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Autonomous cortisol secretion (ACS) could be found in some patients with unilateral primary aldosteronism (uPA). However, the histopathological patterns of uPA with concurrent ACS have not been well elucidated. The adrenal gland with the adenoma from 61 uPA patients who underwent unilateral adrenalectomy were assessed by immunohistochemistry. Bioinformatics analysis, including the Cancer Genome Atlas (TCGA) and Kyoto Encyclopedia of Genes and Genomes, was applied. The prevalence of multiple aldosterone-producing nodules or micronodules (mAPN/mAPM) was 65.6% (40/61) among our uPA patients. Concurrent ACS was identified in 32% of this uPA cohort; they were associated with the interaction of larger tumor size (>1.98 cm) and mAPN/mAPM (odds ratio = 3.08, P = 0.004). Transcriptome analysis uncovered a dominant enrichment of HSD3B7 overexpression (P = 0.004) in the adenomas of the histopathologically classical adrenal uPA lesions with concomitant mAPN/mAPM, compared with those uPA adenomas without concurrent surrounding mAPN/mAPM. We identified a novel linkage of enhanced steroidogenic genes of HSD3B7 expression concurrent with the downstream higher CYP11B1 expression; further relationship was confirmed by immunohistochemical staining and validated by TCGA bioinformatics. The presence of mAPN/mAPM in uPA patients had lower rate for biochemical success after adrenalectomy (P = 0.047). In summary, two-thirds of uPA patients had concomitant mAPN/mAPM; 1/3 of uPA patients had concurrent ACS. Steroidogenic HSD3B7/CYP11B1 signaling was associated with uPA adenomas with surrounding mAPN/mAPM. Interaction of larger adenoma size with the presence of mAPN/mAPM was linked to co-existing ACS. Such uPA patients with concomitant mAPN/mAPM had lower rate of biochemical success.

Context Most patients with adrenal incidentaloma have nonfunctional lesions that do not require treatment, while others have functional or malignant tumors that require intervention. The plasma steroid metabolome may be useful to assess therapeutic need. Objective This work aimed to establish the utility of plasma steroid profiling combined with metanephrines and adrenal tumor size for the differential diagnosis of patients with adrenal incidentaloma. Methods This retrospective cross-sectional study, which took place at 7 European tertiary-care centers, comprised 577 patients with adrenal incidentaloma, including 19, 77, 65, 104 and 312 respective patients with adrenocortical carcinoma (ACC), pheochromocytoma (PHEO), primary aldosteronism (PA), autonomous cortisol secretion (ACS), and nonfunctional adrenal incidentaloma (NFAI). Mesaures of diagnostic performance were assessed (with [95% CIs]) for discriminating different subgroups of patients with adrenal incidentaloma. Results Patients with ACC were characterized by elevated plasma concentrations of 11-deoxycortisol, 11-deoxycorticosterone, 17-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone-sulfate, whereas patients with PA had elevations of aldosterone, 18-oxocortisol, and 18-hydroxycortisol. A selection of those 8 steroids, combined with 3 others (cortisol, corticosterone, and dehydroepiandrosterone) and plasma metanephrines, proved optimal for identifying patients with ACC, PA, and PHEO at respective sensitivities of 83.3% (66.1%-100%), 90.8% (83.7%-97.8%), and 94.8% (89.8%-99.8%); and specificities of 98.0% (96.9%-99.2%), 92.0% (89.6%-94.3%), and 98.6% (97.6%-99.6%). With the addition of tumor size, discrimination improved further, particularly for ACC (100% [100%-100%] sensitivity, 99.5% [98.9%-100%] specificity). In contrast, discrimination of ACS and NFAI remained suboptimal (70%-71% sensitivity, 89%-90% specificity). Conclusion Among patients with adrenal incidentaloma, the combination of plasma steroid metabolomics with routinely available plasma free metanephrines and data from imaging studies may facilitate the identification of almost all clinically relevant adrenal tumors.

Introduction Stress in pregnancy is associated with adverse outcomes in offspring, and developmental programming is a potential mechanism. We have previously shown that depression in pregnancy is a valid and clearly defined stress paradigm, and both maternal antenatal and offspring stress-related biology is affected. This study aims to clarify whether maternal biology in pregnancy and offspring outcomes can also be influenced by a history of a prior depression, in the absence of depression in pregnancy. Our primary hypothesis is that, similarly to women with depression in pregnancy, women with a history of depression but who are not depressed in pregnancy will have increased cortisol secretion and markers of immune system function, and that their offspring will have poorer neuro-developmental competencies and increased cortisol stress response. Methods A prospective longitudinal design was used in 59 healthy controls and 25 women with a past history of depression who were not depressed in pregnancy, named as ‘history-only’, and their offspring. Maternal antenatal stress-related biology (cortisol and markers of immune system function) and offspring outcomes (gestational age at birth, neonatal neurobehaviour (Neonatal Behavioural Assessment Scale, NBAS), cortisol stress response and basal cortisol at 2 and 12 months) and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development (BSID)) were measured. Results Compared with healthy pregnant women, those with a history of depression who remain free of depression in pregnancy exhibit increased markers of immune system function in pregnancy: IL-8 (d = 0.63, p = 0.030), VEGF (d = 0.40, p = 0.008) and MCP-1 (d = 0.61, p = 0.002) and have neonates with lower neurobehavioural scores in most areas, reaching statistical significance in the social-interactive (d = 1.26, p = 0.015) cluster. However, there were no differences in maternal or offspring HPA axis function or in infant development at 12 months. Conclusion Our study indicates that pregnant women with a history of depression have increased markers of immune system function, and their offspring show behavioural alterations that may be the effects of in utero programming, epigenetic factors or genetic predisposition.

