Median Cortisol Research Articles

ODP650 Impaired Cognition in Patients with Mild Autonomous Cortisol Secretion

Abstract Background Limited data describe cognitive deficits in patients with Cushing syndrome (CS). The impact of mild autonomous cortisol secretion (MACS) on cognition is unknown. Objective To determine the impact of MACS on cognitive function. Methods Single-center cross-sectional study of adults with MACS and age and sex-matched volunteers. MACS was defined as cortisol >1.8 mcg/dL following the dexamethasone suppression test (DST) in patients with an adrenal incidentaloma and no features of CS. We measured cognitive function through the NIH toolbox cognition battery (7 standardized tests of attention, episodic and working memory, language, executive function, and processing speed). T-scores corrected for age, sex, education, and race were used for analysis. All patients completed the SF-36 questionnaire. The frailty index was calculated as previously reported (Singh S. JCEM 2020). Results Participants included 50 patients with MACS (median age 61, range 54-68) and 50 volunteers (median age 60 years, range 54-68), with 60% women in both groups. In patients with MACS, median post-DST morning cortisol was 3.6 (range, 2.4-6.2), and median corticotropin was 8.5 (range, 5.9-13) pg/mL (normal 6-60). Patients with MACS had a higher median frailty index (median of 0.26 vs. 0. 05 in volunteers, p<0. 001) and lower quality of life scores on the SF-36 survey (median of 47 vs. 91, p<0. 001). Compared to volunteers, patients with MACS performed worse in the domains of attention and executive function (effective allocation of one's limited capabilities in an abundance of stimuli) (median T-score of 50 vs. 46, p=0. 03), cognitive flexibility (tested as the capacity to plan and monitor goal-directed activities) (median T-score of 61 vs. 55, p=0. 01). The fluid composite score (includes executive function, episodic memory, working memory, and processing speed) was lower in patients with MACS (mean of 53.2 vs. 48.9, p=0. 03). The total composite score was lower in patients with MACS when compared to volunteers (median T score of 50 vs. 54, p=0. 06). The total composite cognitive scores in patients of MACS were associated with the Frailty Index (R2 = 0.13, p = 0. 025) and SF-36 scores (R2 = 0. 08, p = 0. 05), but not post-DST cortisol. Conclusion Compared to volunteers, patients with MACS demonstrate cognitive impairment, particularly in the executive domain, which closely mimics changes observed with aging. These deficits do not correlate with the degree of cortisol excess. Presentation: No date and time listed

Cortisol levels in rural Latina breast cancer survivors participating in a peer-delivered cognitive-behavioral stress management intervention: The Nuevo Amanecer-II RCT

BackgroundCompared to their White counterparts, Latina breast cancer survivors have poorer survival rates and health-related quality of life, and higher rates of depression and anxiety which may be a result of chronic stress. Chronic stress impacts the hypothalamic-pituitary-adrenal (HPA) axis, resulting in cortisol dysregulation which may be associated with breast cancer survival. However, cortisol levels and cortisol profiles of Latina breast cancer survivors are poorly characterized due to their underrepresentation in biomedical research. ObjectiveThe objective of this study was to describe cortisol levels and patterns of cortisol secretions in rural Latina breast cancer survivors participating in an RCT study of Nuevo Amanecer-II, an evidence-based peer-delivered cognitive behavioral stress management intervention. MethodsParticipant-centered recruitment and collection strategies were used to obtain biospecimens for cortisol analysis. Nine saliva samples (3/day for 3 days) and a hair sample were obtained at baseline and 6-months (3-months post-intervention). We describe cortisol levels and profiles, explore correlations of biomarkers with self-report measures of stress and psychological distress, and compare women who received the intervention with a delayed intervention group on biomarkers of stress. Mean hair cortisol concentration (HCC) was used to assess chronic stress. Based on daily measures of cortisol (awakening, 30 min post-awakening, and bedtime), we calculated three summary measures of the dynamic nature of the cortisol awakening response (CAR): 1) the CAR slope, 2) whether CAR demonstrates a percent change ≥40, and 3) total daily cortisol output (AUCg). Linear and log-binomial regression, accounting for multiple samples per participant, were used to compare cortisol measures at 6-month follow-up by treatment arm. ResultsParticipants (n = 103) were from two rural California communities; 76 provided at least one saliva sample at baseline and follow-up and were included in the analysis. At baseline, mean age was 57 years, mean years since diagnosis was 2 years, 76% had a high school education or less, and 34% reported financial hardship. The overall median CAR slope was 0.10, and median cortisol AUCg (in thousands) was 11.34 (range = 0.93, 36.66). Mean hair cortisol concentration was 1751.6 pg/mg (SD = 1148.6). Forty-two percent of samples had a ≥40% change in CAR. We found no statistically significant correlations between the cortisol measures and self-reported measures of stress and psychological distress. At follow-up, no differences were seen in HCC (mean difference between intervention and control: −0.11, 95% CI -0.48, 0.25), CAR slope (0.001, 95% CI -0.005, 0.008), cortisol AUCg (−0.15, 95% CI -0.42, 0.13), or ≥40% change in CAR (prevalence ratio 0.87, 95% CI 0.42, 1.77) between treatment arms. ConclusionOur findings of flattened cortisol profiles among more than half of the sample suggest potential HPA-axis dysregulation among rural Spanish-speaking Latina breast cancer survivors that merits further study due to its implications for long-term survival. Trial registrationhttp://www.ClinicalTrials.gov identifier NCT02931552.

