Lower Morning Cortisol Levels Research Articles

Morning Serum Cortisol May Be Less Accurate for Diagnosing Adrenal Insufficiency in Hospitalized Patients, Particularly Those on Opioids

Abstract Introduction: The positive predictive value of a low morning serum cortisol to diagnose adrenal insufficiency (AI) is reported to be >90%, which is the basis for guidelines recommending morning cortisol as the first-line test for central AI. A level <3 µg/dL is considered diagnostic. However, studies that established this cut-off were conducted primarily in outpatients, not hospitalized patients in whom diurnal variation may be disrupted. Studies suggest that opioids suppress cortisol levels acutely, may disrupt diurnal cortisol rhythm, and cause adrenal insufficiency in 8–50% of chronically-exposed patients. The impact of hospitalization, particularly in the setting of opioid use, on the accuracy of diagnostics for AI is unknown. We hypothesized that low morning cortisol values in hospitalized patients, especially those prescribed opioids, do not accurately diagnose adrenal insufficiency, as determined by corticotropin stimulation test (CST) peak cortisol <18 µg/dL. Methods: We performed a retrospective analysis of CSTs in hospitalized patients in the Mass General Brigham health system from 5/2015 to 9/2020. Opioid-exposed adults who underwent CST were included if they had a morning cortisol (5–9 AM) result. Control patients were matched by age, gender and race and had no opioid prescriptions within 30 days of testing. Patients were excluded if tested in the outpatient or ICU setting, had a history of cirrhosis or pituitary disease, had an elevated ACTH, were prescribed oral estrogen, or received oral, IV or intraarticular glucocorticoids within 30 days. Results: The analysis included 124 opioid-exposed and 322 control patients, mean (±SD) age 60.8±14.4 and 63.8±15.3y, and 55.6% and 45.0% female, respectively. Twenty-two (17.7%) opioid-exposed and 33 (10.2%) control patients were diagnosed with AI by CST (p=0.031). Nineteen opioid-exposed (15.3%) and 22 control (6.8%) patients had morning cortisol of <3 µg/dL (p=0.005). A morning cortisol <3 µg/dL had a positive predictive value of 36.8% (CI 19.1–59.0%) for AI in opioid-exposed and 50.0% (CI 30.7–69.3%) in control patients. In opioid-exposed patients with low morning cortisol levels, mean daily morphine milligram equivalent and duration of opioid exposure did not differ between those with AI confirmed by CST and those with normal CST (p=0.13 and 0.38, respectively). Conclusion: Among hospitalized patients with suspected AI, those prescribed opioids have a higher prevalence of central AI than controls. Serum morning cortisol <3 µg/dL is not an accurate test for AI in hospitalized patients, including those prescribed opioids in whom low morning cortisol is more prevalent than in controls. Given the risks associated with misdiagnosis of AI, caution should be exercised in relying on morning cortisol values for the diagnosis of AI in hospitalized patients.

Gene Expression to Guide Glucocorticoid Replacement in Autoimmune Addison’s Disease

Abstract Objective: Deciding the optimal doses of glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD) is impeded by the lack of reliable biomarkers. This frequently results in over-treatment, with alarming and persistent side-effects, or under-replacement, which could be fatal. There is a need to think new in the quest for robust biomarkers to optimize GC replacement in AAD at an individual level. Aim: We aimed to identify genes that are consistently up- or down-regulated in patients with AAD in response to different GC replacement doses. This information can be used to establish novel biomarkers to guide GC treatment in AAD. Methods: Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. To verify the results, we performed real-time PCR to compare gene expression levels of three of the highly differentially expressed genes (FKBP5, MMP9, and DSIPI) to compare gene expression levels before and two, four, and six hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD. Results: Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression. Conclusions: We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.

