrophase at 20.2h (19.0-21.4) while CRY1 showed night acrophase at 22.4h (20.1-24.6) as well as BMAL1 acrophase at 23.6h (21.7-0.49), respectively. In Cushing´s Disease patients, there was a loss of the pattern of clock genes circadian rhythmicity, in concomitance with the loss of cortisol circadian rhythm. One exception was CRY2, which presented a circadian variation (p<0.01), with acrophase during the dark phase at 0.5h (22.5-2.6). Conclusions: Our data suggest that hypercortisolism leads to dysregulation of circadian clock genes expression in Cushing's disease. CRY2 higher expression at night outlines its putative role in the cortisol circadian rhythm disruption. Although the role of clock genes dysregulation in the pathogenesis of Cushing's disease metabolic derangements is still not completely established, it is possible that it synergistically contributes to hypercortisolism to the severity of metabolic features of Cushing's disease. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SAT-370 Clinical Characteristics and Metabolic Features of Patients with Subclinical Cushing's Syndrome and Its Correlation with Cortisol Level

Objective The aim of this study was to examine the clinical characteristics and metabolic features of subclinical Cushing’s syndrome (SCS), and to investigate the association of the cortisol level with the metabolic features in patients with SCS. Methods 52 patients with non-functioning adenoma (NFA), 45 patients diagnosed with SCS and 61 patients with overt adrenal Cushing’s syndrome (CS) participated in this study. Clinical data and endocrine function of the patients as well as histological findings were all reviewed. Results 1) The average age of patients with SCS was 52.56±13.25 years, 68.9% patients were female. No difference was detected in age, gender and BMI between patients with SCS and NFA (P > 0.05). Compared to patients with SCS, CS was more common in younger and female patients (43.90±13.83, 83.6%). The prevalence of diabetes mellitus, hypertension, and osteopenia/osteoporosis were significantly higher in patients with SCS compared to those with nonfunctioning tumors (57.8% vs 32.7%, 73.3% vs 53.8%, 41.2% vs 19.2%; P < 0.05). No difference was detected between SCS and CS patients in the prevalence of metabolic disease. 2) Compared to patients with NFA, plasma ACTH level is lower in patients with SCS (P < 0.05). Whereas, the midnight cortisol level and cortisol level after 1mg overnight dexamethasone suppression is higher in SCS than NFA (P < 0.05). No difference was detected between SCS and NFA in 24h urinary free cortisol and early-morning cortisol level (P > 0.05). Compared to SCS, the derangement of ACTH-cortisol axis is more prominent in CS patients demonstrated as suppressed plasma ACTH level and elevated plasma and 24h urine cortisol level. 3) In SCS cohort, SBP, FBG and HbA1c correlated positively with 24h urinary free cortisol (r =0.394, P =0.021; r =0.426, P =0.011, r =0.398, P =0.015; respectively). When controlling for age and gender, the correlation was also significant (P < 0.05). No correlations were found between BMI, TG, HDL and 24h urinary free cortisol. Conclusion Patients with SCS showed slight derangement of the circadian rhythm of cortisol and cortisol excess, and increased prevalence of metabolic disease. Furthermore, the cortisol level was related closely to blood glucose and blood pressure. Our findings might suggestive in therapeutic decision making (conservative vs surgery approach) in patients with SCS.

A successful pregnancy in a patient with secondary hypertension caused by adrenal adenoma: a case report