The Association of Cortisol with Prevalent and Incident Type 2 Diabetes in Older Community-Dwelling Adults

Context: Previous studies report cross-sectional associations between circulating cortisol levels and type 2 diabetes in older adults; none assessed the association prospectively.
 Objective: This study’s objective was to examine the association of serum cortisol with prevalent and incident diabetes in community-dwelling older adults.
 Methods: Between 1984-87, 885 men and 729 women aged 50 or older had serum fasting morning cortisol measured and an oral glucose tolerance test administered at a baseline research clinic visit and were followed for up to 25 years. Logistic and cox proportional hazards regression models were used to assess cortisol associations with prevalent and incident diabetes.
 Results: Median age of participants was 75 years, median body mass index was 25kg/m2, and median cortisol was 91mg/ml. At baseline, 249 participants had prevalent diabetes; 118 developed diabetes during follow-up. In unadjusted analyses, the odds of prevalent diabetes for the highest cortisol quartile compared to the lowest was 1.95 (95% CI: 1.32, 2.87) and remained significant after adjusting for age, sex and diabetes risk factors (OR: 1.85, 95% CI: 1.21, 2.83); associations were not significant for the second and third quartiles. Serum cortisol was not associated with incident diabetes before or after adjusting for covariates (fully-adjusted HR for highest versus lowest quartile=1.02, 95% CI: 0.58, 1.78).
 Conclusions: Results suggest that in older adults, elevated cortisol levels may be a result of diabetes and its complications, rather than a cause. Further studies using cohorts with repeated cortisol measures are needed to confirm the direction of the hypercortisolemia-diabetes link.

Long-term outcomes of adrenal insufficiency (AI) due to anti–PD(L)-1 immune checkpoint inhibitors (ICI) among patients with cancer.

12092 Background: Endocrine immune-related adverse events (irAEs) to anti-PD-(L)1 ICI, including hypophysitis, autoimmune insulin-dependent diabetes mellites (ICI-DM), and primary adrenal insufficiency (AI), are rare but often associated with long term co-morbidities. AI from anti-PD-(L)1 ICI without CTLA-4 blockade is not well characterized in the literature. Long term outcomes for AI including need for replacement steroids and cortisol levels are unknown. Methods: We performed a single center retrospective analysis of patients treated with ICI including anti-programmed cell death protein-1 (Anti-PD-1: nivolumab or pembrolizumab), anti-programmed death-ligand-1 (anti-PD-L1: atezolizumab or cemiplimab) and diagnosed with ICI induced AI by a board-certified endocrinologist from 1/1/2011 to 12/31/2021. Patients treated with anti-CTLA-4 based therapy were not included. Patient baseline characteristics, presenting symptoms at the time of AI diagnosis, and treatment with corticosteroids were obtained by chart review. Baseline labs were collected at the time of AI and during routine patient follow-up. Descriptive statistics are reported for the cohort. Results: Twenty-nine patients were identified, 27 diagnosed with secondary and 2 diagnosed with primary AI. The median age was 63 (range 39-84), 18 (62%) males and 11 (38%) females, 14 (48%) receiving anti-PD(L)-1 monotherapy and 22 receiving anti-PD(L)-1 combination therapy either with chemotherapy (7, 24%), targeted therapy (6, 21%) or other/investigational therapy (2, 7%). The common tumor types were 6 renal cell carcinoma, 4 urothelial carcinoma, 4 melanoma, 15 others. The common presenting symptoms were 26 (90%) with fatigue,16 (55%) weakness, 11 (38%) nausea/vomiting, 4 (14%) headaches and 2 (7%) arthralgias. The common concomitant irAEs were 16 (55%) hypothyroidism, 8 (28%) acute kidney injury, 7 (24%) colitis, 6 (21%) joint pain, 3 (10%) pneumonitis & dermatitis. Eleven (38%) patients were treated with high dose steroids. Median follow-up time for survivors in the cohort was 24 months (range 7-68). Median cortisol level at time of AI diagnosis was 1.1 (IQR 0.9, 2.7; n = 27) and 1.8 (IQR 0.6, 6.4; n = 10) at last follow-up (median lab follow-up 39 months, range 29-58); 7 of 10 patients with available data had cortisol < 5.0 at last follow-up. For secondary AI patients, median ACTH at time of diagnosis was 2.3 (IQR 2.0, 5.0; n = 21) and 2.0 (IQR 2.0, 7.2; n = 7) at last follow-up. Twenty-two of 23 patients with available data continued replacement steroids at last follow-up. Conclusions: AI associated with anti-PD(L)-1 ICI is primarily secondary. Cortisol and ACTH levels remain low even during long-term follow-up. Most patients need long-term replacement steroids. Systemic and comprehensive follow-up for patients who develop AI due to anti-PD(L)-1 ICI is needed to confirm these findings.