Treatment of Cushing’s disease with macroadenoma through transsphenoidal surgery

Cushing’s disease (CD) is a rare illness characterized by chronic hypercortisolism secondary to the overproduction of adrenocorticotropic hormone by a pituitary adenoma, which is associated with a high risk of developing serious complications, such as diabetes mellitus, cardiovascular disease, and emotional disorders. Endoscopic transsphenoidal surgery is performed for the treatment of CD, and was initially preferred over other types of treatments. However, the recurrence after pituitary surgery for CD is a common problem after an initial successful surgery. In microadenomas, the remission rates were higher than those of macroadenoma. This patient had a giant tumor that was greater than 4 cm in length on sella magnetic resonance imaging, and panhypopituitarism was detected using a combined pituitary stimulation test. After transsphenoidal surgery, the patient required temporary hormone replacement for a short period of time. After 1 year, he showed a normal cortisol response on the overnight dexamethasone suppression test and low morning cortisol levels. Therefore, we indicated that the patient was cured of giant macroadenoma with panhypopituitarism before surgery, and thus, reported this case. Key words: Cushing disease, Theasinensin A, Adenoma, Pituitary

Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison's Disease.

BackgroundNo reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal.ObjectiveTo explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD.MethodsStep 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In 3 of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and 3, 4, and 6 hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD.ResultsStep 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and levels of ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression.ConclusionsWe introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.

The persistent associations between early institutional care and diurnal cortisol outcomes among children adopted internationally.

Young children in institutional care experience conditions that are incompatible with their needs for attachment relationships. As a result, early institutionalization is expected to have lasting effects on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. The current study tested whether early institutionalization has persistent consequences for diurnal HPA axis outcomes among 130 children who had been adopted internationally between the ages of 6 and 48months. Daily cortisol samples were collected from children at two time points: shortly after adoption (average of 5.3months after adoption) and approximately 3years later (average of 39.2months after adoption). Shortly after adoption, children who had experienced a long duration of institutional care had lower morning cortisol levels and more blunted declines in cortisol across the day than children who experienced minimal or no institutional care. Three years later, children who had experienced a long duration of institutionalization continued to exhibit low morning cortisol levels and also exhibited low bedtime cortisol levels. Altogether, these results support the idea that early adversity results in the downregulation of the HPA axis and suggest that the effects of institutionalization on HPA axis functioning may persist several years after children are adopted into highly enriched families.

The biological underpinnings of perinatal depressive symptoms: A multi-systems approach.

BackgroundWell-established evidence exists of an association between depressive symptoms and alterations in the stress and inflammatory response systems; however, the picture is far less coherent during the perinatal period. This study combines the assessment of multiple stress and inflammatory biomarkers in late pregnancy and after delivery in order to investigate cross-sectional and prospective associations with perinatal depressive symptoms. MethodsOne-hundred-ten healthy women were assessed in late pregnancy (mean gestational age=34.76; SD=1.12) and 89 were re-evaluated after delivery (mean hours after delivery=52.36; SD=19.70) for depressive and anxiety symptoms through the Edinburgh Postnatal Depression Scale and the State-Trait Anxiety Inventory. Serum Interleukin-6 (IL-6), C-Reactive Protein (CRP) and diurnal salivary cortisol levels were measured on both occasions, while diurnal salivary alpha amylase (sAA) levels were assessed in late pregnancy. ResultsUsing Hierarchical Linear Models, higher depressive symptoms were found to be associated with higher IL-6 levels, lower morning cortisol levels and a flatter cortisol diurnal slope during pregnancy, while adjusting for potential confounders. No significant associations were found after delivery or with change in biomarker levels from pre- to post-partum. Furthermore, preliminary evidence of a positive association between inflammation and stress markers in women with higher antenatal depressive symptoms was found. LimitationsThe sample was relatively small and highly selected, thus limiting generalizability of the findings. ConclusionsResults emphasize the need for an integrated multi-systems approach to the understanding of the biological underpinnings of perinatal depression and suggest that the stress-immune interactions represent a promising avenue for future endeavor.