Background Autonomous cortisol secretion was mentioned for the first time in 2016 in the European Guideline on the management of adrenal incidentalomas. Objectives Review of the state of knowledge on diagnosis, epidemiology, co-morbidities, mortality and treatment of autonomous cortisol secretion in comparison to non-hormone producing adenomas. Recommendation for clinical practice based on the current European guideline. Materials und methods Analysis of relevant clinical studies, discussion of basic literature and expert opinions. Results and conclusions Autonomous cortisol secretion is a term used to describe abnormal cortisol secretion diagnosed by a pathological 1‑mg dexamethasone suppression test in patients with adrenal incidentaloma, but without clinical manifestation of overt Cushing's syndrome. It is associated with increased mortality and morbidity, especially hypertension, diabetes mellitus type II, dyslipidemia and obesity. Adrenalectomy, as the only specific therapy option, should be considered in an interdisciplinary tumour board.

Adrenocortical carcinoma (ACC) is a rare but highly aggressive malignancy. Nearly half of ACC tumours overproduce and secrete adrenal steroids. Excess cortisol secretion, in particular, has been associated with poor prognosis among ACC patients. Furthermore, recent immunotherapy clinical trials have demonstrated significant immunoresistance among cortisol‐secreting ACC (CS‐ACC) patients when compared to their non‐cortisol‐secreting (nonCS‐ACC) counterparts. The immunosuppressive role of excess glucocorticoid therapies and hypersecretion is known; however, the impact of the cortisol hypersecretion on ACC tumour microenvironment (TME), immune expression profiles and immune cell responses remain largely undefined. In this study, we characterized the TME of ACC patients and compared the immunogenomic profiles of nonCS‐ACC and CS‐ACC tumours to assess the impact of differentially expressed genes (DEGs) by utilizing The Cancer Genome Atlas (TCGA) database. Immunogenomic comparison (CS‐ vs. nonCS‐ACC tumour TMEs) demonstrated an immunosuppressive expression profile with a direct impact on patient survival. We identified several primary prognostic indicators and potential targets within ACC tumour immune landscape. Differentially expressed immune genes with prognostic significance provide additional insight into the understanding of potential contributory mechanisms underlying failure of initial immunotherapeutic trials and poor prognosis of patients with CS‐ACC.

The stress response involves the activation of both the sympathetic-adrenal response and the hypothalamic-pituitary-adrenal axis. During times of increased stress, the adrenal gland is stimulated to produce increased levels of hormones. Cortisol, the main hormone involved in the stress response, is secreted in increased amounts within minutes of a perceived stressor. Cortisol secretion can increase as much as 20-fold and has several important physiological effects. Short-term surges in cortisol levels can suppress inflammation and at the same time suppress immune function. Though inflammation control is important, surges of sustained levels of cortisol are not healthy and ultimately lead to premature aging, degenerative disease, and increased susceptibility to cancer. Studies show that psycho-social stress activates the hypothalamus-pituitary-adrenal axis causing an increase in morning cortisol levels, which correlated to the subjects reports of increased fatigue and anxiety. Although this stress response is important for survival during an acute stressor, prolonged activation of the stress response may lead to adrenal exhaustion in which cortisol levels drop to insufficient levels resulting in fatigue or illness. Many herbs have been shown to impact adrenal function. Adaptogens are plants that produce a non-specific response improving the physiological resistance to stressors. These herbs are often used in the context of adrenal support formulas to balance adrenal hormone levels. It is believed that adaptogenic herbs can increase low levels of adrenal hormone or decrease levels that are elevated. Additionally, these herbs provide balancing activity on many body systems that are impacted by stress, such as the immune response and blood sugar control.In the present study, we have evaluated the efficacy of ethanolic extract of Ocimum sanctum 47mg/kg p.o, Withania somnifera 23 mg/kg p.o and Bacopa monnieri 23 mg/kg p.o on plasma cortisol level in mice subjected to swim endurance test and cold restraint stress. The standard group was administered water-soluble root powder of Panax ginseng 100 mg/kg p.o and the stress control group was administered distilled water orally for 7 days. It was found that mice pretreated with ethanolic extracts of Ocimum sanctum, Withania somnifera and Bacopa monnieri showed a fall in the plasma cortisol level. The standard group also showed a significant decrease in the plasma cortisol level compared to the stress and normal control groups.

We studied the effect of constant illumination on the effects of administration of arginine vasopressin (AVP), one of the most important regulators of the key adaptive hypothalamic—pituitary—adrenal (HPA) axis under basal conditions and during stress, as well as on the circadian rhythm of activity of HPA axis and the pineal gland in laboratory primates. In young adult female rhesus monkeys exposed to constant illumination for 7 weeks, the rise in the concentration of ACTH and cortisol in response to administration of AVP was markedly reduced in comparison with both the basal period and with the control group of animals. In addition, a destructive effect of constant lighting on circadian rhythm of cortisol secretion was observed in the absence of significant circadian changes in melatonin secretion. The inhibitory effect of constant illumination on the function of the HPA axis under basal conditions and under conditions of its activation can reduce the body’s adaptive abilities.