Exploring Daily Salivary Cortisol Patterns as Biomarkers of Chronic Chemotherapy-Induced Peripheral Neuropathy Pain.

Little is known about the biologic mechanisms of chronic chemotherapy-induced peripheral neuropathy (CIPN) pain. The purpose of this secondary analysis was to explore salivary cortisol patterns among cancer survivors with chronic CIPN pain to provide preliminary data regarding the role of hypothalamic-pituitary-adrenal axis dysregulation in the pathophysiology of this condition. 13 cancer survivors with chronic CIPN pain recruited from the breast, gastrointestinal, and gynecologic cancer centers at Dana-Farber Cancer Institute in Boston, Massachusetts. Salivary cortisol was collected on awakening, 30 minutes after awakening, and before going to bed on two consecutive days. Cortisol awakening response and diurnal cortisol slope were calculated by averaging results across two days. Cortisol was available from 13 participants. The median cortisol awakening response was -0.03 mcg/dl, and the average diurnal cortisol slope was -0.24 mcg/dl. Mechanism-based treatments are needed for cancer survivors with chronic CIPN pain. Nurse scientists may use study results to explore stress-related mechanisms of chronic CIPN pain.

Maternal hair cortisol concentrations across pregnancy and the early postpartum period in a Puerto Rican sample.

Hair cortisol is a noninvasive, long-term biomarker of human stress. Strengths and weaknesses of this biomarker as a proxy measure of perinatal stress are not yet well understood. Hair cortisol data were collected from pregnant women in Puerto Rico to investigate maternal cortisol level variance across pregnancy. In 2017, we recruited 86 pregnant women planning to birth at a large urban hospital. We aimed to collect four hair samples from each participant, one in each trimester and one in the postpartum period. Median cortisol in the first trimester (n=82) was 5.7 picograms/milligram (pg/mg) (range: 1.0-62.4). In the second, third, and postpartum periods, the medians were 6.8pg/mg (1.0-69.5), (n=46), 20.1pg/mg (5.6-89.0), (n=30), and 14.1pg/mg (1.7-39.8), (n=9), respectively. These medians disguise a 10-fold and 50-fold variability for two participants. Our sample sizes declined sharply when Hurricane Maria caused major disruptions in services and participants' lives. Maternal hair cortisol concentrations were lower in the first and second trimester than the third trimester and early postpartum period. We also observed a wide range of variation in cortisol levels throughout pregnancy and in the postpartum period.

The association of gestational and childhood phthalate exposure with adolescent hair cortisol: The HOME Study

BACKGROUND AND AIM: Phthalate exposure during gestation and childhood may disrupt the hypothalamic-pituitary-adrenocortical (HPA) axis to adversely impact children’s neurodevelopment and cardiometabolic health. We evaluated associations of serial urinary phthalate metabolite concentrations with hair cortisol, a measure of HPA-axis homeostasis, to identify periods of heightened susceptibility during gestation, infancy, and childhood. METHODS: We recruited pregnant women from Cincinnati, Ohio (2003-2006) and followed their children until age 12 years. We quantified urinary phthalate metabolites twice during gestation and up to six-times during childhood (1, 2, 3, 4, 5, 8 years). At age 12 years, we quantified children’s hair cortisol concentrations (pg/mg hair). We estimated covariate-adjusted associations of log10-transformed average gestational or average childhood (1-8 years) phthalate metabolites with log10-transformed hair cortisol using linear regression. We used multiple informant models to estimate associations of serial phthalate measures with hair cortisol and assess the heterogeneity of this association across ages (n=207). RESULTS:The median hair cortisol concentration was 2.2 pg/mg (25th,75th percentile= 1.3, 5.2). We did not find evidence of an association between gestational phthalate metabolites and hair cortisol. However, each interquartile range (IQR) increase in average childhood ∑DEHP, MCPP, and MEP was associated with 289% (95%CI: 38, 996%), 78% (95%CI: -9, 255%), and 78% (95%CI: 15, 175%) higher hair cortisol concentrations, respectively; these associations did not vary by exposure period (heterogeneity p-values=0.53, 0.41, and 0.35, respectively). Positive associations of MBzP and MCOP with hair cortisol were stronger for exposure at infancy than in later childhood (heterogeneity p-values=0.06 and 0.16, respectively). An IQR increase in MBzP at age one year and MCOP at age two years was associated with 164% (95%CI: 56, 349%) and 77% (95%CI: 22, 155%) higher hair cortisol concentrations, respectively. CONCLUSIONS:Higher urinary concentrations of several phthalate metabolites during childhood, but not gestation, were associated with elevated hair cortisol concentrations in adolescence. KEYWORDS: phthalates, cortisol, development, susceptibility

Could serum total cortisol level at admission predict mortality due to coronavirus disease 2019 in the intensive care unit? A prospective study.