SAT-187 Altered Mental Status in a Patient with Bilateral Adrenal Masses

IntroductionPrimary adrenal lymphoma (PAL) is a very rare and aggressive form of Non-Hodgkin’s lymphoma originating from the adrenal glands and with no prior history of lymphoma. It can present with symptoms related to adrenal insufficiency due to tumoral destruction of normal adrenal tissue. Hypercalcemia has also been previously reported as a less common presentation of PAL. We describe here a case of PAL presenting with severe hypercalcemia and adrenal insufficiency.Clinical Case75 year male presented with 50 pound weight loss, fatigue and anorexia for several months. On admission, patient had altered mental status. Further investigation revealed severe hypercalcemia (corrected calcium for albumin =15mg/dl) and AKI (serum creatine=3.45mg/dl, blood urea nitrogen=89). He was started on IV fluids for the hypercalcemia and AKI. Additional work up revealed suppressed parathyroid hormone (PTH) levels of 9 (12 - 88 pg/mL), high normal PTH-related peptide 22 (14-27), low 25-OHD 7.34 (20-120 ng/ml), high normal 1,25-(OH)2-D 63.0 (19.9-79 pg/mL). His ACTH level was elevated ~159 (7.2-63.3 pg/ml) with low normal morning cortisol levels ~10 mcg/dl. Patient was started on IV stress dose steroids for concerns of adrenal insufficiency and calcitonin was also initiated for the treatment of hypercalcemia. CT of the abdomen showed bilateral adrenal masses, measuring 9.8 x 6.4 x 10.8 cm on the right and 9.3 x 5.2 x 9.6 cm on the left with marked retroperitoneal lymphadenopathy. After ruling out pheochromocytoma with negative plasma and urine metanephrines, biopsy of the adrenal mass revealed a highly aggressive diffuse B large cell lymphoma, with BCL2 and MYC overexpression. Concurrent flow cytometric analysis also identified an abnormal population of medium to large B cells expressing bright CD20, CD19, CD38, CD45 without CD10, CD5, CD23 or overt kappa or lambda expression. His calcium levels improved with hydration and steroids. Chemotherapy was later initiated.ConclusionPrimary adrenal lymphoma is rare and aggressive type of NHL. While adrenal insufficiency is expected in this clinical scenario, hypercalcemia from 1,25-(OH)2-D excess is a relatively uncommon presentation. Adrenal insufficiency should be ruled out in bilateral infiltrative adrenal masses. Likely etiologies for hypercalcemia in our case appeared to be secondary to elevated 1,25-(OH)2-D production, humoral hypercalcemia of malignancy and worsened by untreated clinically evident adrenal insufficiency.References(1) Laurent C, Casasnovas O, Martin L, et al. Adrenal lymphoma: presentation, management and prognosis. QJM. 2017 Feb 1;110(2):103-109. doi: 10.1093/qjmed/hcw174(2) Masood A, Tumyan A, Nussenzveig D R., Wakefield D N., Barb D, Ghayee H K., Maalouf N M. The Diverse Clinical Presentations of Adrenal Lymphoma. AACE Clinical Case Reports: Autumn 2017, Vol. 3, No. 4, pp. e307-e312. doi: 10.4158/EP161595.CR

How do stress, sleep quality, and chronotype associate with clinically significant depressive symptoms? A study of young male military recruits in compulsory service.

Objective:Although studies have shown an association between poor sleep and chronotype with psychiatric problems in young adults, few have focused on identifying multiple concomitant risk factors.Methods:We assessed depressive symptoms (Beck Depression Inventory [BDI]), circadian typology (Morningness-Eveningness Questionnaire [MEQ]), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), perceived stress (Perceived Stress Scale [PSS]), social rhythm (Social Rhythm Metrics [SRM]), and salivary cortisol (morning, evening and night, n=37) in 236 men (all 18 years old). Separate analyses were conducted to understand how each PSQI domain was associated with depressive symptoms.Results:Depressive symptoms were more prevalent in individuals with higher perceived stress (prevalence ratio [PR] = 6.429, p < 0.001), evening types (PR = 2.58, p < 0.001) and poor sleepers (PR = 1.808, p = 0.046). Multivariate modeling showed that these three variables were independently associated with depressive symptoms (all p < 0.05). The PSQI items subjective sleep quality and sleep disturbances were significantly more prevalent in individuals with depressive symptoms (PR = 2.210, p = 0.009 and PR = 2.198, p = 0.008). Lower levels of morning cortisol were significantly associated with higher depressive scores (r = -0.335; p = 0.043).Conclusion:It is important to evaluate multiple factors related to sleep and chronotype in youth depression studies, since this can provide important tools for comprehending and managing mental health problems.