Preterm birth is associated with immaturity of several crucial physiological functions notably those prevailing in the lung and kidney. Recently, a steroid secretion deficiency was identified in very preterm neonates, associated with a partial yet transient deficiency in 11β-hydroxylase activity, sustaining cortisol synthesis. However, the P450c11β enzyme is expressed in preterm adrenal glands, we hypothesized an inhibition of cortisol production by adrenomedullin (ADM), a peptide highly produced in neonates and whose effect on steroidogenesis remains poorly known. We studied the effects of ADM on three models: 104 cord-blood samples of the PREMALDO neonate cohort, genetically targeted mice overexpressing ADM, and two human adrenocortical cell lines (H295R and HAC15 cells). Mid-regional-proADM (MR-proADM) quantification in cord-blood samples showed strong negative correlation with gestational age (P = 0.0004), cortisol production (P < 0.0001), and 11β-hydroxylase activity index (P < 0.0001). Mean MR-proADM was higher in very preterm than in term neonates (1.12 vs 0.60 nmol/L, P < 0.0001). ADM-overexpression mice revealed a lower 11β-hydroxylase activity index (P < 0.05). Otherwise, aldosterone levels measured by LC-MS/MS were higher in ADM-overexpression mice (0.83 vs 0.46 ng/mL, P < 0.05). More importantly, the negative relationship between adrenal ADM expression and aldosterone production found in control was lacking in the ADM-overexpression mice. Finally, LC-MS/MS and gene expression studies on H295R and HAC15 cells revealed an ADM-induced inhibition of both cortisol secretion in cell supernatants and CYP11B1 expression. Collectively, our results converge toward an inhibitory effect of ADM on glucocorticoid synthesis in humans and should be considered to explain the steroid secretion deficiency observed at birth in premature newborns.

OBJECTIVE Depression and anxiety symptoms are commonly observed among clinical populations, especially among women and maltreated individuals. Few investigations have, however, assessed the existence of distinct symptoms trajectories among clinical populations and how these relate to childhood maltreatment, sex differences, and stress physiology indexed by hair cortisol concentrations (HCC). The current study (1) identified distinct depression and anxious trajectories in a sample of psychiatric inpatients followed-up prospectively from their admission to a psychiatric emergency service (PES), and (2) examined whether HCC, childhood maltreatment and sex independently and jointly predict these trajectories. METHODS Adult inpatients (N = 402, 55% women) were recruited upon admission to PES (T1) during which HCC (reflecting cortisol secretion for the last 3 months), childhood maltreatment, and depression and anxiety symptoms were assessed. Symptoms were re-evaluated when patients were discharged from the hospital (T2), admitted to outpatient clinics (T3), and 12 months later or at the end of outpatient treatment (T4). RESULTS Three trajectories were identified for depression and anxiety symptoms. Among men, higher HCC predicted higher odds of evincing chronic depressive symptoms compared to a Low Stable trajectory (OR 3.46, 95% confidence interval [CI] 1.43-8.40). Greater childhood maltreatment among men predicted higher chances of exhibiting chronic anxious symptoms than the Low Stable (OR 1.47, 95% CI 1.07-2.02) and the High Decreasing trajectories (OR .70, 95% CI .51-.95). Opposite findings were noted for women. CONCLUSIONS Childhood maltreatment and HCC should be further investigated as predictors of anxious and depressive trajectories, during which sex-specific associations ought to be considered.

A description of 4 cases of newly diagnosed Cu­shing’s pituitary syndrome (PCS) is presented. The feature of the first case of PCS is the manifestation of the disease in the form of 2 spontaneous fractures of the foot bones, the absence of classical striae on the trunk and hips, low potassium, normoglycemia, preserved circadian rhythm of cortisol secretion. In the second case of PCS, the first manifestation of the disease is compression fracture of the spine, normoglycemia, preserved circadian rhythm of cortisol secretion, significant adrenal hyperandroge­nism, secondary hyperparathyroidism and vitamin D3-deficiency state, absence of eosinophils in peripheral blood. In the third case of PCS — the early onset (presumably at age 16), absence of compression fractures in the past medical history, clinically significant menstrual disorders, low potassium, disorders of the mineral and carbohydrate metabolism. In the fourth case of PCS — diabetes mellitus, absence of fractures in the past medical history and classical striae on the skin of the trunk and hips.

Primary adrenal insufficiency (PAI) in pediatric age is a rare, but potentially fatal condition caused by diverse etiologies including biochemical defects of steroid biosynthesis, developmental abnormalities of the adrenal gland, or reduced responsiveness to adrenocorticotropic hormone. Compared to adult PAI, pediatric PAI is more often the result of genetic (monogenic, syndromic disorders) than acquired conditions. During the past decade, rare monogenic disorders associated with PAI have helped unravel the underlying novel molecular genetic mechanism. The diagnosis of adrenal insufficiency in children and young infancy is often challenging, usually based on clinical suspicion and endocrine laboratory findings. Pediatric endocrinologists sometimes encounter therapeutic difficulty in finding the balance between undertreatment and overtreatment, determining how to optimize the dose over the patient’s lifetime, and maximizing mimicry of normal cortisol secretion with glucocorticoid replacement therapy.

