Morning Cortisol Concentrations Research Articles

7328 A case of Adrenal Calcifications in a Patient with Familial Cerebral Cavernous Malformations

Abstract Disclosure: R.I. Dorin: None. L.E. Aguirre: None. M. Bomgardner: None. Background: Familial syndromes of cerebral cavernous malformation (fCCM) having autosomal dominant inheritance and variable penetrance and expression have been linked to loss of function mutations at three genetic loci. The association of small focal adrenal calcifications with fCCM was only recently recognized in a New Mexican cohort of subjects predominately carrying the founder common Hispanic mutation in the CCM1 locus (stop codon Q455X in the Krev1 interaction trapped gene 1 [KRIT1]). We report a case of bilateral, focal adrenal calcifications in a patient affected by fCCM. Clinical Case: A 72-year-old Hispanic male with past medical history of intracranial CCM was referred for osteoporosis and hyperthyroidism due to multinodular goiter. Small focal calcifications of the adrenal glands were incidentally noted on prior imaging studies. There was no history of anticoagulant use, adrenal hemorrhage, or systemic/adrenal infection. The patient was without clinical manifestations of adrenal insufficiency, morning cortisol and plasma ACTH concentrations were normal, and exam was negative for hyperpigmentation or cutaneous vascular malformations. Brain MRI revealed the presence of over 100 parenchymal CCM lesions. A family history of CCM was reported in multiple family members, including 7/10 siblings. Conclusion: In addition to cutaneous malformations, small focal adrenal calcifications are now recognized as one of the extra-neurological manifestations of fCCM, particularly in patients harboring the common Hispanic CCM1/KRIT1 mutation. Whether adrenal calcifications are observed in fCCM patients having other mutations of KRIT1 or other genetic loci of fCCM (CCM2 or PDCD10) remains to be determined. The focal adrenal calcifications are believed to be result of dyssynchronous, subclinical hemorrhagic events related to vascular malformations in the adrenal gland. These findings implicate a role for KRIT1 in endothelial development in the adrenal gland in addition to established role in CNS, spinal cord, and skin. Our patient appeared had normal adrenocortical function, as expected for the focal nature of the adrenal lesions. Though adrenal function has not been evaluated in fCCM patients, there are no reports of primary adrenal insufficiency in fCCM in the literature. Adrenal calcifications may be considered to represent an imaging biomarker for fCCM, and fCCM should be included in the differential diagnosis of adrenal calcifications. The incidental recognition of characteristic small, focal adrenal calcifications in either bilateral or unilateral adrenal glands should prompt evaluation for fCCM.

A-080 Morning Cortisol for Rule-in and Rule-out of Adrenal Insufficiency in an Asian Population

Abstract Background Short ACTH stimulation (Synacthen) tests are performed to investigate for adrenal insufficiency. Previous work suggests that morning cortisol concentrations can be used to rule in or out adrenal insufficiency to avoid performance of a Synacthen test. This study aimed to determine the optimal cortisol concentration for rule-in or rule-out adrenal insufficiency based on 30-minute cortisol (COR30) for adequate response using the assay-specific cut-off from The Endocrine Society of Australia/The Australasian Association for Clinical Biochemistry and Laboratory Medicine/The Royal College of Pathologists of Australasia (ESA/AACB/RCPA) Harmonization of Endocrine Dynamic Testing - Adult (HEDTA), in an Asian population. Methods Synacthen tests performed at our institution from 2012-2024, with a baseline cortisol between 6 and 10 am (COR0(6-10)), were extracted from the laboratory database. Plasma cortisol concentrations were measured by Beckman Coulter DxI 800. Synacthen tests were classified as adequate or inadequate based on the Beckman Coulter specific HEDTA cut-off for COR30 of 420 nmol/L. Performance characteristics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under receiver operator characteristic (AUROC) curve) of COR0(6-10) concentrations to predict adequate or inadequate response were calculated using Microsoft Excel. Results 4609 Synacthen tests were included, 77% of which had adequate Synacthen response. COR0(6-10) >300 nmol/L could exclude inadequate COR30 response with sensitivity 95%, specificity 48%, PPV 35%, NPV 97%; and COR0(6-10) >364 nmol/L had sensitivity 99%, specificity 29%, PPV 29%, NPV 99%. COR0(6-10) <155 nmol/L could rule-in inadequate COR30 response with sensitivity 53%, specificity 95%, PPV 76%, NPV 87%; and COR0(6-10) <97 nmol/L had sensitivity 35%, specificity 99%, PPV 91%, NPV 84%. AUROC of COR0(6-10) for adequate COR30 response was 0.86. If patients with COR0(6-10) <97 nmol/L and >300 nmol/L did not proceed to Synacthen testing, up to 46% of tests could be avoided, while keeping misclassification under 5%. Conclusions Morning cortisol cut-offs were determined for rule-in and rule-out of adrenal insufficiency in an Asian population. Patients with morning cortisol >300 nmol/L or <97 nmol/L may be able to avoid Synacthen testing unless there is a strong suspicion of clinical discordance. Such a testing strategy could significantly decrease the number of Synacthen tests while keeping misclassification to a minimum.