Critical diseases usually cause hypercortisolemia via activation of the hypothalamic-pituitary-adrenal axis. To investigate the relationship between serum total cortisol level and mortality among coronavirus disease 2019 (COVID-19) patients in the intensive care unit (ICU), at the time of their admission. Prospective study developed in a pandemic hospital in the city of Şırnak, Turkey. We compared the serum total cortisol levels of 285 patients (141 COVID-19-negative patients and 144 COVID-19-positive patients) followed up in the ICU. The median cortisol level of COVID-19-positive patients was higher than that of COVID-19 negative patients (21.84 μg/dl versus 16.47 μg/dl; P < 0.001). In multivariate logistic regression analysis, mortality was associated with higher cortisol level (odds ratio: 1.20; 95% confidence interval: 1.08-1.35; P = 0.001). The cortisol cutoff point was 31 μg/dl (855 nmol/l) for predicting mortality among COVID-19-positive patients (area under the curve 0.932; sensitivity 59%; and specificity 95%). Among the COVID-19 positive patients with cortisol level ≤ 31 μg/dl (79%; 114 patients), the median survival was higher than among those with cortisol level > 31 μg/dl (21%; 30 patients) (32 days versus 19 days; log-rank test P < 0.001). Very high cortisol levels are associated with severe illness and increased risk of death, among COVID-19 patients in the ICU.

The Association of Low Blood Glucose and Low Serum Cortisol Levels in Severely Ill Children Admitted to Tertiary Referral Hospitals in Malawi: A Case-Control Study

ABSTRACT.Low blood glucose concentrations < 5 mmol/L in severely ill children presenting to hospitals in low-income countries are associated with mortality. Adrenal insufficiency with low cortisol levels may contribute to low blood glucose concentrations. Understanding the association between low cortisol and low blood glucose may assist in improving guidelines for management of severely ill children. The study aimed to determine the association between low serum cortisol and low blood glucose in severely ill children. A matched case-control study of children aged 1 month to 15 years was conducted at two tertiary hospitals in Malawi. Cases were children with blood glucose < 5 mmol/L. Two age-matched controls with blood glucose of ≥ 5–15 mmol/L were enrolled per case. Low cortisol was defined as serum cortisol of < 25 µg/dL (690 nmol/L) and adrenal insufficiency as serum cortisol of < 10 µg/dL (276 nmol/L). A total of 54 cases and 108 controls were enrolled with, median age of 2.8 years (interquartile range [IQR]: 1.7–4.4). The median cortisol level was 58.7 µg/dL (IQR: 42.3–61.8) in cases and 40.9 µg/dL (IQR: 33.7–51.2) in controls (P = 0.911). The proportion of low cortisol was 4/54 (7.4%) in cases and 9/108 (8.3%) in controls. Logistic regression shows no association between low cortisol and low blood glucose (adjusted odds ratio: 0.33; 95% confidence interval, 0.04–3.02). Results suggest that there is no association between low cortisol and low blood glucose among severely ill children presenting to hospitals in Malawi. The reason for low blood glucose needs further investigation.

Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion.

Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000−2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9–32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, p < 0.0001) and ACTH (8.3 vs. 16 pg/mL, p < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS.

Cortisol as biomarker for CYP17 inhibition in mCRPC patients treated with abiraterone acetate.

5035 Background: Abiraterone acetate is an effective metastatic castration resistant prostate cancer (mCRPC) treatment, however, there is a high variability in response. It inhibits CYP17, thereby preventing the production of androgens. Abiraterone trough concentrations (Cmin) &gt; 8.4 ng/mL have been associated with an increased progression free survival (PFS) (Eur J Cancer. 2017;72:54-61; Prostate Cancer Prostatic Dis. 2020;23(2):244-251). However, plasma levels do not directly provide information on the level of CYP17 inhibition. Ideally, testosterone levels should be measured, but these levels are below the detection limit of available assays. The synthesis of cortisol is also inhibited by abiraterone via CYP17 inhibition and might therefore be a biomarker for CYP17 inhibition. The objective of this study was to investigate if cortisol levels are related to abiraterone levels and to clinical response. Methods: An observational study was performed in mCRPC patients treated with abiraterone acetate. At the outpatient clinic, plasma samples were collected for pharmacokinetic (PK) monitoring at each hospital visit. Reference populations of healthy volunteers and mCRPC patients using enzalutamide were included to investigate the influence of mCRPC and abiraterone treatment on the circadian rhythm of cortisol. Abiraterone and cortisol levels were measured using validated liquid chromatography-mass spectrometry (LC-MS/MS) assays. Clinical (prostate specific antigen (PSA) independent) PFS and PSA response were evaluated. Results: In total, 117 mCRPC patients using abiraterone acetate, 100 mCRPC patients using enzalutamide and 12 healthy volunteers were included. A clear circadian rhythm of cortisol was described in healthy volunteers and unaffected in mCRPC patients using enzalutamide. Contrarily, a circadian rhythm of cortisol could not be identified in mCRPC patients using abiraterone acetate, due to continuous suppression throughout the day. Patients with an abiraterone Cmin &gt; 8.4 ng/mL (n = 77) had a median cortisol concentration of 1.03 ng/mL vs. 2.59 ng/mL in patients with an abiraterone Cmin ≤8.4 ng/mL (n = 40) (p = 0.020). The median cortisol concentration in PSA responders (n = 63) was 1.02 ng/mL vs. 2.59 ng/mL for PSA non responders (n = 54) (p = 0.037). Patients in the highest cortisol tertile ( &gt; 3.03 ng/mL) had a median PFS of 3.7 months (n = 39) vs. 13.8 months in patients with cortisol levels ≤3.03 ng/mL (n = 78) (p = 0.007). The median PFS was 16.3 months in patients with an abiraterone Cmin &gt; 8.4 ng/mL and cortisol concentration &lt; 3.03 ng/ml vs. 5.3 months in patients with an abiraterone Cmin &gt; 8.4 ng/mL and cortisol concentration &gt; 3.03 ng/ml (p = 0.02). Conclusions: This study demonstrates that cortisol levels are of additional value to abiraterone concentrations as a marker for abiraterone acetate efficacy. This might help be helpful to assess efficacy of abiraterone treatment.