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. Relative to the control group, the survivors group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivors group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivors group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. The small sample size was the main limitation of this study. Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.

Limbic response to stress linking life trauma and hypothalamus-pituitary-adrenal axis function

Trauma alters neuroendocrine responses to stress and increases vulnerability to stress-related disorders. Yet, relationships among trauma, stress-induced neural changes and hypothalamic–pituitary–adrenal (HPA) axis activity have not been determined. The present study used functional magnetic resonance imaging to investigate the impact of life trauma on basal cortisol levels and neural responses to acute stress in 73 healthy individuals during brief stress and neutral-relaxing imagery using a well-established, individualized imagery method. We hypothesized that trauma experience would have a negative impact on brain function, resulting in altered basal cortisol levels via dysregulated neural control over the HPA axis system. Results showed that higher life trauma exposure was significantly associated with lower basal cortisol levels. Neuroimaging results indicated that both higher life trauma and low morning cortisol levels were associated with increased response to acute stress in limbic-medial temporal lobe (MTL) regions including the amygdala and hippocampus. A mediation analysis showed that increased limbic-MTL response to stress mediated the relationship between life trauma and low cortisol levels. Findings revealed a significant impact of lifetime trauma on neural responses to acute stress and HPA axis activity. Life trauma may sensitize limbic-MTL regions and its related peripheral systems, which could compromise stress regulation and HPA axis function, and increase risk for negative stress-related health outcomes.

Aggression as an independent entity even in psychosis – The role of cortisol

Aggression is a common entity in psychiatric disorders, particularly psychotic disorders. Glucocorticoid hypofunction has been linked to abnormal forms of aggressive behavior in various studies in a ‘possibly causal’ role. We hypothesise that aggression, even among those having psychosis is associated with glucocorticoid alterations similar to those who are aggressive but not psychotic. To our knowledge, this is the first study attempting to look at the cortisol functioning in relation to both aggression and psychosis. The present study included 80 participants divided into four groups depending upon presence or absence of aggression and psychosis. Morning cortisol, afternoon cortisol and their variability were measured using ELISA. The groups were compared on measures of aggression, psychosis, morning cortisol, afternoon cortisol and their variability using standard statistical instruments. The present study found lower levels of morning cortisol, afternoon cortisol and cortisol variability among the aggressive group (vs. non aggressive group) and among the diseased group (vs. non diseased group). The differences were most marked for cortisol variability which was related to both aggression and psychosis independently. There were statistically significant correlation between cortisol variability and aggression, which was retained even after controlling for psychosis. There was no significant correlation of cortisol variability with psychosis severity (after controlling for aggression score) or with age, gender or duration of psychosis. We conclude that aggression, even among patients with psychosis, is an independent entity characterized by lower levels of morning cortisol and cortisol variability. The etio-pathology may lie in some altered neuro-immune parameters executed by cortisol and psychosis as trigger.

Parental depression and parent and child stress physiology: Moderation by parental hostility.

This study examined the moderating role of parental hostility on the associations between parental depression and the cortisol awakening response (CAR) and morning cortisol levels of both parents and children. 148 parents and 148 preschool-aged children provided salivary cortisol samples at waking, 30 and 45 min post-waking on two consecutive days. Parental depression was assessed using a clinical interview, and parental hostility was assessed using an observational parent-child interaction task. Results indicated that the combination of parental lifetime depression and high parental hostility was associated with lower morning cortisol levels in both parents and children. This interactive effect was present in children regardless of their exposure to parental depression. In addition, the combination of higher levels of parents' current depressive symptoms and parental hostility was associated with lower parent CAR. Lastly, parents' and children's lower morning cortisol levels were associated with parent-reported child externalizing symptoms. Findings demonstrate that parents and children have similar stress system functioning related to parental depression and the parenting context, as well as children's behavioral problems, which may play a role in the intergenerational transmission of risk for psychopathology.