Altered Histone Deacetylase Versus Histone Acetyltransferase Activity in Peripheral Blood Mononuclear Cells from Apparently Healthy Young Adults with Prior Exposure to Adverse Childhood Experiences

Introduction: Adverse childhood experiences (ACEs) are severe psychosocial stressors which occur in early developmental periods and promote later life cardiometabolic disease in a dose-dependent manner. ACE-related risk may be mediated in part by epigenetic alterations, particularly in myeloid lineage immune cells. Histone acetylation is a dynamic epigenetic process that regulates gene expression via modification of chromatin structure and is dictated by the opposed actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). An appropriate balance between HDAC and HAT activity is critical for maintaining cellular function, and an imbalance has been implicated in the premature development of human diseases including cardiometabolic disease. Glucocorticoids (e.g., cortisol) are well-described regulators of immune function and can influence histone acetylation through glucocorticoid receptors. Thus, we hypothesized that HDAC:HAT activity would be altered in young adults with prior ACE exposure, and that HDAC:HAT activity would be associated with salivary cortisol concentrations. Purpose: We examined HDAC:HAT activity in peripheral blood mononuclear cells (PBMCs) in apparently healthy young adults with versus without prior exposure to ACEs and explored whether circulating cortisol was associated with HDAC:HAT activity. Methods: PBMCs were isolated from whole blood collected within 1 hour of wakening from 27 young adult women who reported high (≥ 4 ACEs) ACE exposure (ACE4+; mean ± SD; age = 21 ± 3 y, BMI = 25.7 ± 4.5 kg/m2) and from 14 young adult women who reported no ACE exposure (CON; age = 21 ± 3 y, BMI = 26.1 ± 6 kg/m2). Salivary cortisol was also collected within 1 hour of wakening and 8 hours later. Nuclear proteins were isolated from PBMCs and HDAC and HAT activities were quantified by commercially available assay kits. Salivary cortisol was quantified via ELISA. Independent samples t-tests were used to examine differences in HDAC:HAT, HDAC, and HAT activity. Pearson correlation coeffcients were used to examine the relation of HDAC:HAT activity with morning and afternoon cortisol concentrations, and the diurnal cortisol slope in the complete sample. Results: HDAC:HAT activity was reduced in ACE4+ versus CON (140.4 ± 52 vs. 189.6 ± 42 arbitrary units, p = 0.004). This difference was primarily driven by reduced HDAC activity (13,706 ± 4,696 vs. 18,060 ± 3,641 ng/h/mg, p = 0.004) in ACE4+ versus CON, whereas HAT activity was not different (99.7 ± 11 vs. 96.1 ± 9 ng/h/mg, p = 0.30). HDAC:HAT activity was not associated with morning (r=0.27, p = 0.07) or afternoon (r=-0.23, p = 0.16) cortisol, but was associated with the diurnal cortisol slope (r=-0.37, p = 0.02). Discussion: Young adults with prior ACE exposure have an altered balance between HDAC and HAT activity in PBMCs that appears to be driven by lower HDAC activity, and which is negatively related to diurnal cortisol slope. These findings warrant further exploration, particularly regarding the specific HDACs implicated, their role in reduced cellular function as it relates to disease risk, and whether these can be modulated to improve function among those with ACE exposure. Further, our data support future examination of the role of glucocorticoid signaling in regulating histone acetylation in this population. This study was supported by the Center for Integrative Research on Childhood Adversity (Grant #P20GM109097), through the National Institute of General Medical Sciences (to NDMJ and TKT). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

On Primary Adrenal Insufficiency with Normal Concentrations of Cortisol - Early Manifestation of Addison's Disease.

