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Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

This study assessed pasireotide, a somatostatin-receptor–binding analogue, at two dose levels for the treatment of Cushing's disease. The median urinary free cortisol level decreased by about 50% by month 2 and remained stable in the higher-dose and lower-dose groups. Cushing's disease is a rare disorder of chronic hypercortisolism due to a corticotropin-secreting pituitary adenoma. The disorder is associated with central obesity, osteoporosis, arterial hypertension, insulin resistance, glucose intolerance, diabetes mellitus, dyslipidemia, cardiovascular disease, and increased mortality. 1 – 5 Transsphenoidal surgery is the primary therapy in most patients, with remission rates of 65 to 90% when an expert pituitary surgeon operates. 6 However, remission definitions vary, and relapse occurs in up to 30% of patients. Second-line options include repeat pituitary surgery, radiation therapy, bilateral adrenalectomy, and medical therapy. However, current medical treatments have not been tested in large prospective, randomized trials. Corticotroph . . .

Short sleep duration and decreased sleep quality are emerging risk factors for obesity and its associated morbidities. Chronotype, an attribute that reflects individual preferences in the timing of sleep and other behaviors, is a continuum from morningness to eveningness. The importance of chronotype in relation to obesity is mostly unknown. Evening types tend to have unhealthy eating habits and suffer from psychological problems more frequently than Morning types, thus we hypothesized that eveningness may affect health parameters in a cohort of obese individuals reporting sleeping less than 6.5 hours per night. BASELINE DATA FROM OBESE (BMI: 38.5±6.4 kg/m(2)) and short sleeping (5.8±0.8 h/night by actigraphy) participants (n = 119) of the Sleep Extension Study were analyzed (www.ClinicalTrials.gov, identifier NCT00261898). Assessments included the Horne and Ostberg Morningness-Eveningness questionnaire, a three-day dietary intake diary, a 14-day sleep diary, 14 days of actigraphy, and measurements of sleep apnea. Twenty-four hour urinary free cortisol, 24 h urinary norepinephrine and epinephrine levels, morning plasma ACTH and serum cortisol, fasting glucose and insulin, and lipid parameters were determined. Eveningness was associated with eating later in the day on both working and non-working days. Progression towards eveningness was associated with an increase in BMI, resting heart rate, food portion size, and a decrease in the number of eating occasions and HDL-cholesterol. Evening types had overtly higher 24 h urinary epinephrine and morning plasma ACTH levels, and higher morning resting heart rate than Morning types. In addition, Evening types more often had sleep apnea, independent of BMI or neck circumference. Eveningness was associated with eating later and a tendency towards fewer and larger meals and lower HDL-cholesterol levels. In addition, Evening types had more sleep apnea and higher stress hormones. Thus, eveningness in obese, chronically sleep-deprived individuals compounds the cardiovascular risk associated with obesity.

Stress and recovery from stress significantly affect interactions between the central nervous system, endocrine pathways and the immune system. However, the influence of acute stress on circulating immune-endocrine mediators in humans is not well known. Using a double-blind, randomized study design, we administered a CO 2 stress test to n  = 143 participants to identify the effects of acute stress and recovery from stress, on serum levels of several mediators with immune function (IL-6, TNF-α, leptin and somatostatin), as well as on noradrenaline and two hypothalamic–pituitary–adrenal axis hormones (ACTH and cortisol). Moreover, during a 1 h-recovery period, we repeatedly measured these serum parameters and administered an auditory mood-induction protocol with positive music and a neutral control stimulus. The acute stress elicited increases in noradrenaline, ACTH, cortisol, IL-6 and leptin levels. Noradrenaline and ACTH exhibited the fastest and strongest stress responses, followed by cortisol, IL-6 and leptin. The music intervention was associated with more positive mood and stronger cortisol responses to the acute stressor in the music group. Our data show that acute (CO 2 ) stress affects endocrine, immune and metabolic functions in humans and they show that mood plays a causal role in the modulation of responses to acute stress.