BackgroundSecondary hypertension is a rare complication in pregnancy that causes poor outcomes, such as preeclampsia, premature delivery, intrauterine growth retardation, stillbirths, spontaneous abortion or intrauterine death. Cushing’s disease caused by an adrenal adenoma is rare during pregnancy and may be overlooked by obstetricians and physicians, but can lead to hypertension, diabetes mellitus and an increased risk of fetal and maternal morbidity. Approximately 200 cases have been reported in the literature. Here, we report the successful management of a pregnant patient with Cushing’s syndrome due to an adrenal adenoma.Case presentationThe 35-year-old Chinese female had no individual or family medical history of hypertension, and did not exhibit chronic kidney disease, diabetes mellitus, autoimmune and common endocrine diseases. Her blood pressure was elevated from the 16th week of gestation and was not controlled by 30 mg nifedipine twice a day. Examination in our department revealed her 24 h urinary free cortisol (24 h UFC) level was 1684.3 μg/24 h (normal range: 20.26–127.55 μg/24 h) and plasma adrenocorticotropic hormone was < 1.00 ng/L in three independent measurements (normal range: 5–78 ng/L). Ultrasonography demonstrated a mass (2.9 cm × 2.8 cm) in the right side of the adrenal gland. Magnetic resonance imaging without contrast showed a 3.2 cm diameter mass in the right-side of the adrenal gland. Other medical tests were normal. Laparoscopic adrenalectomy was performed at the 26th week of gestation by a urological surgeon in the West China Hospital. Histopathology revealed an adrenocortical adenoma. After surgery, the patient accepted glucocorticoid replacement therapy. The remaining trimester continued without complication and her blood pressure was normal at the 32nd week of gestation without antihypertensive therapy. The patient gave birth to a healthy boy at the 40th week of gestation.ConclusionsCushing’s syndrome caused by adrenal adenoma is rare during pregnancy. This unique case suggested that analysis of the UFC level and circadian rhythm of plasma cortisol provides a suitable strategy to diagnose Cushing’s syndrome during pregnancy. Laparoscopic surgical resection in the second trimester provides a reasonable approach to treat pregnant patients exhibiting Cushing’s syndrome caused by an adrenal adenoma.

The phase of the estrous cycle modifies the endocrine, metabolic and behavior rhythms in ewes

The aim of this study was to compare circadian rhythms of serum cortisol and insulin concentrations, glycemia, glycemia:insulin ratio (GLY:INS), rectal, vaginal and surface (ST) temperatures as well behavioral patterns during the follicular (FOL) and luteal (LUT) phases in ewes. All the variables were measured during both phases of the estrous cycle in 8 West African ewes during a 24 h period. Cortisol concentrations were greater during FOL than LUT (30.9 ± 2.1 ng mL−1 vs 24.1 ± 2.1 ng mL−1; P < 0.01); cosinor analysis revealed also differences in the circadian pattern: while the acrophase of the cortisol secretion during the FOL occurred at 10:00 ± 0:49 h, coinciding with higher environmental temperatures during the LUT was observed at 05:07 ± 0:49 h (P < 0.05). There were no differences in insulin concentrations according to the phase of the estrous cycle (FOL: 43.3 ± 6.6 μg mL−1 vs LUT: 44.9 ± 6.6 μg mL−1); however, insulin secretion varied according to the time of the day (P < 0.01) and showed a strong robustness in both phases of the estrous cycle (>40%), with acrophase occurring at sunset. Glycemia was greater during the FOL than the LUT (69.9 ± 1.1 mg dL−1 vs 63.9 ± 1.1 mg dL−1, respectively; P < 0.01), and varied according to the time of the day (P < 0.05), without interaction between both effects. However, the strength of rhythmicity was <40% during both phases. GLY:INS ratio was greater in FOL than LUT (2.2 ± 0.2 vs 1.8 ± 0.2, respectively; P = 0.04), indicating that the greater glycemia observed during FOL did not trigger the same secretion of INS than during LUT. Rectal and vaginal temperatures, as well as nasal vein, front and neck ST were greater during FOL than during LUT (P < 0.05). There was no circadian rhythm for vaginal temperature but, both rectal temperature and the mean surface temperature showed a strong robustness (>65%). The mesor of the rectal temperature was greater during the FOL than during the LUT (39.2 ± 0.1 °C vs 38.8 ± 0.1 °C, respectively; P < 0.05). Ewes were observed urinating more times during the FOL than during the LUT (7.3 ± 1.5% vs 1.7 ± 1.5%, respectively, P < 0.05). Ewes were observed standing, drinking water and in bipedal position more times during FOL than during the LUT (P = 0.07, P = 0.08 and P = 0.07, respectively). In conclusion, the phase of the estrous cycle affected the secretion and the circadian rhythm of cortisol and in consequence the metabolic activity, thermoregulatory response and behavior pattern in ewes.

Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency.

Adrenal insufficiency is defined as impaired adrenocortical hormone synthesis. According to its source, the deficit is classified as primary (adrenal steroidogenesis impairment), secondary (pituitary adrenocorticotropic hormone deficit) or tertiary (hypothalamic corticotropin-releasing hormone deficit). The management of adrenal insufficiency resides primarily in physiological replacement of glucocorticoid secretion. Standard glucocorticoid therapy is shrouded in several controversies. Along the difficulties arising from the inability to accurately replicate the pulsatile circadian cortisol rhythm, come the uncertainties of dose adjustment and treatment monitoring (absence of reliable biomarkers). Furthermore, side effects of inadequate replacement significantly hinder the quality of life of patients. Therefore, transition to circadian hydrocortisone therapy gains prominence. Recent therapeutic advancements consist of oral hydrocortisone modified-release compounds (immediate, delayed and sustained absorption formulations) or continuous subcutaneous hydrocortisone infusion. In addition to illustrating the current knowledge on conventional glucocorticoid regimens, this review outlines the latest research outcomes. We also describe the management of pediatric patients and suggest a novel strategy for glucocorticoid replacement therapy in adults.

A Clinical Study on the Circadian Rhythm of Salivary Cortisol on Aggressive Periodontitis and Its Correlation with Clinical Parameters using Electrochemiluminescence Immunoassay Method

Periodontal pathologies are gaining importance as there is a clear indication of bi-way control on general homeostasis of an individual. The study of HPA axis in various diseases has proved that there is evident vulnerability existing for any organism when the Cortisol diurnal rhythm is altered. The aim was to compare the diurnal rhythm of salivary cortisol in aggressive periodontitis with control patients. This study also compared various parameters like body mass index (BMI), waist circumference, Hamilton anxiety scale, OHI-S, clinical attachment loss in aggressive periodontitis. 30 control patients were compared against 30 aggressive periodontitis patients in Salivary cortisol diurnal rhythm. It was estimated using the electrochemiluminescence (ECL) method on a 3 point analysis-Soon after waking up, 30 minutes after waking up, 1 hour before sleep to see the diurnal variation in aggressive periodontitis patients. The samples were transferred to CABRI labs to be frozen to -20°C. The analysis was done using Cobas e-411 autoanalyzer by Roche, USA. The average cortisol in aggressive patients was found to be higher compared to control patients and was found to be statistically significant with a p value of 0.012. Control group is moderately skewed left (negative skewness graph) while the aggressive p periodontitis patients showed moderately skewed right (+ve skewness graph). The cortisol awakening response seen in control patients is not observed in aggressive periodontitis. Instead of giving a surge, the cortisol showed a dip in the first 30 minutes followed by a gradual increase in aggressive periodontitis instead of decline as observed in normal patients. The study will focus on the importance of cortisol circadian rhythm on periodontal health allowing the microorganism to create an environment of dysbiosis.

Hair cortisol concentration in a population without hypothalamic-pituitary-adrenal axis disorders.