Primary adrenal insufficiency (AI) is an endocrine disorder in which hormones of the adrenal cortex are produced to an insufficient extent. Since receptors for adrenal steroids have a wide distribution, initial symptoms may be nonspecific. In particular, the lack of glucocorticoids can quickly lead to a life-threatening adrenal crisis. Therefore, current guidelines suggest applying a low threshold for testing and to rule out AI not before serum cortisol concentrations are higher than 500 nmol/l (18 μg/dl). To ease the diagnostic, determination of morning cortisol concentrations is increasingly used for making a diagnosis whereby values of>350 nmol/l are considered to safely rule out Addison's disease. Also, elevated corticotropin concentrations (>300 pg/ml) are indicative of primary AI when cortisol levels are below 140 nmol/l (5 μg/dl). However, approximately 10 percent of our patients with the final diagnosis of primary adrenal insufficiency would clearly have been missed for they presented with normal cortisol concentrations. Here, we present five such cases to support the view that normal to high basal concentrations of cortisol in the presence of clearly elevated corticotropin are indicative of primary adrenal insufficiency when the case history is suggestive of Addison's disease. In all cases, treatment with hydrocortisone had been started, after which the symptoms improved. Moreover, autoantibodies to the adrenal cortex had been present and all patients underwent a structured national education program to ensure that self-monitored dose adjustments could be made as needed.

Salivary Diurnal Glucocorticoid Profiles in Monozygotic Twins With Intratwin Birthweight Differences.

Low birthweight (bw) and unfavorable intrauterine conditions have been associated with metabolic sequelae in later life, but little is known about their impact on glucocorticoid metabolism. We studied monozygotic twins with intratwin bw differences to analyze the long-term impact of bw on glucocorticoid metabolism. 46 monozygotic twin pairs with bw differences of <1 SDS (concordant; n = 29) and ≥1 SDS (discordant; n = 17) were recruited. At 6.9 years (mean age), saliva samples were collected (at 7 hours, 13 hours, 18 hours and 21 hour) and analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found significant or highly significant intratwin correlations in all twin pairs at 3 of 4 (cortisol), and 4 of 4 (cortisone) time points. Graphic evaluation of the diurnal cortisol patterns for each twin pair showed a distinct alignment in all groups. Analyses of the change of intratwin differences over the day by mixed linear modeling showed no intratwin differences in diurnal patterns. Regression analyses of intratwin differences at 7:00 hours showed a significant influence of catch-up growth, indicating lower cortisol concentrations in smaller twins with more catch-up growth (adj. R2 = 0.159, P = .014, ß = -3.71, F(1,42) = 9.15, f2 = 0.19). In monozygotic twins with intratwin bw differences, intratwin catch-up growth showed a moderate influence on intratwin differences in morning cortisol concentrations. We observed no differences regarding diurnal patterns. In contrast, in all groups, we found significant intratwin correlations for cortisol and cortisone over the day and a pronounced graphic alignment of cortisol diurnal patterns. We therefore suggest a predominant significance of the genetic background compared with bw differences on cortisol metabolism.

Effects of nature-adapted lighting solutions ("Virtual Sky") on subjective and objective correlates of sleepiness, well-being, visual and cognitive performance at the workplace.

Exposure to natural daylight benefits human well-being, alertness, circadian rhythms and sleep. Many workplaces have limited or no access to daylight. Thus, we implemented a light-panel ("Virtual Sky"), which reproduced nature-adapted light scenarios. In a laboratory office environment, three lighting scenarios were presented during the day: two lighting conditions with nature-adapted spectral light distributions, one with static and one with dynamic clouds, and a standard office lighting condition. We compared the impact of the three lighting scenarios on subjective and objective measures of alertness, cognitive performance, wellbeing, visual comfort, contrast sensitivity, and cortisol levels in 18 healthy young male volunteers in a within-participant cross-over study design. We found no evidence that an 8-h lighting scenario with static or dynamic clouds during the waking day (9am-5pm) was associated with any significant effect on objective and/or subjective alertness, cognitive performance and morning cortisol concentrations compared to standard workplace lighting. However, the dynamic light scenario was accompanied with lower levels of perceived tensionafter completing cognitive tasks and less effort to concentrate compared to the static lighting scenarios. Our findings suggest that apart from smaller effects on tension and concentration effort, nature-adapted lighting conditions did not improve daytime alertness and cognitive performance in healthy well-rested young participants, as compared to standard office lighting.