The present study investigated associations between occupation, job stress, and salivary cortisol levels after psychological tasks. We examined 766 (273 men and 493 women) healthy employed Japanese participants aged 21 to 68 years (mean age = 46.4 years, standard deviation = 8.5) with three types of occupation: manager, teacher, and general worker. The Brief Job Stress Questionnaire was used to evaluate participants’ job stress levels, including job demand, job control, support from supervisors, and support from coworkers. Salivary cortisol levels were measured at pre-session, post-stressful tasks, and post-relaxation. All samples were assayed using an enzyme-linked immunosorbent assay test. Natural log transformation was applied before statistical analyses. A multiple regression analysis and a repeated measures analysis of covariance were conducted to test associations between occupation and salivary cortisol levels, adjusting for confounding factors. Statistical analyses were conducted separately for men and women. Among both men and women, general workers had higher cortisol levels than managers throughout the experimental session (men 0.6 μg/dL and 0.4 μg/dL, respectively; women 0.5 μg/dL and 0.4 μg/dL, respectively). Job control was positively associated with cortisol levels measured in all sessions, after adjusting for confounding factors (standardized beta 0.15, 0.21, and 0.18 for pre-session, post-stressful-tasks, and post-relaxation, respectively, all p

Objective Socioeconomic status (SES) remains a robust risk factor for mortality. Various theoretical models postulate that lower SES is associated with higher negative affect, which then initiates a cascade of physiological disturbances that contribute to illness and early mortality. However, few studies have explicitly investigated the interplay between psychological and biological factors in determining SES disparities in mortality. This study examined the role of daily negative affect and cortisol secretion in explaining the SES-mortality link in a large sample of US adults. Methods Using data from the Midlife in the United States study (N = 1,735, Mage = 56.40 ± 12.10 years, 56.4% female), we tested longitudinal associations between SES, daily negative affect, daily cortisol levels, and all-cause mortality 13 years later. Daily negative affect was classified into three clusters reflecting depressive affect, anxiety, and anger. Results Higher SES was linked to a lower risk of all-cause mortality (hazard ratio = 0.94, 95% CI [0.90, 0.97]). Furthermore, there was a sequential link between higher SES and lower mortality through lower daily depressive affect and a steeper ("healthier") diurnal cortisol slope (indirect effect = -0.001, Z = -2.14, p = .032, 95% CI = [-0.002, 0.000]). Daily anxiety and anger were not associated with cortisol levels or mortality (ps > .05). Conclusions These findings suggest that daily negative emotional experiences and the hypothalamic-pituitary-adrenal axis functioning may constitute important psychological and physiological pathways underlying the link between SES and all-cause mortality.

Several studies have demonstrated that a dysregulated hypothalamic-pituitary-adrenal (HPA) axis is related to worse health status (e.g., depression, posttraumatic stress, or diabetes, among others). However, less is known about the association between the individual's perception of their own health status and HPA-axis functioning in healthy older people. The aim of the present study was to examine the relationship between HPA-axis functioning and health-related quality of life (HRQoL) in healthy older people. To do this, 140 healthy older people (69 men and 71 women) from 56 to 76 years old collected eight saliva samples on two consecutive weekdays to measure the diurnal cortisol cycle (i.e. awakening cortisol levels, cortisol awakening response (CAR), overall morning cortisol levels, change in the cortisol levels during the day, and bedtime cortisol levels). In addition, they completed the SF-36 questionnaire to obtain a measure of HRQoL (i.e. reflecting physical and mental functional health status). Results showed that higher awakening and bedtime cortisol levels and the CAR were associated with a better perception of both physical and mental health. In addition, the wake-to-bed cortisol slope was only positively related to physical health. No sex differences were found. These findings suggest that the awakening and bedtime cortisol levels and the CAR are the most relevant indices of diurnal cortisol secretion for understanding the relationship between HPA-axis functioning and HRQoL status in older people.

EgierskaDominika, Pietruszka Paulina, Buchta Justyna. The importance of sleep in selected diseases. Journal of Education, Healthand Sport. 2021;11(8):334-341. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2021.11.08.037 https://apcz.umk.pl/czasopisma/index.php/JEHS/article/view/JEHS.2021.11.08.037 https://zenodo.org/record/5299703 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2021; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 05.08.2021. Revised: 15.08.2021. Accepted: 26.08.2021. The importance of sleep in selected diseases Dominika Magdalena Egierska Affiliation Wroclaw Medical University Country Poland Bio Statement — Principal contact for editorial correspondence. Paulina Pietruszka Affiliation Wroclaw Medical University Country Poland Bio Statement — Justyna Buchta Affiliation Wroclaw Medical University Country Poland Bio Statement — Abstract Introduction: There are specific differences in physiological and biochemical processes during sleep. Adenosine and melatonin are involved in the regulation of circadian rhythms. During sleep, you can observe the secretion of growth hormone, a reduction in cortisol secretion, and a decrease in muscle tone and blood pressure. Sleep can have a major impact on the development of systemic diseases. Aim of the study: A review of the literature aimed at identifying selected negative factors influencing the quality of sleep and systemic diseases which are related to sleep disorders. State of knowledge: Factors that negatively affect sleep include stress, as well as excessive time spent in front of light-emitting screens. Long-term lack of sleep increases the risk of obesity, diabetes, cardiovascular diseases and psychiatric diseases. Summary: Sleep plays an important role in the proper functioning of the body. Its quality is affected by many factors. Sleep disorders can be both the effect and cause of many diseases. Especially in diagnosing psychiatric diseases, attention should be paid to the occurrence of sleep disorders. Key words: sleep, stress, mobile phone, obesity, atrial fibrillation, mental diseases

Introduction: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may contribute to the symptom burden in bipolar disorder (BD). Further characterization of cortisol secretion is needed to improve understanding of the connection between mood, sleep, and the HPA axis. Here, we observe diurnal cortisol patterns in individuals with BD and healthy controls (HCs) to determine time points where differences may occur. Methods: Salivary cortisol was measured at 6 time points (wake, 15, 30, and 45 min after wake, between 2:00 and 4:00 p.m. and 10:00 p.m.) for 3 consecutive days in individuals with symptomatic BD (N = 27) and HC participants (N = 31). A general linear model with correlated errors was utilized to determine if salivary cortisol changed differently throughout the day between the 2 study groups. Results: A significant interaction (F = 2.74, df = 5, and p = 0.02) was observed between the time of day and the study group (BD vs. HC) when modeling salivary cortisol over time, indicating that salivary cortisol levels throughout the day significantly differed between the study groups. Specifically, salivary cortisol in BD was elevated compared to HCs at the 10:00 p.m. time point (p = 0.01). Conclusion: Significantly higher levels of cortisol in participants with BD in the night-time suggest that the attenuation of cortisol observed in healthy individuals may be impaired in those with BD. Reregulation of cortisol levels may be a target of further study and treatment intervention for individuals with BD.