Measuring hair cortisol seems to be a good alternative to laboratory tests used thus far in routine endocrine diagnostics, primarily because it is independent of the circadian rhythm of cortisol. Due to the average hair growth of 1 cm per month, the results are related to the average blood cortisol levels over the previous weeks, months or years (depending on the length of the hair sample). The aim of this study is an attempt to apply hair cortisol concentration (HCC) measurements to clinical endocrine diagnostics, based on reference cortisol concentrations in the blood in a population without disorders of the hypothalamic-pituitary-adrenal axis (HPA). In the final selection process, 44 patients were enrolled in the study, all with negative interviews regarding disorders of the HPA and with reference levels of cortisol concentration obtained in routine laboratory tests. In the pre-analytic phase, we used 1 cm proximal hair strands cut from the posterior vertex area of the head, followed by the incubation of a 20 mg hair sample in methanol. The final cortisol measurement was done using an enzyme-linked immunosorbent assay (ELISA). The results of HCC ranged from 2 pg/mg up to 51.63 pg/mg. The diurnal decrease in cortisol levels was significantly lower in females than in males (p = 0.031), but we do not consider that difference to be clinically significant. The difference in the HCC between males and females was not statistically significant (p = 0.767). The linear regression coefficient for age was not statistically significant (p = 0.847). Neither the regression coefficients for gender nor the gender and age interactions were statistically significant (p = 0.815). Hair cortisol concentration measurement, unlike other endocrinological tests, gives information about the cortisol concentration in the long-term perspective. The results obtained in this study may be used as a reference for further research aimed at determining normal values of HCC.

Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment.

Background Central adrenal insufficiency (CAI) is characterized by impaired adrenocorticotropin (ACTH) secretion because of a disease or injury to the hypothalamus or the pituitary, leading to a reduced cortisol production. CAI suspicion arises more frequently in patients with pituitary tumors, cranial irradiation/surgery/injury/infections, as well as after exogenous glucocorticoid withdrawal. Nevertheless, a late diagnosis is not uncommon because CAI may present with nonspecific signs or symptoms, as fatigue or hyponatremia. Content The PubMed database was searched (years 1980-2018), using "central adrenal insufficiency" and "ACTH deficiency" as keywords. Subsequently, reference sections of the retrieved articles were searched. Summary Dynamic tests are needed when morning basal cortisol levels are not sufficient to exclude or to confirm CAI. Short Synacthen Test (SST) is the most used, and Endocrine Society's guidelines recommend a cortisol peak >500 nmol/L to exclude CAI. Despite thresholds, understanding the pretest probability of ACTH deficiency (the clinical background of the patient) is essential because the diagnostic accuracy of SST in case of a negative result is suboptimal. Glucocorticoid replacement therapy, able to replicate cortisol circadian rhythm, is required in patients with CAI; fludrocortisone treatment is not necessary. Short-acting glucocorticoid drugs (hydrocortisone or cortisone acetate) are the most used; lower doses than previously used are nowadays recommended to reduce cortisol-related comorbidities. Promising results have been obtained with modified-release hydrocortisone, especially regarding glucose metabolism in patients with primary adrenal insufficiency. Outlook An accurate clinical diagnosis and a careful individualized therapy are mandatory in patients with CAI.

Adrenal Incidentaloma: Picking out the High-Risk Patients.

Patients with adrenal incidentalomas and autonomous cortisol secretion (ACS) have been recognized as a category at risk of developing cardiovascular and metabolic co-morbidities. Considering the increasing number of patients affected by this condition, it is important to perform an accurate subtyping of the patients, in the light of a tailored treatment. This review aims to identify the phenotypic characteristics of patients with adrenal incidentalomas and ACS who are at risk of developing severe cortisol-related co-morbidities. ACS has been associated with severe alteration of the cardiovascular profile, including hypertension, diabetes, and atherosclerosis. Moreover, ACS has been identified as a contributing factor to the development of cardiovascular events and related mortality. Patients with ACS are also at risk of incident bone fractures, which occur in half of the patients independently of the bone mass density, and infectious diseases. Severity and persistence of hypercortisolism are among the main contributing factors for cardiovascular diseases and bone fractures. Moreover, progression of hypercortisolism over time and altered circadian cortisol rhythm seem to be important additional factors. The role of potential novel biomarkers is also discussed in this review.

Does Psychodrama Affect Perceived Stress, Anxiety-Depression Scores and Saliva Cortisol in Patients with Depression?