Impaired Muscle Strength and Performance in Patients With Mild Autonomous Cortisol Secretion

Background: Glucocorticoid-induced myopathy is well-recognized in overt Cushing syndrome (CS), but the impact of mild cortisol secretion on muscle is unclear. Recent data suggest that patients with mild autonomous cortisol secretion (MACS) are frailer and report more weakness than patients with non-functioning adrenal adenomas. We hypothesized that MACS is associated with 1) objective measures of impaired muscle strength and performance and 2) increased tissue accumulation of advanced glycation end products (AGEs), a measure of accelerated aging. Aim: To determine the effect of MACS on muscle mass, strength, performance, and tissue accumulation of AGEs. Methods: We conducted a cross-sectional analysis as part of an ongoing cohort study in patients with MACS compared to age and sex-matched referent subjects without cortisol excess. MACS was defined as serum cortisol >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST), in the absence of overt signs and symptoms of CS. We measured hand grip strength with hand grip dynamometer and evaluated functional performance on the timed up and go test, 6 minute walk test, and gait speed assessment. Tissue accumulation of AGEs was measured with point-of-care AGE reader. Appendicular lean mass was calculated and adjusted for height in participants who underwent body composition scan. Results: A total of 23 patients with MACS and 23 age and sex-matched referent subjects without cortisol excess were enrolled. The median age of diagnosis was 63 years (range, 51–81), and 26 (56%) were women. In the MACS cohort, median cortisol following 1 mg DST was 2.6 µg/dL (range, 1.9–13.0), median DHEA-S 37 µg/dL (range, 5.0- 141.0), and median ACTH 8.5 pg/mL (range, 5.0–38.0). Patients with MACS had lower hand grip strength (median 29.3 vs. 32.5 kg, p=0.052), slower gait speed (median 1.1 vs. 1.4 m/s, p=0.001), covered less distance during the 6 minute walk test (median 453 vs. 510 m, p=0.001), and took longer to complete the timed up and go test (median 10.1 vs. 8.6 s, p=0.04) than referent subjects without cortisol excess. Accumulation of AGEs was higher in patients with MACS (median 2.9 vs. 2.4, p=0.01). No significant difference was observed in appendicular lean mass (n=19 pairs, 7.8 vs. 7.5 kg/m2, p=0.57). Conclusions: MACS is associated with decreased muscle strength and performance without a significant change in muscle mass, suggesting poor muscle quality. We also observed increased tissue accumulation of AGEs in MACS patients, consistent with our hypothesis of MACS-induced accelerated aging. These findings may help explain the increased frailty observed in MACS, and suggest muscle assessment be considered in all patients with autonomous cortisol secretion. Further studies should examine the impact of muscle and functional impairments on morbidity in MACS, and its possible reversal with either a structured exercise intervention or adrenalectomy.

Impaired Cognitive Performance in Patients With Mild Autonomous Cortisol Secretion