Purpose Evidence is growing that high salt intake is an independent risk factor for obesity, but the mechanisms are unknown. Our novel working hypothesis is that high salt intake drives cortisol production, which in turn, drives obesity. The current study aimed to demonstrate an acute cortisol response following a single high salt meal. Methods Eight participants (age 30.5 ± 9.8 years [mean ± SD], 50% female), consumed high salt (3.82 g; 1529 mg sodium) and low salt (0.02 g; 9 mg sodium) meals in a randomized cross-over design. Results Urinary and salivary cortisol and plasma adrenocorticotropic hormone (ACTH) demonstrated order effects. When high salt was given second, there was a peak above baseline for urinary cortisol (26.3%), salivary cortisol (9.4%) and plasma ACTH (4.1%) followed by a significant decline in each hormone (treatment*time, F[9, 18] = 2.641, p = 0.038, partial η 2  = 0.569; treatment*time, F[12, 24] = 2.668, p = 0.020, partial η 2  = 0.572; treatment*time, F[12, 24] = 2.580, p = 0.023, partial η 2  = 0.563, respectively), but not when high salt was given first (p > 0.05 for all). Conclusion These intriguing findings provide partial support for our hypothesis and support a need for further research to elucidate the role of high salt intake in cortisol production and, in turn, in the aetiology of obesity. Trial registration number ACTRN12623000490673; date of registration 12/05/2023; retrospectively registered.

Abstract Study Objectives: Severe sleep restriction results in elevated evening cortisol levels. We examined whether this relative hypercortisolism is associated with alterations in the pituitary–adrenocortical response to evening corticotropin-releasing hormone (CRH) stimulation. Methods: Eleven subjects participated in 2 sessions (2 nights of 10 hours vs. 4 hours in bed) in randomized order. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 09:00 to 24:00 for adrenocorticotropic hormone (ACTH) and cortisol measurements, and perceived stress was assessed hourly. Ovine CRH was injected at 18:00 (1 µg/kg body weight). Results: Prior to CRH injection, baseline ACTH, but not cortisol, levels were elevated after sleep restriction. Relative to the well-rested condition, sleep restriction resulted in a 27% decrease in overall ACTH response to CRH (estimated by the incremental area under the curve from 18:00 to 24:00; p = .002) while the cortisol response was decreased by 21% (p = .083). Further, the magnitude of these decreases was correlated with the individual amount of sleep loss (ACTH: r Sp = −0.65, p = .032; cortisol: r Sp = −0.71, p = .015). The acute post-CRH increment of cortisol was reduced (p = .002) without changes in ACTH reactivity, suggesting decreased adrenal sensitivity. The rate of decline from peak post-injection levels was reduced for cortisol (p = .032), but not for ACTH. Scores of perceived stress were unaffected by CRH injection and were low and similar under both sleep conditions. Conclusions: Sleep restriction is associated with a reduction of the overall ACTH and cortisol responses to evening CRH stimulation, and a reduced reactivity and slower recovery of the cortisol response.

Abstract A 12-year-old, male Labrador Retriever was presented because of polyuria, polydipsia, polyphagia, joint pain, and physical features consistent with acromegaly. Circulating insulin-like growth factor-1 (IGF-1) concentration was increased (> 1000 ng/mL; reference interval [RI], 42–449), suggestive of hypersomatotropism. An abnormal low-dose dexamethasone suppression test and increased circulating adrenocorticotropic (ACTH) concentration indicated pituitary-dependent hypercortisolism. Computed tomography identified an enlarged pituitary gland. Treatment with cabergoline initially decreased circulating IGF-1 and ACTH concentrations and urinary cortisol-to-creatinine ratio (UCCR), with a notable reduction in acromegalic physical features. However, 7 months after the start of cabergoline treatment, IGF-1, ACTH, and UCCR had increased again, although pituitary gland size remained stable. Because of worsening joint pain, euthanasia was performed. On necropsy, double immunohistochemistry identified pituitary tumor cells with cytoplasmic co-expression of both growth hormone (GH) and ACTH, consistent with a monomorphic plurihormonal macroadenoma. This case shows that concurrent hypersomatotropism and hypercortisolism can occur in dogs caused by a plurihormonal pituitary adenoma.

