Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study

Cortisol exerts a broad anti-inflammatory effect on the immune system. Inflammatory cytokines contribute to the molecular signalling pathways implicated in various autoimmune and inflammatory conditions. However, the mechanisms by which cortisol modulates such signalling pathways remain uncertain. Leveraging summary-level data from the CORtisol NETwork (CORNET, n = 25,314) and FINRISK (n = 8293) genome-wide association studies, we used two-sample Mendelian randomisation to investigate the causal effect of genetically proxied increased morning cortisol levels on 42 circulating cytokines. We found that increased genetically proxied morning cortisol levels were associated with reduced levels of IL-8 and increased levels of MIF. These results provide mechanistic insight into the immunomodulatory effects of endogenous cortisol and the therapeutic effects of exogenous corticosteroids. Clinically, our findings underline the therapeutic importance of steroids in inflammatory conditions where IL-8 and MIF play a central pathophysiological role in the onset and progression of disease.

Alterations in Cortisol and Interleukin-6 Secretion in Patients With COVID-19 Suggestive of Neuroendocrine-Immune Adaptations

Purpose: The beneficial effect of glucocorticoids in coronavirus disease (COVID-19) is established, but whether adrenal cortisol secretion is impaired in COVID-19 is not fully elucidated. In this case-control study we investigated the diurnal free bioavailable salivary cortisol secretion in COVID-19 patients.Methods: Fifty-two consecutive COVID-19 patients -before dexamethasone treatment- recruited between April 15th -June15th-2021, (NCT04988269) at Laikon Athens University-Hospital, and 33 healthy age- and sex-matched controls were included. Diurnal salivary cortisol (8am, 12, 6, and 10pm), plasma adrenocorticotropin (ACTH) and aldosterone, and serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were assessed. Diurnal salivary dehydroepiandrosterone (DHEA) and IL-6 were also assessed in subgroups of patients.ResultsMedian CRP and IL-6 measurements were about 6-fold higher in patients than controls (both p<0.001) Morning salivary cortisol levels did not differ between the two groups, but patients exhibited higher median levels of evening and nocturnal salivary cortisol compared to controls [0.391(0.054, 0,663) vs. 0.081(0.054, 0.243)μg/dl, p<0.001 and 0.183(0.090, 0.834) vs. 0.054(0.054, 0.332)μg/dl, p<0.001, respectively], resulting in higher time-integrated area under the curve (AUC) (4.81±2.46 vs. 2.75±0.810, respectively, p<0.001). Circulating ACTH, DHEA, and aldosterone levels were similar in patients and controls. Serum IL-6, but not ACTH levels, WAS strongly correlated with nocturnal cortisol salivary levels (rho=0.555, p<0.001) in patients.ConclusionIncreased evening and nocturnal but not morning cortisol secretion occur in even clinically mild COVID-19. In the context of acute viral infection (Covid-19), IL-6 may partially replace ACTH as a stimulus of the glucocorticoid-secreting adrenal zona-fasciculata without influencing the secretion of DHEA and aldosterone.

Clinical profile, etiology, and diagnostic challenges of primary adrenal insufficiency in Sudanese children: 14-years’ experience from a resource limited setting

Objectives Primary adrenal insufficiency (PAI) in children is an uncommon condition. Congenital adrenal hyperplasia (CAH) is the commonest cause followed by autoimmune disorders. Diagnosis and management are challenging especially in resource-limited settings. Studies from Africa are scanty and here we describe for the first time the clinical presentation, possible etiologies, and challenges in diagnosis and management of PAI in a large cohort of Sudanese children. Methods This was a descriptive hospital-based study where all patients diagnosed with PAI between 2006 and 2020 were reviewed. The diagnosis was based on clinical presentation, low morning cortisol ± high adrenocorticotropic hormone (ACTH), or inadequate response of cortisol to synacthen stimulation. Challenges faced in diagnosis and management were identified. Results From 422 PAI suspected patients, 309 (73.2%) had CAH, and 33 (7.8%) had PAI-like symptoms and were not furtherly discussed. Eighty patients (19%) had fulfilled the study criteria: 29 had Allgrove syndrome, nine auto-immune polyendocrinopathy syndrome, seven adrenoleukodystrophy, and one had an adrenal hemorrhage. Hyperpigmentation was the cardinal feature in 75 (93.8%) while the adrenal crisis was not uncommon. Lack of diagnostic facilities has obscured the etiology in 34 (42.5%) patients. Conclusions PAI is not uncommon in Sudanese children where genetic causes outweigh the autoimmune ones. Many cases were missed due to nonspecific presentation, lack of awareness, and difficult access to tertiary health care facilities. In addition to the clinical findings, early morning cortisol ± ACTH levels can be used in diagnosis where facilities are limited particularly synacthen stimulation test.