СТАН ВЕГЕТАТИВНОЇ РЕГУЛЯЦІЇ В ОСІБ ІЗ ВИСОКИМ РІВНЕМ ПРОФЕСІЙНО ЗУМОВЛЕНОГО ПСИХОЕМОЦІЙНОГО НАВАНТАЖЕННЯ – ВОДІЇВ ПАСАЖИРСЬКОГО ЕЛЕКТРОТРАНСПОРТУ

Метою дослідження стало вивчення стану вегетативної регуляції в осіб із високим рівнем професійно зумовленого психоемоційного навантаження – водіїв пасажирського електротранспорту. Стан вегетативної регуляції визначали за даними варіабельності ритму серця (методом кардіоінтервалографії), активності та біоритміки гормонів стресу – кортизолу та катехоламінів. Стан вегетативної регуляції варіабельності ритму серця в обстеженого контингенту відзначався суттєвим підвищення ролі центрального контуру керування та значною компенсаторною активністю парасимпатичної ланки вегетативної регуляції із суттєвим зростанням активності автономного контуру керування. Стан активності та біоритміки гормонів стресу характеризувався суттєво вищим рівнем вмісту в крові катехоламінів, більш низьким рівнем кортизолу вранці та більш високим рівнем кортизолу ввечері, зменшенням різниці між ранковим і вечірнім рівнями кортизолу порівняно з працівниками без психоемоційного навантаження. Загалом, результати дослідження встановили, що у водіїв пасажирського електротранспорту підвищену активність симпато-адреналової системи організму та гормонів стресу і перекручення біологічного ритму регуляції вегетативних механізмів адаптації.

The Impact of Complicated Grief on Diurnal Cortisol Levels Two Years After Loss: A Population-Based Study.

Few studies have focused on the effect of complicated grief-unresolved and prolonged grief-on the neuroendocrine systems. The present study examined the association of complicated grief and normal grief with the diurnal cortisol patterns in a large population-based study. This study was set in the Rotterdam Study and comprised 2084 persons aged older than 55 years (mean [SD] age, 64.9 [5.5] years). Participants were assessed with the Complicated Grief Inventory and classified into no grief (n = 1922), normal grief (n = 131), or complicated grief (n = 31) if they experienced the loss in the past 2 years. Saliva samples were collected to measure cortisol levels. Morning cortisol and summary measures (area under the curve and the slope) were studied to account for the diurnal pattern of cortisol. Persons with depressive disorders were excluded, and analyses were additionally adjusted for depressive symptoms. Compared to normal grievers, participants with complicated grief showed lower levels of morning cortisol (11.26 vs 15.51 nmol/L; difference, -4.24; 95% confidence interval [CI] = -7.87 to -0.62; p = .022), and lower levels of overall diurnal cortisol (6.89 vs 8.98 nmol/L; difference, -2.09; 95% CI = -3.81 to -0.37; p = .017). No difference was observed in slope between both groups. Participants with complicated grief also showed lower levels of morning cortisol than the nongrievers (11.26 vs 14.71; difference, -3.46; 95% CI = -6.78 to -0.13; p = .042). In contrast, cortisol secretion patterns did not differ between persons with normal grief and nongrieving controls. Participants with complicated grief showed low levels of morning cortisol and low overall diurnal cortisol levels characteristic for a chronic stress reaction.

Dysregulation of the cortisol diurnal rhythm following prenatal alcohol exposure and early life adversity.