The aim of this study was to evaluate the diagnostic accuracy of the 1 mg dexamethasone suppression test (DST) for the prediction of autonomous cortisol secretion (ACS)-related comorbidities in patients with adrenal incidentalomas (AIs). This was a retrospective multicenter study. We recruited patients with AI/s ≥ 1 cm, excluding those who, during the study, were found during the extension study of an extra-adrenal cancer, with a known diagnosis of hereditary syndromes characterized by adrenal tumors, those presenting with overt hormonal excess syndromes, and those in whom the DST results were missing. A total of 823 patients met the inclusion criteria. Based on the 1.8, 3.0, and 5.0 µg/dl post-DST cortisol thresholds, the prevalence of ACS was 33.5%, 13.7%, and 5.6%, respectively. The prevalence of hypertension (OR = 1.8, 95% CI = 1.3–2.4), diabetes (OR = 1.6, 95% CI = 1.2–2.2), and dyslipidemia (OR = 1.4, 95% CI = 1.0–1.9) was higher with cortisol post-DST ≥ 1.8 µg/dl; the prevalence of hypertension (OR = 2.1, 95% CI = 1.4–3.3) and diabetes (OR = 1.7, 95% CI = 1.1–2.6) was higher with values ≥ 3.0 µg/dl; and the prevalence of hypertension (OR = 2.0, 95% CI = 1.0–3.7) was higher with levels ≥ 5.0 µg/dl. However, the diagnostic accuracy of the DST for the prediction of cardiometabolic comorbidities in patients with AIs was poor, with areas under the ROC curve

Adrenal tumors are commonly discovered incidentally on cross-sectional abdominal imaging performed for reasons other than adrenal mass. Incidence of adrenal tumors increased 10-fold in the past 2 decades, with most diagnosed in older adults. In any patient with a newly discovered adrenal mass, determining whether the adrenal mass is malignant and whether it is hormonally active is equally important to guide the best management. Malignancy is diagnosed in 5% to 8% of patients with adrenal tumors, with a higher risk in young patients, if history of extra-adrenal malignancy, in those with large adrenal tumors with indeterminate imaging characteristics, and in bilateral adrenal tumors. Although overt hormone excess is uncommon in adrenal incidentalomas, mild autonomous cortisol secretion can be diagnosed in up to 30% to 50% of patients. Because autonomous cortisol secretion is associated with increased cardiovascular morbidity and metabolic abnormalities, all patients with adrenal incidentalomas require work up with dexamethasone suppression test. Management of adrenal tumors varies based on etiology, associated comorbidities, and patient’s preference. This article reviews the current evidence on the diagnosis and evaluation of patients with adrenal mass and focuses on management of the most common etiologies of adrenal incidentalomas.

Retinoids play a pivotal role in adrenal development and differentiation. Recent clinical trials revealed therapeutic potential of both all-trans and 9-cis retinoic acid in patients with cortisol excess due to a pituitary ACTH-secreting adenoma and indicated that retinoids might act also on the adrenal. Aim of the present study was to evaluate the effect of 9-cis retinoic acid on adrenals from patients with ACTH-dependent Cushing’s syndrome. Adrenal specimens from six patients with Cushing’s disease were incubated with 10 nM–1 µM 9-cis retinoic acid with and without 10 nM ACTH. Cortisol secretion was measured by immunoassay and expression of genes involved in steroidogenesis as well as retinoic acid action were evaluated by real-time RT-PCR. Incubation with 10–100 nM 9-cis retinoic acid increased spontaneous cortisol secretion and expression of STAR and CYP17A. On the other hand, in wells treated with ACTH, 9-cis retinoic acid markedly diminished ACTH receptor upregulation and no stimulatory effect on cortisol secretion or steroidogenic enzyme synthesis was observed. ACTH itself increased ligand-induced retinoic acid receptor expression, possibly enhancing sensitivity to retinoic acid. Our findings indicate that the effect of 9-cis retinoic acid in presence of ACTH is distinct from unchallenged wells and support the hypothesis of a direct adrenal action in patients with Cushing’s disease.

Many temperate zone animals exhibit seasonal rhythms in physiology and behavior, including seasonal cycles of reproduction, energetics, stress responsiveness, and immune function, among many others. These rhythms are driven by seasonal changes in the duration of pineal melatonin secretion. The neural melatonin target tissues that mediate several of these rhythms have been identified, though the target(s) mediating melatonin's regulation of glucocorticoid secretion, immune cell numbers, and bacterial killing capacity remain unspecified. The present results indicate that one melatonin target tissue, the paraventricular nucleus of the thalamus (PVT), is necessary for the expression of these seasonal rhythms. Thus, while radiofrequency ablations of the PVT failed to alter testicular and body mass response to short photoperiod exposure, they did block the effect of short day lengths on cortisol secretion and bacterial killing efficacy. These results are consistent with the independent regulation by separate neural circuits of several physiological traits that vary seasonally in mammals.