ObjectiveLittle is known about the effects of psychodrama group therapy on the level of stress, anxiety and depression of the group members, and the biological markers of stress. The aim of this study test cortisol level as a biological reflection of some mental characteristics gained by the psychodrama method in coping with stress. MethodsDepressive patients aged between 18 and 65 years, who diagnosed with depression according to DSM-5, without psychiatric comorbidity, who do not use drugs and were available for psychodrama were enrolled into the study. These patients were evaluated using the Perceived Stress Scale, State-Trait Anxiety Inventory and Beck Depression Inventory. In order to observe the circadian rhythm of cortisol, samples were collected from the participants before lunch, before dinner and before going to sleep on the day before psychodrama and on the 0, 15th, and 30th minutes after awakening in the morning of the psychodrama day; as well as just before and after the psychodrama session. Saliva cortisol level just before the initial session of psychodrama group therapy was compared with the saliva cortisol level just after the last psychodrama session at the end of 16 weeks. ResultsStatistically significant difference was determined between the scores of perceived stress scale, STAI-1, STAI-2, beck depression inventory and salivary cortisol level before and after psychodrama session. There was significant decrease in both the scale scores and salivary cortisol after vs. before psychodrama. ConclusionThis results is important as it shows the biological aspect of clinical improvement. Further studies would provide us with better understanding of the effects of psychodrama group psychotherapy on depressive mood and biological projections by means of short-term and long-term follow-up studies.

Effects of Glucagon-Like Peptide-1 Receptor Agonists on Hypothalamic-Pituitary-Adrenal Axis in Healthy Volunteers.

Recent findings from animal and human studies indicate that glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) modulate stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis, which may have relevant clinical implications. To investigate the influence of GLP-1 RA treatment on HPA axis activity compared with placebo in healthy volunteers. Double-blind, randomized, crossover study. University Hospital Basel, Switzerland. Twenty healthy volunteers. Dulaglutide (Trulicity®) 1.5 mg and placebo (0.9% sodium chloride) were given subcutaneously once weekly for 3 weeks. Twenty-four-hour urinary free cortisol, circadian rhythm of serum and salivary cortisol, cortisol after 1 mg dexamethasone suppression test, and cortisol levels before and after stimulation with ACTH. Urinary free cortisol levels were similar under dulaglutide [median (interquartile range) 240 nmol/L (164, 324)] vs placebo [188 nmol/L (133, 338), P = 0.131]. The circadian rhythm of serum and salivary cortisol were comparable in both groups as were cortisol levels after dexamethasone [dulaglutide 28 nmol/L (22, 47.5) vs placebo 26.5 nmol/L (15.8, 45.5), P = 0.4]. Serum cortisol levels in dulaglutide and placebo treated participants were 522 nmol (388, 710) and 530 nmol/L (394, 747), before (P = 0.6), and 658 nmol/L (604, 810) and 636 nmol/L (512, 910) after ACTH stimulation (P = 0.87). Our results suggest that there is no activation of the HPA axis by long-term GLP-1 RA exposure, particularly dulaglutide, at the medically approved dosage of 1.5 mg once weekly.

Light therapy as a treatment of cancer-related fatigue in (non-)Hodgkin lymphoma survivors (SPARKLE trial): study protocol of a multicenter randomized controlled trial