The hypothalamic-pituitary-adrenal (HPA) axis is impacted by a multitude of pre- and postnatal factors. Developmental programming of HPA axis function by prenatal alcohol exposure (PAE) has been demonstrated in animal models and in human infants, but remains understudied in older children and adolescents. Moreover, early life adversity (ELA), which occurs at higher rates in children with PAE than in non-exposed children, may also play a role in programming the stress response system. In a cohort of children and adolescents with PAE and ELA (PAE+ELA), we evaluated HPA function through assessment of diurnal cortisol activity compared to that in typically developing controls, as well as the associations among specific ELAs, adverse outcomes, protective factors, and diurnal cortisol. Morning and evening saliva samples were taken under basal conditions from 42 children and adolescents (5-18 years) with PAE+ELA and 43 typically developing controls. High rates of ELA were shown among children with PAE, and significantly higher evening cortisol levels and a flatter diurnal slope were observed in children with PAE+ELA, compared to controls. Medication use in the PAE+ELA group was associated with lower morning cortisol levels, which were comparable to controls. Complex associations were found among diurnal cortisol patterns in the PAE+ELA group and a number of ELAs and later adverse outcomes, whereas protective factors were associated with more typical diurnal rhythms. These results complement findings from research on human infants and animal models showing dysregulated HPA function following PAE, lending weight to the suggestion that PAE and ELA may interact to sensitize the developing HPA axis. The presence of protective factors may buffer altered cortisol regulation, underscoring the importance of early assessment and interventions for children with FASD, and in particular, for the many children with FASD who also have ELA.

Multidimensional assessment of neuroendocrine and psychopathological profiles in maltreated youth.

It has been debated whether children who have experienced early life stress (ELS), such as early caregiver separation show elevated risk for stress-related psychiatric disorders and a multi-symptom psychopathological profile that is not fully reflected in categorical assessments. In this study, we investigated dimensional measures of stress-related psychopathology in children in permanent out-of-home care, taking into account potential neuroendocrine interactions. In the current study, 25 children who had been placed in permanent out-of-home care before age 3 (years) and 26 controls (aged 10.6 ± 1.75 years) were investigated with categorical (DSM-IV) and dimensional assessments (CBCL) of psychopathology and diurnal salivary cortisol levels were assessed. Semi-structured interviews (K-DIPS) revealed no significant group differences in full-scale psychiatric diagnoses, whereas dimensional assessment (CBCL) revealed significant group differences in externalizing and total problem behaviours within the clinical range for children with ELS. Only children with ELS showed a combined symptom profile of clinical-range internalizing and externalizing problems. Lower morning cortisol values and subsequent flatter decline was found in subjects with ELS children compared to controls, showing group differences in diurnal cortisol secretion. Lower morning cortisol values were associated with more problem behaviour in the ELS group. Results show that ELS children exhibited increased psychopathological symptom severity and complexity associated with lower morning cortisol levels, which was not fully reflected in categorical assessments. This highlights the importance of incorporating dimensional assessments and neurobiological factors into psychopathological evaluations of children in out-of-home care in order to facilitate early identification of children at high risk for stress-related disorders.

Highly resilient coping entails better perceived health, high social support and low morning cortisol levels in parents of children with autism spectrum disorder

The negative consequences of caring for people with developmental disabilities have been widely described. However, the ability to bounce back from the stress derived from care situations has been less studied. Those caregivers who have shown this ability are considered as resilient. This study aims to evaluate the relationship between resilience and self-reported health and cortisol awakening response (CAR) in a sample of caregivers of people with autism spectrum disorders (ASD). It also aims to evaluate the role of social support as a mediator in the association between resilience and health. Caregivers with higher resilience show better perceived health, lower morning cortisol levels, and less area under the curve with respect to ground (AUCg). Social support was positively related to resilience and mediated the relationship between resilience and perceived health. This mediating effect was not found in the association between resilience and CAR. Resilience could be a protective factor that modulates the negative consequences of chronic stress in the care context. Social support could be an important variable mediating the effects of resilience on health outcomes in caregivers. All these results must be considered when implementing effective psychological programs for helping caregivers.