Background The impact of adrenalectomy on morbidity in patients with mild hypercortisolism and non-functioning adrenocortical adenoma is unclear. The present study evaluated morbidity before and after adrenalectomy in patients with benign adrenocortical tumour with Cushing´s syndrome (CS), autonomous cortisol secretion (ACS) and non-functioning adrenocortical adenoma as assessed by national and quality registries. Methods Patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) 2009–2017 with CS, ACS or non-functioning adrenocortical adenoma, were included in this retrospective study and analysed with age- and sex-matched controls, 1:3. Morbidity associated with CS was assessed pre- and postoperatively by analysing data from the Swedish National Patient Register and the Swedish Prescribed Drug Register. Results Some 271 patients were included, CS (127), ACS (45) and non-functioning adrenocortical adenoma (99), with 813 matched controls. The frequency of hypertension was almost 50% in all tumour groups. Antihypertensive medication preoperatively was more frequent in all tumour groups compared with controls. No preoperative differences in medication were detected between patients with CS and ACS. A decrease in the use of hypertensive drugs was noticed annually for all patient groups after adrenalectomy. Conclusions Hypertension is common in patients with benign adrenocortical tumours regardless of cortisol hypersecretion. The use of antihypertensive drugs in patients with CS, ACS and non-functioning adrenocortical adenoma was reduced after adrenalectomy. These findings highlight the need for a randomized controlled trial to investigate the impact of adrenalectomy on morbidity in patients with mild hypercortisolism.

Context Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are frequent accompaniments of depression, and studies have documented the role of stress and stressful life events in the ontogeny of perimenopausal depressions (PMD). Because HPA axis function in women is further modulated both by aging and ovarian steroids, it is possible that a dysregulated HPA axis contributes to the increased risk of PMD. Objective We examined HPA axis function in perimenopausal women with and without depression using the combined dexamethasone–corticotropin-releasing hormone (Dex/CRH) test. Methods Dex/CRH tests were performed on 20 women with PMD and 20 women who were also perimenopausal but without current or past depression (control women). Main outcome measures were plasma levels of cortisol and adrenocorticotropin (ACTH) and 24-hour urinary free cortisol (UFC). Five women took chronic stable medications, otherwise all women were medically healthy, and both groups were comparable with respect to reproductive stage and age. Standardized symptom rating scales were administered to each woman prior to Dex/CRH testing. Results No group differences were present in either baseline or stimulated ACTH and cortisol secretion. Baseline plasma measures of estradiol, progesterone, and 24-hour UFC levels similarly did not differ in PMD and control women. Conclusion Despite reports of increased stress responsiveness in PMD, we observed no abnormalities of HPA axis activity associated with PMD compared with women without depression. These findings suggest that PMD is not uniformly associated with HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from women with nonreproductive-related depressions.

Metabolic syndrome (MetS) is a highly prevalent disorder defined as a cluster of cardiometabolic risk factors including obesity, hyperglycemia, hypertension, and dyslipidemia. It is believed that excessive cortisol secretion due to psychosocial stress-induced hypothalamic-pituitary-adrenal axis activation might be involved in the pathogenesis of MetS. We sought to explore the association between MetS and psychosocial risk factors, as well as cortisol concentration measured in different biological specimens including saliva, blood serum, and hair samples. The study was conducted on a sample of 163 young and middle-aged men who were divided into groups according to the presence of MetS. Hair cortisol concentration (HCC) was determined using high performance liquid chromatography with UV detection, while blood serum and salivary cortisol levels were measured by enzyme-linked immunoassay. Lipid metabolism biomarkers were determined using routine laboratory methods. Anthropometric and lifestyle characteristics, as well as self-reported psychosocial indicators, were also examined. Significantly higher HCC and lower social support level among participants with MetS compared with individuals without MetS were found. However, no significant differences in blood serum and salivary cortisol levels were observed between men with and without MetS. In conclusion, chronically elevated cortisol concentration might be a potential contributing factor to the development of MetS.

Background The dexamethasone suppression test (DST) is the recommended first-tier test for suspected Cushing syndrome (CS). Missed dexamethasone intake or insufficient dexamethasone serum exposure may yield false positive results. Quantification of serum dexamethasone in DST samples may therefore improve test performance. Methods Simultaneous quantification of dexamethasone and cortisol by liquid chromatography-tandem mass spectrometry in 400 DST serum samples (100 overt CS, 200 excluded CS, 100 adrenal incidentalomas with (possible) autonomous cortisol secretion, AI-ACS) randomly selected within the indication groups. The 2.5th percentile of dexamethasone in patients with excluded CS was considered the lower limit of normal (LLN). Results Serum dexamethasone varied from undetectable to 20.2 ng/mL with a median of 4.8 ng/mL (95% CI 4.5-5.1 ng/mL). Dexamethasone was undetectable in only 16 patients (4%), suggesting non-compliance. The dexamethasone LLN was 1.8 ng/mL (4.6 nmol/L). Decreased glomerular filtration rate and diabetes mellitus were associated with higher serum dexamethasone concentration, while body mass index, sex, age, nicotine, and oral contraceptives had no significant effect. By excluding the 27 samples with dexamethasone Conclusions Quantification of dexamethasone and method-specific cortisol cutoffs in DST samples may reduce the false positive rate and lower the proportion of patients requiring further workup.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. For stage I and II tumors, surgery is a curative option, but even in these cases recurrence is frequent. Practical guidelines advocate a combination of mitotane with etoposide, doxorubicin, and cisplatin as first-line therapy for metastatic adrenocortical carcinoma. However, this scheme presents limited efficacy and high toxicity. The use of Immune Checkpoint Inhibitors (ICI) and multi-Tyrosine Kinase Inhibitors (mTKI) has modified the approach of multiple malignancies. The expectation of their applicability on advanced adrenocortical carcinoma is high but the role of these new therapies persists unclear. This article provides a short summary of last years’ findings targeting outcomes, limitations, and adverse effects of these new therapeutic approaches. The results of recent trials and case series pointed pembrolizumab as the most promising drug among these new therapies. It is the most often used ICI and the one presenting the best results with less related adverse effects when in comparison to the standard treatment with mitotane. Hereafter, the identification of specific molecular biomarkers or immune profiles associated with ICI or mTKI good response will facilitate the selection of candidates for these therapies. So far, microsatellite instability and Lynch Syndrome related germline mutations are suggested as predictive biomarkers of good response. Contrarywise, cortisol secretion has been associated with more aggressive ACC tumors and potentially poor responses to immunotherapy.