BackgroundCancer related fatigue (CRF) is one of the most prevalent and distressing long-term complaints reported by (non-) Hodgkin survivors. To date there has been no standard treatment for CRF in this population. A novel and promising approach to treat CRF is exposure to bright white light therapy. Yet, large scale randomized controlled trials testing its efficacy in these patients and research on potential mechanisms is lacking. The objective of the current study is to investigate the efficacy of light therapy as a treatment for CRF and to explore potential mechanisms.Methods/designIn a multicenter, randomized controlled trial we are evaluating the efficacy of two intensities of light therapy in reducing CRF complaints and restrictions caused by CRF in survivors of Hodgkin lymphoma or diffuse large B-cell lymphoma. Secondary outcomes include sleep quality, depression, anxiety, quality of life, cognitive complaints, cancer worries, fatigue catastrophizing, self-efficacy to handle fatigue, biological circadian rhythms of melatonin, cortisol and activity, and biomarkers of inflammation. We will recruit 128 survivors, with fatigue complaints, from academic and general hospitals. Survivors are randomized to either an intervention (exposure to bright white light) or a comparison group (exposure to dim white light). The longitudinal design includes four measurement points at baseline (T0), post-intervention at 3.5 weeks (T1), 3 months post-intervention (T2) and 9 months post-intervention (T3). Each measurement point includes self-reported questionnaires and actigraphy (10 days). T0 and T1 measurements also include collection of blood and saliva samples.DiscussionLight therapy has the potential to be an effective treatment for CRF in cancer survivors. This study will provide insights on its efficacy and potential mechanisms. If proven to be effective, light therapy will provide an easy to deliver, low-cost and low-burden intervention, introducing a new era in the treatment of CRF.Trial registrationThe study is registered at ClinicalTrials.gov on August 8th 2017(NCT03242902).

Chronic intermittent stress exposure and access to grass silage interact differently in their effect on behaviour, gastric health and stress physiology of entire or castrated male growing-finishing pigs

Entire male pigs display more aggressive and sexual behaviour. This might cause a condition of chronic stress and impair their welfare. In order to assess chronic stress in entire and castrated male pigs, as well as effects of providing grass silage as occupational and feed material on behaviour and health, we carried out a 2 × 2 × 2-factorial experiment with 147 growing-finishing pigs. Factors investigated were castration (entire/castrated), chronic intermittent social stress exposure (yes/no) and access to grass silage (yes/no), as well as their interactions. The stress exposure treatment consisted of repeated short-term confrontations and separations. We recorded different behavioural variables, circadian rhythm of salivary cortisol, response to an ACTH (adrenocorticotropic hormone) challenge test, pathological changes in the gastric mucosa and morphology of the intestinal epithelium. Stress exposure caused a decrease in posture changes and head knocks/bites in the home pen. Reference indicators affected by stress exposure did not differ between entire and castrated male pigs, indicating that there is no permanently increased baseline level of stress in entire male pigs. However, entire males responded more pronouncedly to the stress exposure compared to castrated males in terms of posture changes and play behaviour. Pigs provided with grass silage showed more play behaviour and less manipulative behaviours than pigs not receiving grass silage. Stress treated pigs had more hyperkeratosis in the gastric mucosa and gastric ulcers, while offering grass silage reduced such changes. In conclusion, our results indicate that the increased behavioural stress response of entire male pigs might require some adaptations in housing and management of entire male pigs. Gastric ulceration scoring turned out to be a potential post mortem indicator for chronic stress. Finally, providing roughages like grass silage could be a means to positively affect behaviour and gastric health in pigs.

Improved salivary cortisol rhythm with dual-release hydrocortisone

Introduction and AimThe purpose of replacement therapy in adrenal insufficiency (AI) is mimicking endogenous cortisol levels as closely as possible: dual release hydrocortisone (DR-HC) has been introduced to replicate the circadian cortisol rhythm. Multiple daily saliva collections could be used to assess the cortisol rhythm during real life: our aim was to study the salivary cortisol profile in AI.Materials and MethodsWe prospectively evaluated, in an observational study, 18 adult outpatients with AI (11 primary and 7 secondary AI), switched from conventional treatment (conv-HC, 25 mg/day) to the same dose of DR-HC. We collected six samples of saliva in a day, measuring cortisol (F) and cortisone (E) with LC-MS/MS. Forty-three matched healthy subjects served as controls.ResultsF levels were similar in the morning (and higher than controls) in patients treated with conv-HC or DR-HC; otherwise F levels and exposure were lower in the afternoon and evening in patients with DR-HC, achieving a cortisol profile closer to healthy controls. Daily cortisol exposure, measured with area under the curve, was lower with DR-HC. Morning F and E presented sensitivity and specificity >90% to diagnose AI (respectively threshold of 3 and 9.45 nmol/L). Total cholesterol and HbA1c levels reduced with DR-HC.ConclusionsSalivary cortisol daily curve could be used as a new tool to assess the cortisol profiles in patients treated with conv-HC and DR-HC. A lower daily cortisol exposure was achieved with DR-HC (despite the same HC dose), especially in the afternoon-evening.