Abstract Background: Cognitive deficits in memory, language, and executive function have been described in Cushing’s syndrome, but the impact of mild cortisol secretion on cognition is unclear. Rather than overt hypercortisolism, mild autonomous cortisol secretion (MACS) is typically associated with abnormal circadian cortisol production. Aim: To characterize the effect of MACS on cognitive performance. Methods: We conducted a cross-sectional analysis as part of an ongoing cohort study in patients with MACS compared to age and sex-matched referent subjects without cortisol excess. MACS was defined as serum cortisol concentration &amp;gt;1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST), in the absence of signs and symptoms of overt Cushing syndrome. We used the National Institute of Health Toolbox Cognition Battery to assess cognitive performance. A series of seven IPad-based tests were administered to evaluate five key domains: 1) executive function, 2) episodic memory, 3) working memory, 4) language, and 5) processing speed. Performance was reported using fully corrected T-scores for age, sex, education, and race with a normative mean of 50 and a standard deviation of 10. T-scores were generated for the individual components as well as three summary measures: 1) fluid cognition (includes executive function, episodic memory, working memory, and processing speed), 2) crystallized cognition (includes language), and 3) total cognition (composite of fluid and crystalized cognition). Results: A total of 23 patients with MACS and 23 age and sex-matched referent subjects without cortisol excess were enrolled. The median age of diagnosis was 63 years (range, 51–81), and 26 (56%) were women. In the MACS cohort, median cortisol following 1 mg DST was 2.6 ug/dL (range, 1.9–13.0) with median ACTH of 8.5 pg/mL (range, 5.0–38.0) and median DHEA-S of 37 mcg/dL (range, 5.0- 141.0). On cognitive assessment, patients with MACS had lower total cognition (T-scores 50 vs. 54, p=0.05) and fluid cognition (T-scores 48 vs. 53, p=0.01) composite scores compared to referent subjects without cortisol excess. In particular, patients with MACS performed worse on tests of executive function (Dimensional Change Card Sort: T-scores 55 vs. 63, p= 0.02 and Flanker Inhibitory Control and Attention: T-scores 45 vs. 52, p=0.01). There were no significant differences observed in the remaining individual domains of language, processing speed, working memory, and episodic memory, or crystallized cognition. Conclusions: MACS is associated with impaired total cognition, and in particular, executive function and fluid cognition. These findings suggest that patients with MACS are susceptible to cortisol-mediated changes in the brain. Additional studies should examine the contribution of neuropsychiatric symptoms on cognition in MACS, and possible improvement following treatment for cortisol excess.

306 Circadian activity rhythms and alertness among rapid-shift work female nurses

Abstract Introduction Circadian rhythms play an important role in regulating sleep. Sleep disturbances are prevalent in shift-work nurses, particularly for those work in rapid-shift rotation, including night shifts and day shifts. This study aimed to: 1) describe the characters of sleep-wake index (total sleep time [TST], wake after sleep onset [WASO], circadian activity rhythms [CAR]), psychomotor vigilance test (PVT), salivary cortisol, fatigue, and activity level during 8- and 12-hour rapid-shift work nurses; and 2) compare the parameters between two different shifts. Methods This exploratory study used registered nurses (RNs) from nine intensive care units in Beijing area. 7-days consecutive wrist actigraphy data, including TST and WASO were collected. Cosiner analysis was used for computing the CAR, including amplitude and mesor. PVT and saliva cortisol were used to assess alertness level, which measured before and after shift. Self-reported fatigue severity was measured by Lee Fatigue Scale-Short Form and assessed before and after shift. Results A total of 152 RNs (12-hour, n=82; 8-hour, n=70) participated this study, with a mean age of 31.81 (SD= 6.09). Compared with the 8-hour shift nurses, the 12-hour shift nurses were significantly higher in TST (456 vs. 364 minutes), median saliva cortisol level (before day shift, 0.54 vs. 0.31), and median PVT reaction time (before night shift). However, CAR were 0.53 (SD=0.13) and 0.50 (SD=0.18) for 12-hour and 8-hour shift RNs, respectively, and indicates desynchronized CAR in both groups. Regardless shift rotation, almost three-quarters of the RNs had a 500 ms PVT reaction time. For the 12-hour and 8-hour nurses, the level of activity during day shift was similar. However, during night shift work it was significantly lower in 12-hour nurses compared to the 8-hour nurses. All RNs experienced clinical significant fatigue severity (ranged 3.78 to 8.14) regardless before or after shift work; however, the 12-hour group reported lower fatigue severity than 8-hour group. Conclusion In this study, findings revealed shift-work RNs experienced fatigue and desynchronized CAR. The TST was low and reaction time was prolonged before and after shift work. Sleep intervention should be mandatorily included in clinical continue education. Support (if any) This project was supported by Chinese National Natural Science Foundation (71603279).

Confirmation of Feasibility of Selective Glucocorticoid Replacement Following Unilateral Adrenalectomy for Hypercortisolism and Primary Aldosteronism