Background. Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy. ACCs often secrete adrenal steroid hormones including cortisol and androgens; however, aldosterone-producing ACC is very rare. Although adrenal production of aldosterone is assessed by adrenal venous sampling, the use of sampling from the relevant vein to assess aldosterone production from a tumor arising from ACC metastasis has not been previously reported. Case Presentation. We report the case of a 69-year-old Japanese man with aldosterone-producing ACC with hepatic metastasis. He presented with a history of treatment-resistant hypertension and hypokalemia. Endocrinological examination showed markedly increased plasma aldosterone concentration and suppressed plasma renin activity. Serum cortisol concentration was not suppressed by administration of dexamethasone 1 mg, and normal circadian variation of cortisol secretion was disrupted. Abdominal computed tomography showed a large tumor in the left adrenal gland and multiple tumors in the liver. Together, these results strongly suggested ACC with multiple liver metastases causing primary aldosteronism and subclinical Cushing syndrome. Adrenal and hepatic venous sampling showed markedly increased aldosterone concentration in the left adrenal vein but no increase in the hepatic vein, despite a pathological diagnosis of ACC with hepatic metastasis, with immunohistochemical investigation showing both primary and secondary tumors to have synthetic capability for aldosterone. The patient received mitotane but declined combination chemotherapy and died 2 months later. Conclusion. This is the first report of adrenal and hepatic venous sampling in a case of aldosterone-producing ACC with hepatic metastasis. The case suggests that hepatic venous sampling is unable to detect aldosterone production from liver metastases arising from ACC.

There are no data regarding periodontal derangements in patients with adrenal incidentalomas (AI). We assessed the frequency and severity of periodontitis in patients with AI [non-functioning adrenal incidentaloma (NFAI) and possible autonomous cortisol secretion (ACS)] and compared with individuals with normal adrenal. A cross-sectional study evaluated thirty-five individuals with AI and 26 controls. NFAI and possible ACS diagnosis was based on the current guidelines: NFAI [cortisol levels after 1 mg dexamethasone suppression test (1 mg-DST) ≤ 1.8 µg/dL (≤ 50 nmol/L)]; possible ACS [cortisol levels after 1 mg-DST 1.9–5.0 µg/dL (51–138 nmol/L)]. Sociodemographic data were collected, and a full-mouth periodontal evaluation was performed. There was no significant difference between groups regarding age, sex, income, ethnicity, education level, smoking, body mass index, dysglycemia, and arterial hypertension. Patients with AI exhibited worse periodontal conditions than controls for the following periodontal clinical parameters: mean percentage of probing pocket depth (PPD) and clinical attachment level (CAL) ≥ 5 mm (p

To evaluate differences between patients with unilateral and bilateral adrenal incidentalomas (AIs) in the prevalence of autonomous cortisol secretion (ACS) and related comorbidities. In this multicentre retrospective study, AIs ≥ 1 cm without overt hormonal excess were included in the study. ACS was defined by a post-dexamethasone suppression test (DST) serum cortisol ≥ 5.0 µg/dl, in the absence of signs of hypercortisolism. For the association of ACS with the prevalence of comorbidities, post-DST serum cortisol was also analysed as a continuous variable. Inclusion criteria were met by 823 patients, 66.3% had unilateral and 33.7% bilateral AIs. ACS was demonstrated in 5.7% of patients. No differences in the prevalence of ACS and related comorbidities were found between bilateral and unilateral AIs (P > 0.05). However, we found that tumour size was a good predictor of ACS (OR = 1.1 for each mm, P

Patients with adrenal insufficiency are usually treated with conventional hydrocortisone replacement therapy which fails to mimic the circadian rhythm of cortisol secretion. Dual-release hydrocortisone (DR-HC) resembles the daily normal cortisol profile improving metabolic parameters and quality of life. However, currently little is known about its impact on cognitive function. Aim of this study was to evaluate cognitive function and well-being in DR-HC treated patients compared to healthy controls and conventional HC treatment. Twenty adults with adrenal insufficiency treated with DR-HC (Plenadren®) underwent 10 neuropsychological tests, evaluating cognitive functions. Furthermore, demographic data, quality of life, symptoms of depression, and quality of sleep were evaluated by well-established questionnaires. Patients were compared by diagnosis (PAI/SAI) and dose (≥20 mg). In addition, eighteen DR-HC treated adults were compared to eighteen matched conventionally treated adults. With respect to diagnosis patients with PAI performed significantly better on intellectual abilities (p = 0.038) and on executive functioning (p = 0.026) and reported a significant longer time to fall asleep (p = 0.026). Regarding DR-HC dosage, there were no significant differences in cognitive functions. Patients on high dose reported a better subjective quality of sleep (p = 0.028) than patients on low dose. In comparison to conventional HC treatment, patients with DR-HC tended to show better results in executive functioning (p = 0.099). Patients with PAI reached better results in several cognitive functions and had a worse quality of sleep than patients with SAI. Our data suggest a positive impact of DR-HC on quality of sleep. DR-HC may be better for executive functioning.