Stress across the Transition from Preschool to School: Association with the Development of Anxiety Symptoms in Children

Children experiencing maladjustment during the transition from preschool to school could further develop internalizing disorders, such as anxiety. Children’s sensitivity to stress is a good indicator of children’s adjustment, but atypical sensitivity, measured by cortisol concentrations, was often linked to later development of anxiety symptoms. Our previous study (PNEC, 2022) showed that most children’s morning cortisol concentrations increased during the first two weeks of kindergarten, and that the adaptation response rate varied between children two months after school entry. The current study aimed to test whether children’s atypical morning cortisol concentration across the transition to kindergarten was associated with an increase in anxiety symptoms 1.5 years later. To model morning cortisol concentrations during the transition, a latent growth model was used (n = 384; one sample for each of the four time-points). Anxiety symptoms were measured twice, before kindergarten entry and in first grade, by parent-report questionnaires. The items were combined using latent variables, one for each time-point. Controlling for pre-transition anxiety symptoms, cortisol level during the first week of school (β = -0.18) predicted anxiety symptoms 1.5 years later. Changes in cortisol levels across the transition did not add to the prediction. This study showed that low morning stress response to a normative environmental stressor was followed by increased levels of anxiety symptoms. Consistent with the stress sensitization hypothesis, this lower stress response is frequently linked to anxiety problems in children who previously experienced adversity; this remains to be examined in this sample.

Renin, Aldosterone, and Cortisol in Pregnancy-Induced Hypertension.

We aimed to assess renin, aldosterone, and cortisol in the early stages of pregnancy-induced hypertension (PIH), i. e., at the time of diagnosis. During the postural test, we measured aldosterone, renin [Liason DiaSorin Inc. (Italy)], as well as cortisol, sodium, potassium, and 24-h urinary sodium and potassium excretion in 62 women with newly diagnosed PIH, 70 healthy women during the 3rd trimester of pregnancy, and in 22 healthy non-pregnant women. In all groups, there was a significant increase in aldosterone and renin in upright versus supine posture (p<0.01). Both supine and upright aldosterone concentrations were higher in healthy pregnant women than in women with PIH and the lowest in healthy not-pregnant [supine (median±intequartile range): 25.04±18.4 ng/dL, 18.03±12.58 ng/dL, and 7.48±4.78 ng/dL, p<0.001, upright: 31.60±21.32 ng/dL, 25.11±13.15 ng/dL, and 12.4±12.4 ng/dL, p<0.001, for healthy pregnant, pregnant with PIH, and non-pregnant, respectively]. Supine renin concentrations were higher only in healthy pregnant (p<0.001), while in the upright position, there was a difference only between healthy pregnant and women with PIH (p=0.002). Both in supine and upright positions, there was no difference in the aldosterone-to-renin ratio between healthy pregnant women and women with PIH, though, in both groups, the ratio was higher than in non-pregnant women (p<0.001). Morning cortisol concentrations and 24-h urinary sodium excretion were lower in women with PIH than in healthy pregnant (p<0.001, p=0.002, respectively). Hyperaldosteronism is not involved in the etiology of PIH. In PIH, there is also a tendency towards lower sodium excretion and lower morning cortisol concentrations.

The association of bone mineral density Z-score with the early postoperative remission and characteristics of bone mineral loss in patients with Cushing’s disease: a retrospective study

To investigate the association of bone mineral density (BMD) Z-scores with early-postoperative remission rate and clinical parameters in patients with Cushing's disease (CD). We retrospectively evaluated the records of patients diagnosed with CD. After the exclusion of 230 patients, 87 CD patients were finally enrolled. BMD was determined by dual-energy x-ray absorptiometry (DXA) at the lumbar spine 1-4 (L1-4) and left femur. Early-postoperative remission was defined as a morning cortisol concentration on the first day after surgery of less than 5 μg/dL. The diagnosis of BMD "below the expected range for age" was defined as a Z-score≤-2.00 standard deviations. DXA results were not significantly associated with early postoperative remission. They also did not significantly differ between eugonadal and menopausal groups. Preoperative morning cortisol significantly negatively but weakly correlated with Z-score of the total femur, while preoperative adrenocorticotropic hormone/cortisol ratio positively but weakly correlated with DXA results of L1-4. The severity of bone loss was not significantly related to the failure of transsphenoidal surgery for Cushing's disease.

Stress Hormones Cortisol and Aldosterone, and Selected Markers of Oxidative Stress in Response to Long-Term Supplementation with Omega-3 Fatty Acids in Adolescent Children with Depression.