IntroductionLabour pain is among the severest pains primigravidae may experience during pregnancy. Failure to address labour pain and anxiety may lead to abnormal labour. Despite the many complementary non-pharmacological approaches to coping with labour pain, the quality of evidence is low and best approaches are not established. This study protocol describes a proposed investigation of the effects of a combination of breathing exercises, foot reflexology and back massage (BRM) on the labour experiences of primigravidae.Methods and analysisThis randomised controlled trial will involve an intervention group receiving BRM and standard labour care, and a control group receiving only standard labour care. Primigravidae of 26–34 weeks of gestation without chronic diseases or pregnancy-related complications will be recruited from antenatal clinics. Eligible and consenting patients will be randomly allocated to the intervention or the control group stratified by intramuscular pethidine use. The BRM intervention will be delivered by a trained massage therapist. The primary outcomes of labour pain and anxiety will be measured during and after uterine contractions at baseline (cervical dilatation 6 cm) and post BRM hourly for 2 hours. The secondary outcomes include maternal stress hormone (adrenocorticotropic hormone, cortisol and oxytocin) levels, maternal vital signs (V/S), fetal heart rate, labour duration, Apgar scores and maternal satisfaction. The sample size is estimated based on the between-group difference of 0.6 in anxiety scores, 95% power and 5% α error, which yields a required sample size of 154 (77 in each group) accounting for a 20% attrition rate. The between-group and within-group outcome measures will be examined with mixed-effect regression models, time series analyses and paired t-test or equivalent non-parametric tests, respectively.Ethics and disseminationEthical approval was obtained from the Ethical Committee for Research Involving Human Subjects of the Ministry of Health in the Saudi Arabia (H-02-K-076-0319-109) on 14 April 2019, and from the Ethics Committee for Research Involving Human Subjects (JKEUPM) Universiti Putra Malaysia on 23 October 2019, reference number: JKEUPM-2019–169. Written informed consent will be obtained from all participants. Results from this trial will be presented at regional, national and international conferences and published in indexed journals.Trial registration numberISRCTN87414969, registered 3 May 2019.

Objective An acute severe stress response associated with major surgery can adversely affect the inflammatory and hormonal responses. We hypothesised that total intravenous anaesthesia (TIVA) combined with thoracic epidural anaesthesia and analgesia (TEA) attenuates the stress response and postoperative pain in patients undergoing radical oesophagectomy. Methods Forty patients scheduled for elective radical oesophagectomy were randomly assigned to one of two groups: TIVA or TIVA+TEA. The plasma levels of stress hormones and cytokines, consumption of fentanyl, postoperative visual analogue scale (VAS) scores within 48 hours, and extubation time were assessed. Results The plasma levels of interleukin-6, norepinephrine, cortisol, and adrenocorticotropic hormone at 3 hours after the beginning of surgery were significantly higher in the TIVA group than TIVA+TEA group. The plasma level of interleukin-10 at 3 hours after the beginning of surgery was significantly lower in the TIVA group than TIVA+TEA group. The consumption of fentanyl was significantly greater, VAS scores were significantly higher, and extubation time was significantly longer in the TIVA group than TIVA+TEA group. Conclusions The findings suggest that combination of TIVA and TEA may attenuate the intraoperative stress response and postoperative pain in patients undergoing radical oesophagectomy.

Rationale Use of etomidate in the critically ill is controversial due to its links with an inadequate response to corticotropin and potential for excess mortality. In a septic shock population, we tested the hypotheses that etomidate administration induces more non-responders to corticotropin and increases mortality and that hydrocortisone treatment decreases mortality in patients receiving etomidate. Methods An a-priori sub-study of the CORTICUS multi-centre, randomised, double-blind, placebo-controlled trial of hydrocortisone in septic shock. Use and timing of etomidate administration were collected. Endpoints were corticotropin response and all-cause 28-day mortality in patients receiving etomidate. Measurements and main results Five hundred patients were recruited, of whom 499 were analysable; 96 (19.2%) were administered etomidate within the 72 h prior to inclusion. The proportion of non-responders to corticotropin was significantly higher in patients who were given etomidate in the 72 h before trial inclusion than in other patients (61.0 vs. 44.6%, P  = 0.004). Etomidate therapy was associated with a higher 28-day mortality in univariate analysis ( P  = 0.02) and after correction for severity of illness (42.7 vs. 30.5%; P  = 0.06 and P  = 0.03) in our two multi-variant models. Hydrocortisone administration did not change the mortality of patients receiving etomidate (45 vs. 40%). Conclusions The use of bolus dose etomidate in the 72 h before study inclusion is associated with an increased incidence of inadequate response to corticotropin, but is also likely to be associated with an increase in mortality. We recommend clinicians demonstrate extreme caution in the use of etomidate in critically ill patients with septic shock.