Background: Secondary adrenal insufficiency (AI) can develop following unilateral adrenalectomy (UA) foradrenal-dependent hypercortisolism (HC) and has been reported after UA for primaryaldosteronism (PA). An institutional study previously demonstrated that cosyntropin stimulationtesting on postoperative day 1 (POD1-CST) successfully identified patients who requiredglucocorticoid replacement (GR) following UA; 50% of HC patients required GR and no PApatients required GR. The aim of this study was to reevaluate the need for GR following UA forpatients with HC and PA in a larger cohort of patients. Methods We reviewed 108 patients from a prospectively maintained adrenal database who underwent UAfor HC (n=74), PA (n=22), and concurrent HC/PA (n=12) from 9/2014-10/2020. PA patientswithout preoperative evaluation for HC were excluded. Patients with 1mg dexamethasonesuppression test (DST) cortisol >1.8 (µg/dL) were defined as having mild HC, with ³5 defined asovert Cushing’s Syndrome (CS). All patients underwent our institutional POD1-CST protocoland GR was initiated for patients with basal cortisol £5 or stimulated cortisol £14 (<18 prior to4/2017). Results: Overall, 51 (47%) patients had an abnormal POD1-CST and were discharged on GR (44 HC, 1PA, and 6 HC/PA). Two (2%) patients with CS had a normal POD1-CST but developed AIrequiring GR at 8 and 12 weeks post UA. Of the 74 patients with HC, 44 (59%) had an abnormalPOD1-CST and were discharged on GR, including 19/28 (68%) with CS and 25/46 (54%) withmild HC. Preoperative DST cortisol was higher in HC patients who required GR compared topatients with a normal POD1-CST (4.1 vs 3.6; p=0.007). Median cortisol levels for HC patientswith an abnormal POD1-CST vs those with a normal test were: basal: 3.8 vs 15.6 (p=0.027); 30-minute: 10.1 vs 20.1 (p=0.403); and 60-minute 11.4 vs 22.2 (p=0.260). Of the 22 PA patients, 19(86%) had a normal POD1-CST. Median cortisol levels for PA patients with an abnormal POD1-CST vs those with a normal test were: basal: 0.4 vs 12.1; 30-minute: 8.8 vs 24.6; and 60-minute:12.2 vs 28.9. Of the 3 (14%) PA patients with an abnormal POD1-CST, 1 was dischargedwith GR and began tapering after 2 weeks; the other 2 did not require GR and did not developAI. Of the 12 patients with combined PA/HC, 6 (50%) were discharged on GR based on POD1-CST. GR was required by 30 (59%) patients for <3 months and 82% for <12 months; 7/9 whorequired GR >12 months had CS. Conclusions: Using a standard protocol for POD1-CST in patients who underwent unilateral adrenalectomyfor HC, PA, or combined PA/HC, this study demonstrated that routine GR is not required in 32%of patients with CS and 46% of patients with mild HC. POD1-CST safely identifies patients whowill require GR with no immediate concern for adrenal insufficiency. These data also suggestthat routine evaluation for AI in postoperative PA patients is not needed if cortisol excess hasbeen excluded preoperatively.

Secondary Adrenal Insufficiency and Growth Hormone Deficiency in Patients with Fibromyalgia.

PurposePatients with fibromyalgia (FM) may demonstrate low cortisol concentrations during diagnostic evaluation. However, it remains unclear whether low cortisol reflects underlying pituitary dysfunction. We aimed to determine if a subset of patients with FM have concomitant secondary adrenal insufficiency (SAI) and growth hormone deficiency (GH).Patients and MethodsThis is a retrospective study of all patients with FM diagnosed with SAI based on abnormal insulin tolerance test (ITT) between June 2002 and August 2019. Patients were excluded if they had other reasons for SAI. Measurements include cortisol and GH during ITT in all patients, and peak cortisol during cosyntropin stimulation test in a subset of patients.ResultsWe identified 22 patients (median age of 38 years (range 19–65), 18 (82%) women) diagnosed with secondary AI based on abnormal ITT (peak median cortisol level of 11 mcg/dL (range 5.4–17)). Concomitant GH deficiency was diagnosed in 19 (86%) patients. Cosyntropin stimulation test was performed in 14 (64%) patients and was normal in 11 (79%) (peak cortisol ≥18 mcg/dL). MRI pituitary imaging was performed in 20 patients and showed no significant pituitary pathology. All patients were started on physiologic glucocorticoid replacement, and 5 patients were started on GH replacement. Of the 13 patients with follow-up, 8 (62%) reported symptom improvement after starting treatment.ConclusionPatients with FM can have concurrent SAI and GH deficiency. Cosyntropin stimulation test should not be used to exclude SAI in patients with FM. Appropriate glucocorticoid and/or GH replacement may improve symptoms in some patients.

Correlation between the stress scale with cortisol levels in leprosy patients

Introduction: Leprosy is an infectious disease caused by Mycobacterium leprae (M. leprae) that causes a complex problem. Stress can trigger several physiological responses, including the endocrine, nervous, and immune systems. In leprosy patients, stimulation in the form of infection and cytokine secretion lasts a long time, causing adrenal exhaustion, resulting in decreased serum cortisol production. This study aims to determine the correlation between the stress scale and cortisol levels in leprosy patients.Methods: This was a cross-sectional analytic correlation study with a consecutive sampling method. The research subjects were obtained from the Dermatology and Venereology Polyclinic of Universitas Sumatera Utara Hospital and the Dermatology and Venereology Polyclinic of Dr. Pirngadi Hospital Medan from March until November 2020. The research variables consisted of a stress scale and cortisol levels. Data analysis using the Spearman test. P-value &lt;0.05 was significant. The study was conducted after approval from the Ethics Committee Faculty of Medicine, Universitas Sumatra Utara.Result: A total of 35 patients enrolled in the study, the majority had characteristics of the male gender, multibacillary type of leprosy, duration of leprosy in the group &gt; 12 months, with a median age of 36 (19 - 79) years. The mean stress scale was 15.17 ± 6.3, with the mild stress scale was the most common. The median cortisol levels were 9.5 (4 – 20,8) g/dl, which was still in the low category. The lowest median cortisol levels were found in the multibacillary type of leprosy, duration of leprosy in the group &gt; 12 months, and severe stress scale. There was a significant moderate negative correlation between the stress scale and cortisol levels in leprosy patients (p = 0.017; r = -0.402).Conclusion: The heavier the stress scale, the lower the cortisol levels in leprosy patients.