Late childhood and adolescence are crucial periods of brain development with high vulnerability to environmental insults. The aim of this study was to test the hypotheses that in adolescents with depression (a) 12 weeks-supplementation with omega-3 fatty acids results in the attenuation of salivary stress hormone concentrations; (b) the mentioned supplementation improves potentially disrupted daily rhythm of stress hormones; (c) stress hormone concentrations correlate with values of selected markers of oxidative stress. The sample consisted of 60 patients suffering from depression aged 11–18 years. Hormone concentrations in saliva were measured in the morning and midday before (baseline) and after (6, 12 weeks) food supplementation with omega-3 or omega-6 (as comparator) fatty acids. Morning cortisol decreased in response to omega-3 but not omega-6 fatty acids at 12 weeks compared to baseline. No changes were observed in aldosterone concentrations. The obtained results show that adolescent children with depression preserved the daily rhythm of both stress hormones. Baseline morning cortisol concentrations correlated positively with depression severity and lipoperoxides, and negatively with docosahexaenoic acid. Aldosterone concentrations correlated positively with 8-isoprostane. Thus, both hormones showed positive correlation with the selected markers of oxidative stress suggesting that enhanced stress hormone secretion may be associated with increased oxidative tissue damage in adolescent children with depression. This study was registered with the ISRCTN registry (DEPOXIN study, ISRCTN81655012).

The Contribution of Oral and Inhaled Glucocorticoids to Adrenal Insufficiency in Asthma

Exposure to any form of glucocorticoid preparation is associated with a risk of adrenal insufficiency (AI). To establish the contribution of oral corticosteroid (OCS) and inhaled corticosteroid (ICS) exposure to the risk of AI in a cohort of patients (n= 80) with severe, uncontrolled asthma. We compiled individualized cumulative OCS and ICS exposure data using a combination of health care records and electronic inhaler monitoring using an Inhaler Compliance Assessment device and estimated the risk of AI for each participant using a morning serum cortisol concentration. The predicted prevalence of AI based on morning cortisol concentrations was 25% (20 of 80). Participants on maintenance OCS therapy had the highest risk of AI at 60% (6 of 10) compared with 17% (11 of 65) in those with no recent OCS exposure. Morning serum cortisol correlated negatively with both OCS exposure (mg/kg prednisolone) (r=-0.4; P<.0002) and ICS exposure (mg/kg fluticasone propionate) (r=-0.26; P= .019). Logistic regression of risk of AI against the number of standard treatment courses of OCS demonstrated a positive relationship although this did not reach statistical significance (odds ratio, 1.41; 95% CI, 0.97-2.05; P= .073). Logistic regression analysis, categorizing patients as high-risk AI (cortisol <130 nmol/L) or not (cortisol >130 nmol/L), showed that cumulative ICS exposure remained a significant predictor of AI, even when exposure to OCS was controlled for (odds ratio, 2.17 per 1 mg/kg increase in cumulative fluticasone propionate exposure; 95% CI, 1.06-4.42; P= .033). Our data suggest that AI is common among patients with asthma and highlights that the risk of AI is associated with both high-dose ICS therapy and intermittent treatment courses of OCS.

Transition from preschool to school: Children’s pattern of change in morning cortisol concentrations

Many studies show a general increase in stress hormones at the exposure to school entry, but inconsistencies among them due to small samples with varying methodologies and very few time-points, preclude robust conclusions. The current study aimed to describe the pattern of morning cortisol concentration in children across the transition from preschool to school by examining whether we could identify a response to the school entry, but also an anticipatory stress response (pre-entry) and a stress adaptation response (post-entry). We further tested the robustness of this pattern across several characteristics. Participants were 384 children recruited from two cohorts of the 3D pregnancy study, and followed across their transition from preschool to kindergarten. Children’s morning salivary cortisol samples were collected over five time-points: twice before school entry, once at school entry and twice after school entry (one sample per time-point). Although no anticipatory stress response 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 normative environmental stressor. In contrast, two months after school entry, some children showed stress adaptation whereas others showed a prolonged stress response to school entry. This between-children variance could not be explained by any specific sociodemographic characteristic. This study showed that the morning stress response rises at school entry and is sustained for at least two weeks in most children. However, the observed variability in the stress adaptation response remains to be elucidated and linked to functional correlates.