Hypercortisolism is associated with a high prevalence of depression and impaired health-related quality of life (QoL). According to the available literature, studies examining the depression risk in patients with adrenal incidentalomas (AI), nonfunctioning and the ones with (possible) autonomous cortisol secretion ((P)ACS) are scarce. The aim of this observational, case–control study was to screen patients with nonfunctioning adrenal incidentalomas (NAI) and the ones with (P)ACS for depression and to assess their QoL. The total studied group consisted of 92 subjects—26 with NAI, 34 with (P)ACS and 32 age-matched healthy controls (HC). To screen for depression, we used the Beck Depression Inventory-II (BDI-II) and to assess the QoL, we used the Short-Form 36 Health Survey (SF-36). Patients with (P)ACS had significantly higher BDI-II scores and substantially lower QoL than patients with NAI or HC. Midnight cortisol level was the most significant predictor of BDI-II and SF-36 score. The receiver operating characteristic curve analysis demonstrated that a midnight cortisol value of 86.95 nmol/l had a high sensitivity (82.8%) and high specificity (80%) for detection of mild depression in patients with (P)ACS. Screening for depression and QoL assessment should become an integral part of clinical evaluation in patients with (P)ACS.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been associated with altered immune function, but the underlying molecular mechanisms are unclear. Epigenetic processes, including DNA methylation, respond to the glucocorticoid end-products of the HPA axis (cortisol in humans) and could be involved in this neuroendocrine-immune crosstalk. Here we examined the extent to which variations in HPA axis regulation are associated with peripheral blood DNA (CpG) methylation changes in 57 chronically stressed caregivers and 67 control women. DNA methylation was determined with the Illumina 450k array for a panel of genes involved in HPA axis and immune function. HPA axis feedback was assessed with the low-dose dexamethasone suppression test (DST), measuring the extent to which cortisol secretion is suppressed by the synthetic glucocorticoid dexamethasone. After multiple testing correction in the entire cohort, higher post-DST cortisol, reflecting blunted HPA axis negative feedback, but not baseline waking cortisol, was associated with lower DNA methylation at eight TNF and two FKBP5 CpG sites. Caregiver group status was associated with lower methylation at two IL6 CpG sites. Since associations were most robust with TNF methylation (32% of the 450k-covered sites), we further examined functionality of this epigenetic signature in cultured peripheral blood mononuclear cells in 33 participants; intriguingly, lower TNF methylation resulted in higher ex vivo TNF mRNA following immune stimulation. Taken together, our findings link chronic stress and HPA axis regulation with epigenetic signatures at immune-related genes, thereby providing novel insights into how aberrant HPA axis function may contribute to heightened inflammation and disease risk.

Glucocorticoid preparations, adreno-cortical steroids, with strong anti-inflammatory and immunosuppressive effects, are widely used for treating various diseases. The number of patients exposed to steroid therapy prior to surgery is increasing. When these patients present for surgery, the anesthesiologist must decide whether to administer perioperative steroid supplementation. Stress-dose glucocorticoid administration is required during the perioperative period because of the possibility of failure of cortisol secretion to cope with the increased cortisol requirement due to surgical stress, adrenal insufficiency, hemodynamic instability, and the possibility of adrenal crisis. Therefore, glucocorticoids should be supplemented at the same level as that of normal physiological response to surgical stress by evaluating the invasiveness of surgery and inhibition of the hypothalamus-pituitary-adrenal axis. Various textbooks and research articles recommend the stress-dose of glucocorticoids during perioperative periods. It has been commonly suggested that glucocorticoids should be administered in an amount equivalent to about 100 mg of cortisol for major surgery because it induces approximately 5 times the normal secretion. However, more studies, with appropriate power, regarding the administration of stress-dose glucocorticoids are still required, and evaluation of patients with possible adrenal insufficiency and appropriate glucocorticoid administration based on surgical stress will help improve the prognosis.

The risks associated with negative peer relationships and low socioeconomic status (SES), and how they impact diurnal cortisol and the cortisol response to negative experiences, have never been studied together in early adolescents; this study aims to fill this gap in the literature. Saliva was collected from 95 early adolescents (Mage = 10.80, SD = 0.72) and daily diaries were completed 30 min after awakening, beginning of school, 15 min after first recess, 15 min after lunch, and at the end of the school day across four consecutive days. Hierarchical Linear Modelling was used to estimate the within- and between-person variances of diurnal cortisol and the cortisol response to stress in the context of SES and peer experiences. Cortisol secretion differed by gender and was predicted by SES and social status within the peer group. Low-SES early adolescents had higher morning cortisol. Girls who were from higher SES families had the steepest diurnal cortisol slope. Non-accepted early adolescents had low cortisol in response to both positive and negative social experiences. The findings from this study clarify the impact of both SES and peer relations on early adolescent psychophysiological development.