History of Stress-related Health Changes: A Cue to Pursue a Diagnosis of Latent Primary Adrenal Insufficiency

Routine delays in the diagnosis of primary adrenal insufficiency (PAI) are well known and conceivably attributable to the absence of cues, other than anti-adrenal autoantibodies, to pursue subclinical PAI. Subclinical PAI is latent unless the afflicted patient encounters stress such as an acute illness, surgery, psychosocial burden, etc. It remains to be demonstrated whether a history of stress-related health changes is a useful cue to pursue a diagnosis of latent PAI. The patients were selected for a history of recurrent symptoms, i.e., gastrointestinal symptoms, fatigue, or lassitude, aggravated by stress and alleviated by the removal of stress, and signs, i.e., weight loss, hypotension, and hyperpigmentation. As the early morning cortisol levels were low or low-normal and the adrenocorticotropic hormone (ACTH) levels were within the reference ranges, provocation tests, i.e., insulin-induced hypoglycemia tests and low-dose (1 μg) corticotropin tests (LDTs), were used to estimate the hypothalamus-pituitary-adrenal (HPA) axis status. Patients with the HPA axis dysfunction on two provocation tests were supplemented with physiologic doses of glucocorticoids (GCs). The effects of GC supplementation on stress-related health changes were observed. The ACTH levels after insulin-induced hypoglycemia were higher and the cortisol levels were lower in the patients than in the control subjects. The cortisol levels in the patients were increased less significantly by LDT than those observed in the control subjects. Stress-related health changes ceased to recur and signs, i.e., a low body weight, hypotension, and hyperpigmentation, were ameliorated following GC supplementation. A history of stress-related health changes is useful as a cue to pursue latent PAI in patients with low or low-normal early morning cortisol levels.

Diurnal cortisol pattern, eating behaviors and overweight in low-income preschool-aged children

This study examined, among children, the associations among chaos in the home, diurnal cortisol patterns, eating behaviors and being overweight. Participants included 331 low-income children aged 3–4years. Mean salivary cortisol–intercept (representing morning peak, 60min since waking) and cortisol-slope (representing diurnal decline after peak) were calculated using mixed models from samples obtained across 3days. Parents reported chaos in the home by questionnaire and responded to the Children’s Eating Behavior Questionnaire, generating subscales Food Responsiveness (FR), Emotional Overeating (EO), Enjoyment of Food (EF), and Satiety Responsiveness (SR). Body mass index was categorized as overweight vs. not. Path analysis evaluated associations among chaos, cortisol patterns, eating behaviors, and weight status. Children living in more chaotic homes had lower morning cortisol levels, consistent with “hypocortisolism” reported among individuals who have experienced significant allostatic load as a result of substantial early life chronic stress. Among girls, the hypocortisolism pattern predicted a higher likelihood of being overweight both directly and mediated through reduced Satiety Responsiveness; in boys, the association of the hypocortisolism pattern with being overweight was mediated entirely through Emotional Overeating. In summary, our results provide support for the conceptual model that psychosocial stress contributes to hypocortisolism, which contributes directly to a higher likelihood of being overweight in girls, and indirectly through reduced Satiety Responsiveness in girls and through increased Emotional Overeating in boys.

Atypical Hypocortisolism

To report a patient who had developed reversible hypocortisolism during the use of quetiapine. Early morning cortisol levels were measured on two separate days. In addition, the patient underwent testing with intravenous synthetic adrenocorticotropic hormone (1 mcg tetracosactide) before and after tapering of quetiapine. Pituitary function was assessed and magnetic resonance imaging (MRI) was performed. The patient had low early morning cortisol levels at presentation when using quetiapine. Tetracosactide testing indicated hypocortisolism. A MRI of the pituitary was unremarkable. The patient was treated temporarily with hydrocortisone and quetiapine was tapered. After quetiapine had been discontinued, the patient's cortisol production had returned to normal. Although lowering cortisol levels has been previously reported, this is the first report of hypocortisolism associated with the use of quetiapine. It is possible symptoms of malaise in patients who use quetiapine could be attributed to quetiapine-related hypocortisolism.