Salivary Morning Cortisol as a Potential Predictor for High Academic Stress Level in Dental Students: A Preliminary Study

Students experience different levels of acute and chronic stress during the academic year. Selected salivary biochemical parameters change as a result of stress. Our preliminary study aimed to indicate possible links between alterations in the salivary biochemical parameters (such as cortisol and total antioxidant status) and different accompanying stress levels in dental students during the academic year. The study group consisted of 20 volunteer dental students at the Poznan University of Medical Sciences—both genders, aged 20–26 years. Students were asked to fill in the electronic version of the author’s survey on experiencing and coping with stress. Samples of unstimulated saliva were collected in the morning and late evening at four-time points: in the middle of the academic year, during the examination period, at the beginning of the academic year, and in the middle of the following academic year, together with a determination of currently experienced stress on the Stress Numerical Rating Scale-11. According to the circadian rhythm of cortisol secretion, morning levels of the hormone in saliva were much higher than in the evening. In evening cortisol, significant differences were observed during the studied periods—the highest level was found at the beginning of the academic year. However, the morning cortisol concentrations correlated more strongly with the declared stress levels and showed better predictability for high-stress levels. Salivary morning cortisol could be a potential marker of academic stress levels. Further studies are needed on a larger group to confirm.

Steroid stress hormone changes throughout the menstrual cycle: A rise in evening aldosterone concentration in early luteal phase precedes the symptoms of premenstrual syndrome.

There is still a lack of consistent evidence on dysregulation of steroid stress hormones cortisol and aldosterone in premenstrual syndrome (PMS). We aimed to test the hypothesis that, in healthy women, salivary aldosterone concentrations are higher in those with PMS compared to controls, particularly during the luteal phase of the menstrual cycle. In total, 99 female subjects (49 women with and 50 women without PMS) participated in a prospective non-interventional case-control study. Saliva sampling was performed in the follicular (day 8), early luteal (day 20) and late luteal phase (2days before expected onset of bleeding) of the menstrual cycle in the morning and the evening. The results confirmed the hypothesis that salivary aldosterone concentrations are higher in women with PMS during the early luteal phase compared to controls (p<.01) in the evening. Early luteal phase aldosterone concentrations positively correlated with the frequency of premenstrual symptoms. Women with PMS exhibited a flatter morning to evening aldosterone slope compared to controls (p<.05). Morning and evening salivary cortisol concentrations were unchanged throughout the menstrual cycle in both groups of women. In conclusion, evening salivary aldosterone, but not cortisol concentrations, are increased in women with PMS during the early luteal phase compared to controls. Cortisol does not appear to be involved in the mechanisms contributing to the course of PMS. High evening salivary aldosterone in the early luteal phase may represent an important risk factor and could be of predictive value for the occurrence of premenstrual symptoms.

Ciclesonide Impacts Clinicopathological Features of Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergen-mediated disease of the esophagus. Pharmacologic treatment has largely relied on repurposing corticosteroids. Ciclesonide (CIC) is a corticosteroid for the treatment of asthma with biochemical properties that improve topical potency. To determine whether CIC decreased clinicopathological features of EoE. We performed a retrospective cohort study of patients with EoE treated with CIC at a pediatric hospital from 2010 to 2019. Data were extracted from the electronic health record. Patients who were prescribed CIC with pre- and post-CIC endoscopic and histological data available were included for analysis. A total of 281 patients were treated with CIC and 81 met criteria for inclusion. Use of CIC was associated with reduced symptoms including dysphagia (P < .001), abdominal pain (P < .001), vomiting (P= .01), heartburn (P= .02), and behavior changes (P= .02). Average composite endoscopic reference scores decreased from 2.54 to 1.37 (P < .001), with improvement in exudates, edema, and furrows (all P < .001). Peak eosinophil counts decreased from 48 to 23 eosinophils/hpf (P < .001). Forty-three patients (53%) achieved remission (<15 eosinophils/hpf). Esophageal Candida was reported in 1 patient. Fasting morning cortisol concentrations were low in 10 of 31 patients tested. Six of these 10 patients had abnormal adrenocorticotropic hormone stimulation testing, 5 of 6 diagnosed with adrenal insufficiency before transition to CIC and 3 of 6 with subsequent normalization of adrenal function on CIC therapy. Patients with EoE treated with CIC experienced significant reductions in clinicopathological features of EoE. CIC can be considered an alternative therapy in patients with known adrenal insufficiency or at risk of developing adrenal insufficiency.