A Comprehensive Examination of Severely Ill ME/CFS Patients

One in four myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients are estimated to be severely affected by the disease, and these house-bound or bedbound patients are currently understudied. Here, we report a comprehensive examination of the symptoms and clinical laboratory tests of a cohort of severely ill patients and healthy controls. The greatly reduced quality of life of the patients was negatively correlated with clinical depression. The most troublesome symptoms included fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments. Lower morning cortisol level and alterations in its diurnal rhythm were observed in the patients, and antibody and antigen measurements showed no evidence for acute infections by common viral or bacterial pathogens. These results highlight the urgent need of developing molecular diagnostic tests for ME/CFS. In addition, there was a striking similarity in symptoms between long COVID and ME/CFS, suggesting that studies on the mechanism and treatment of ME/CFS may help prevent and treat long COVID and vice versa.

Transition from Preschool to School: Children’s Pattern of Change in Morning Cortisol Concentrations

Many studies showed a global acute increase in stress hormones at kindergarten entry, but inconsistencies among them due to small samples with varying methodologies and very few measurement points, preclude robust conclusions. The current study aimed to describe the pattern of morning cortisol concentration in children during the transition from preschool to school by examining whether we could identify certain stress responses such as stress reactivity, but also anticipatory stress and stress recovery. We further tested the robustness of this pattern across several characteristics. Participants were 384 children recruited from two cohorts of a pregnancy study, and followed across their transition from preschool to kindergarten. Five morning salivary cortisol samples were collected over time from the children: twice before school entry and three times after school entry. Although no anticipatory stress was observed two weeks before school entry, latent growth curve models showed that most children’s morning cortisol concentrations increased during the first two weeks of school, and was not associated with any sociodemographic characteristics, supporting the hypothesis that school entry is a universal social stressor. In contrast, the rate of recovery measured two months after school entry, however, revealed between children variance, which could not be explained by any specific sociodemographic characteristics. This study showed that stress reactivity at school entry is sustained for at least two weeks in most children. However, the observed variability in the rate of recovery might be associated with adaptation to the school transition and will allow further testing of functional correlates.

Clinical course and management of pembrolizumab-associated isolated adrenocorticotrophic hormone deficiency: a new case and literature review

Hypophysitis is rarely reported in patients receiving pembrolizumab-only immunotherapies. Since the clinical presentation is usually as isolated adrenocorticotrophic hormone (ACTH) deficiency, patients may be misjudged as having clinical symptoms due to cancer or chemotherapy. A 49-year-old male with laryngeal cancer applied to our clinic just after the tenth cycle of his pembrolizumab treatment, with weakness and nausea/vomiting. Serum morning cortisol and ACTH were 0.47 mcg/dl and 10.1 pg/ml, respectively; the remaining anterior pituitary hormone levels were normal. Pituitary MRI revealed mild glandular enlargement and loss of posterior pituitary bright-spot. All symptoms and signs improved with low-dose prednisolone. This is the second reported case of pembolizumab-associated isolated ACTH deficiency having abnormal pituitary MRI findings as we have reviewed all reported cases in the literature.

Childhood Trajectories of Hyperactivity/Inattention Symptoms and Diurnal Cortisol in Middle Adolescence: Results from a UK Birth Cohort

Objective Children with attention-deficit/hyperactivity disorder (ADHD) show hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Whether the association between hyperactivity/inattention symptoms with HPA axis dysfunction holds in the general child population too is not clear. Method We assessed associations between longitudinal trajectories of hyperactivity/inattention symptoms during ages 4 to 13 years and basal cortisol profiles at age 15 in a British general population cohort. Results Adolescents with persistently high levels of hyperactivity/inattention symptoms since childhood showed lower total morning cortisol and a smaller diurnal decline, even after adjusting for confounders. No associations were found between any of the symptom trajectories and cortisol awakening response, diurnal slope or daily output of cortisol. Conclusion This study provides evidence for hypocortisolism among adolescents with chronic hyperactivity/inattention symptoms in the general population.

The Window Matters: A Systematic Review of Time Restricted Eating Strategies in Relation to Cortisol and Melatonin Secretion

Time-Restricted Eating is an eating pattern based on the circadian rhythm which limits daily food intake (usually to ≤12 h/day), unique in that no overt restriction is imposed on the quality, nor quantity, of food intake. This paper aimed to examine the effects of two patterns of TRE, traditional TRE, and Ramadan fasting, on two markers of circadian rhythm, cortisol and melatonin. PubMed and Web of Science were searched up to December 2020 for studies examining the effects of time restricted eating on cortisol and melatonin. Fourteen studies met our inclusion criteria. All Ramadan papers found statistically significant decrease in melatonin (p < 0.05) during Ramadan. Two out of the three Ramadan papers noted an abolishing of the circadian rhythm of cortisol (p < 0.05). The non-Ramadan TRE papers did not examine melatonin, and cortisol changes were mixed. In studies comparing TRE to control diets, Stratton et al. found increased cortisol levels in the non-TRE fasting group (p = 0.0018) and McAllister et al. noted no difference. Dinner-skipping resulted in significantly reduced evening cortisol and non-significantly raised morning cortisol. Conversely, breakfast skipping resulted in significantly reduced morning cortisol. This blunting indicates a dysfunctional HPA axis, and may be associated with poor cardio-metabolic outcomes. There is a paucity of research examining the effects of TRE on cortisol and melatonin. The contrasting effect of dinner and breakfast-skipping should be further examined to ascertain whether timing the feeding window indeed has an impact on circadian rhythmicity.