Absence of relationship between serum cortisol and critical illness in premature infants

BackgroundInadequate cortisol production in response to critical illness in extremely preterm infants may exacerbate poor outcomes. Despite commonly measuring cortisol concentration and administering hydrocortisone for presumed adrenal insufficiency, the relationship...

Mid-axillary transversus abdominis plane block and stress response after abdominal hysterectomy: A randomised controlled placebo trial.

The hormonal response to surgical trauma can have detrimental effects on patients. Transversus abdominis plane (TAP) block, which can improve analgesia after total abdominal hysterectomy (TAH) might attenuate the peri-operative stress response. To evaluate the ability of the TAP block to reduce stress response, opioid consumption and pain following TAH and multimodal analgesia. Randomised, placebo-controlled double-blind study. The current study was conducted at a university hospital from July 2016 to September 2017. Fifty patients scheduled for TAH were included. Anaesthesia and postoperative analgesia were standardised. After induction of anaesthesia, patients were allocated into two groups: ultrasound-guided bilateral mid-axillary TAP block with 20 ml of bupivacaine 0.25% (Group T) or 0.9% saline (Group C). Levels of free serum cortisol, metanephrine and normetanephrine at 60 min and 6, 12 and 24 h after surgical incision. Pain scores and opioid consumption during the first 24 h after surgery. There was no statistically significant difference between the median [IQR] peri-operative levels of stress hormones and pain scores between groups. Compared with baseline value 9.90 [4.2 to 23.1], free serum median cortisol levels were significantly high at 6 h in Group T, 23.6 [10.1 to 42.9] P = 0.015 and Group C 23.6 [9.9 to 46.3] P = 0.014. Only Group C showed significant elevation from the baseline median levels of plasma metanephrine at 60 min, 52.8 [33.4 to 193.2] P = 0.001, 6 h, 92.70 [2.4 to 202.6] P = 0.005 and normetanephrine at 60 min 83.44 [28.98 to 114.86] P = 0.004, 6 h 78.62 [36.6 to 162.31] P = 0.0005 and 24 h 80.96 [8.6 to 110.5] P = 0.025. Mean ± SD opioid consumption was similar in both groups: 39.60 ± 14.87 in Group T vs. 43.68 ± 14.93 in Group C (P = 0.338). Mid-axillary TAP block does not improve stress response and analgesia in patients undergoing TAH receiving multimodal analgesia. ClinicalTrial.gov identifier: NCT03443271.

ACTH-cortisol dissociation in patients with Kawasaki disease: a retrospective study.

ACTH-cortisol dissociation is recognized in patients with critical illnesses. Cytokines, including tumor necrosis factor-α and interleukin-6 induce hypercortisolemia by enhancing the ACTH-independent synthesis and secretion of cortisol and by reducing cortisol breakdown. Subsequently, hypercortisolemia suppresses ACTH secretion by negative feedback inhibition. ACTH-cortisol dissociation in patients with systemic inflammatory diseases has not been reported. Here, we examined whether ACTH-cortisol dissociation is recognized in patients with Kawasaki disease (KD) associated with hypercytokinemia, as well as the possible cytokine involvement in ACTH-cortisol dissociation, retrospectively. The levels of serum cortisol, plasma ACTH, and cytokine-induced proteins, i.e., plasma C-reactive protein (CRP), serum ferritin, and urinary β2-microglobulin (U-β2MG), in 232 patients with KD were measured at diagnosis. Quartile groups based on cytokine-induced protein levels were formed (Q1, Q2, Q3, and Q4). We found a low median plasma ACTH [median (range): 8.9 (<2.0-332.0) pg/mL] but a high median serum cortisol level [median (range): 25.8 (1.4-99.8) μg/dL] in the entire study population. The median serum cortisol levels were significantly higher in the CRP-Q4, ferritin-Q4, and U-β2MG-Q4 groups than in the CRP-Q1, ferritin-Q2, and U-β2MG-Q1 groups, respectively (p < 0.01; p < 0.01; p < 0.001). The median plasma ACTH levels were significantly lower in the CRP-Q4 and ferritin-Q4 groups than in the CRP-Q1 and ferritin-Q1 groups, respectively (p < 0.001; p < 0.001). ACTH-cortisol dissociation was identified in patients with KD. Our findings suggest that inflammatory cytokines are involved in ACTH-independent hypercortisolemia in patients with KD. ACTH-cortisol dissociation in other systemic inflammatory diseases needs further investigation.