Prevalence of Suppressed Morning Serum Cortisol and Its Relationship With Cumulative Glucocorticoid Exposure in a Moderate-Severe Asthma Patient Cohort

The extent to which inhaled glucocorticoid exposure (ICS) contributes to risk of adrenal insufficiency (AI) is not fully understood. The aim of this study was to establish the relative contribution of both oral (OCS) and inhaled (ICS) glucocorticoid exposure to risk of AI.82 patients with severe asthma treated with fluticasone propionate (FP) who participated in a 32-week prospective randomised trial INCA SUN, (NCT02307669) were studied. Cumulative ICS exposure was calculated using a unique digital device, which creates an acoustic recording of inhaler adherence and technique. Analysis of this data provides an exact measure of the ICS dose received by each patient. Morning serum samples collected during the final study visit (week 32) were analysed for serum cortisol concentration (cortisol) using Roche Elecsys Cortisol II immunoassay. Participants were then stratified into three groups based on cortisol concentration to predict risk of AI; cortisol < 100nmol/l (high risk), 100–315 nmol/l (indeterminate risk) and > 315 nmol/l (low risk) based on locally derived reference ranges. 21% participants were classified as low risk, 18% as high risk and the remaining 61% at indeterminate risk of AI. Median morning cortisol in the low risk group was ten-fold higher than those in the high risk group (380 vs 38.5 nmol/l, p=0.001). OCS exposure was a significant predictor of risk of AI (OR 1.1 [1.03–1.17] per mg/kg increase in prednisolone exposure, p=0.004)). Participants at high risk were more likely to be on maintenance OCS (33% vs 0%, p=0.015) and had a greater median cumulative OCS exposure over the study period (7.55 vs 0.66 mg/kg prednisolone, p=0.002). ICS exposure was also associated with risk of AI. Participants at high risk AI had a greater adherence to ICS therapy (78% vs 62%, p=0.049) and greater cumulative received ICS dose over the study duration than those at low risk AI (178.2 vs 127.9 mg, p=0.036). ICS exposure remained a significant predictor of AI even when OCS exposure is controlled for (OR 2.49 [1.06–5.82] per 1mg/kg increase in FP exposure). Both the asthma control test (ACT) & asthma quality of life questionnaire (AQLQ) scores correlate with morning cortisol concentration (ACT r=0.2, p=0.068, AQLQ r=0.26, p=0.019). Interestingly, participants with cortisol < 100nmol/l reported worse asthma control (ACT score 16 vs 20, p=0.07) and a lower AQLQ score (4.1 vs 5.8, p=0.02) than the low risk group despite objectively better lung function (FEV1 90.6 vs 77.6% predicted). Our data suggests that both cumulative oral and inhaled glucocorticoid exposure contribute independently to cortisol suppression and risk of AI. The discrepancy between objective (FEV1) and more subjective measures of asthma control (ACT score) in the high risk group suggests that undiagnosed AI, as well as other non-airway co-morbidities, may contribute to the symptom burden experienced by these patients.

No association of cigarette smoking and depressive symptoms with cortisol concentration in adolescents. Results from a population-based Swedish cohort

Several studies have shown that smoking increases the risk of depressive symptoms, and suggested a possible role of the hypothalamic-pituitary-adrenal axis in the smoking-depression pathway. This study aimed to assess if smokers have higher cortisol levels than non-smokers, and if higher cortisol levels are associated with depressive symptoms. Saliva samples were collected from a subgroup of 409 participants at enrolment (13-14 years old) and two years later (15-16 years old). First, we examined the association between smoking phenotypes and cortisol concentration. Second, we evaluated whether these associations differed between adolescents with and without depressive symptoms. The mean difference between smokers and non-smokers in cortisol concentrations was close to zero at both time points. For instance, the adjusted mean difference for morning cortisol concentration between current and non-current smokers was 0.000 µg/dl [95% CI -0.055, 0.056]. In addition, there were no differences in cortisol concentration at the second time-point between those who had smoked and those who did not during the two previous years. Moreover, cortisol levels were not associated with depressive symptoms. The hypothesis that dysregulation of the hypothalamic-pituitary-adrenal axis might be involved in the association between smoking behavior and depressive symptoms during adolescence was not supported by this data.