Circadian Rhythms of Urinary Cortisol Levels Vary Between Individuals in Wild Male Chimpanzees: A Reaction Norm Approach

Investigating the repeatability of trait variation between individuals, that is the amount of individual variation in relation to overall phenotypic variation, indicates an upper level of heritability and reveals whether a given trait may be subject to selection. Labile traits are characterized by high levels of flexibility and consequently low trait repeatability is expected. Indeed, research examining glucocorticoid levels in various non-mammal species found low repeatability scores. However, mammals may be different in this respect as (i) differential maternal care early in life has the potential to prime hypothalamic-pituitary-adrenal axis functioning and (ii) allelic variation affecting hypothalamic-pituitary-adrenal axis functioning has been reported. Individuals often differ from each other in average and/or plastic labile trait expression, two aspects that can be described using a reaction norm approach. Both consistent and flexible reaction norm expression has been argued to serve adaptive purposes, depending on the stability and predictability of environmental conditions. Here we investigated both trait and reaction norm repeatability of urinary cortisol levels in wild adult male chimpanzees. To capture the expression of the circadian urinary cortisol rhythm of individual males over time, urine samples were collected throughout the day. In total data of 30 males collected over a period of 8 years were included in the dataset. No male was sampled over the whole 8-year period however. We found minor levels of trait repeatability but considerable reaction norm repeatability. This implies a minor role of genetic or priming factors on cortisol excretion, but reveals that males differ consistently in average urinary cortisol levels and the shape of the circadian urinary cortisol rhythm. Relating these results to fitness parameters will provide answers to questions on the adaptive value of reaction norm repeatability of this labile hormonal trait in the future.

Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study.

Adrenal insufficiency (AI) requires lifelong glucocorticoid (GC) replacement. Conventional therapies do not mimic the endogenous cortisol circadian rhythm. Clock genes are essential components of the machinery controlling circadian functions and are influenced by GCs. However, clock gene expression has never been investigated in patients with AI. To evaluate the effect of the timing of GC administration on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of patients from the Dual Release Hydrocortisone vs Conventional Glucocorticoid Replacement in Hypocortisolism (DREAM) trial. Outcome assessor-blinded, randomized, active comparator clinical trial. Eighty-nine patients with AI were randomly assigned to continue their multiple daily GC doses or switch to an equivalent dose of once-daily modified-release hydrocortisone and were compared with 25 healthy controls; 65 patients with AI and 18 controls consented to gene expression analysis. Compared with healthy controls, 19 of the 68 genes were found modulated in patients with AI at baseline, 18 of which were restored to control levels 12 weeks after therapy was switched: ARNTL [BMAL] (P = 0.024), CLOCK (P = 0.016), AANAT (P = 0.021), CREB1 (P = 0.010), CREB3 (P = 0.037), MAT2A (P = 0.013); PRKAR1A, PRKAR2A, and PRKCB (all P < 0.010) and PER3, TIMELESS, CAMK2D, MAPK1, SP1, WEE1, CSNK1A1, ONP3, and PRF1 (all P < 0.001). Changes in WEE1, PRF1, and PER3 expression correlated with glycated hemoglobin, inflammatory monocytes, and CD16+ natural killer cells. Patients with AI on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to controls, paralleling the clinical outcomes of the DREAM trial (NCT02277587).

Relationship between salivary cortisol circadian rhythm and body composition in the postmenopausal women of the population cohort OsteoLaus

Relationship between salivary cortisol circadian rhythm and body composition in the postmenopausal women of the population cohort OsteoLaus