The association between insulin-like growth factor 1 levels within reference range and early postoperative remission rate in patients with Cushing’s disease

ABSTRACT Introduction The relationship between growth hormone (GH)/insulin-like growth factor 1 (IGF-1) and glucocorticoids (GC) was examined in various studies. Long-term GC treatment was shown to decrease GH concentration and, interestingly, to increase IGF-1 concentration. We performed a retrospective study in order to examine how preoperative IGF-1 concentrations vary within the reference range and if tertiles of age- and sex-adjusted normal IGF-1 are predictive for early postoperative remission in the patients with Cushing’s Disease (CD). Patients and Methods Patients diagnosed with CD were retrospectively evaluated. After the exclusion of 67 patients, a final cohort of 250 CD patients were included. Age- and sex-adjusted normal IGF-1 levels were divided into tertiles (T1, T2 and T3). Early postoperative remission was defined as a nadir morning cortisol concentration measured within the first 3 consecutive days following surgery of less than 5 µg/dL (138 nmol/L). Results Early postoperative remission rate was the lowest in T1 and highest in T3; 49.1% (n = 28) versus 77.3% (n = 75), p = .001, respectively. Binary logistic regression analysis showed the remission rate in T3 was three times higher than that in T1 (p = .003). Cortisol and ACTH concentration were significantly higher and GH concentrations were significantly lower in T1 compared to those in the other two tertiles. Conclusions As the first study evaluating the correlation between early postoperative remission rate in patients with CD and the tertiles of normal age- and sex-adjusted IGF-1 levels, we have shown that higher IGF-1 levels could predict better outcome in CD.

Associations Between Morning Salivary and Blood Cortisol Concentrations in Individuals With Obstructive Sleep Apnea Syndrome: A Meta-Analysis.

BackgroundObstructive sleep apnea syndrome (OSAS) may be associated with an increase in hypothalamic-pituitary-adrenocortical axis activity (HPA AA). We reviewed research comparing morning salivary and blood (serum and plasma) cortisol concentrations of individuals with OSAS to those of healthy controls.MethodsWe made a systematic search without any restrictions of the PubMed/Medline, Scopus, Cochrane Library, and Web of Science databases for relevant articles published up to August 25, 2019.ResultsSixteen studies were analyzed in this meta-analysis; five studies compared morning salivary concentrations, five compared serum concentrations, four compared plasma cortisol concentrations, and two compared both salivary and plasma concentrations. In pediatric samples, compared to healthy controls, those with OSAS had significantly lower saliva morning cortisol concentrations (MD = -0.13 µg/dl; 95% CI: 0.21, -0.04; P = 0.003). In contrast, no significant differences were observed for serum cortisol concentrations, plasma cortisol concentrations, or salivary morning cortisol concentrations between adults with and without OSAS (p = 0.61, p = 0.17, p = 0.17).ConclusionCortisol concentrations did not differ between adults with OSAS and healthy controls. In contrast, morning salivary cortisol concentrations were lower in children with OSAS, compared to healthy controls. Given that a reduced HPA AA is observed among individuals with chronic stress, it is conceivable that children with OSAS are experiencing chronic psychophysiological stress.

Cortisol Concentration as Predictor of Tobacco Initiation in Adolescents: Results From a Population-Based Swedish Cohort

PurposeStress potentiates the smoking reward, decreases the ability to resist smoking, and increases the risk of smoking relapse in adulthood. This study aimed to clarify if salivary cortisol, as an indicator of stress, may be prospectively associated with the onset and phenotype of tobacco use in adolescents. MethodsThis study was based on a cohort of Swedish adolescents, among whom saliva specimens were collected from a nested sample. We included adolescents with salivary cortisol measurements and without a history of tobacco use (n = 381, aged 13–14 years). Quartiles of morning and afternoon cortisol concentration and cortisol area under the curve were considered as predictors. We categorized tobacco use according to the product mainly used: cigarette smoking, snus use, or either type of tobacco. For each product use, two outcomes were considered: initiation and duration of use. Poisson regression models were used to calculate rate ratios. ResultsA quartile increase in morning cortisol levels and cortisol area under the curve was consistently associated with a 1.2- to 1.4-fold increased risk of initiation of cigarette smoking snus use, or any tobacco use. Similar results were obtained examining the dose–response relationship and using the duration of use as outcome. No associations were apparent between afternoon cortisol concentration and any of the outcomes. All associations were similar between sexes. ConclusionsMorning cortisol concentration, an indicator of hypothalamic–pituitary–adrenal axis activation, is prospectively associated with tobacco use in adolescents. Whether this activation indicates the cumulative effect of stressors during the life course remains to be elucidated.