Hypothalamic-pituitary-adrenal Dysfunction Research Articles

Prevalence of Depression and Anxiety in Patients with Diabetes Mellitus at a Secondary Level Government Health-Care Facility in Northern India

Abstract Background: Diabetes is one of the largest global health emergencies of the 21st century. As per the International Diabetes Federation (IDF) in 2020, 463 million people have diabetes in the world and 88 million people in the Southeast Asia region. Seventy-seven million out of 88 million belong to India. The prevalence of diabetes in the population is 8.9%, according to the IDF. There exists a bidirectional association between diabetes and depression/anxiety, with both worsening each other’s prognosis. The prevalence rates of depression could be up to three times higher in patients with type 1 diabetes and twice as high in people with type 2 diabetes, while anxiety disorders are seen in 40% of the patients with type 1 or 2 diabetes mellitus. Although no single cause has been identified for the positive correlation between diabetes and depression and anxiety, it is widely accepted that hypothalamic–pituitary–adrenal dysfunction, pro-inflammatory cytokines, and a host of other epigenetic factors are responsible for the increased prevalence. This study was undertaken to check the prevalence of anxiety and depression in patients with diabetes mellitus attending the outdoor clinics of internal medicine department at a district hospital, Fatehgarh Sahib, Punjab. Materials and Methods: Four hundred patients were included in our study. A semi-structured pro forma was used to collect demographic details, and anxiety and depression were screened using the Hamilton Anxiety and Depression Rating Scales, respectively. Data collected were subjected to statistical analysis. Results: Fifty-eight percent of the sample population had depression and 27% had anxiety, with a vast majority having mild symptoms. Gender and duration of diabetes were statistically significant variables affecting prevalence and severity, with females having a higher mean scores of depression and anxiety than males and higher scores with greater duration of the illness. Conclusions: This study implies need for routine screening of depression and anxiety symptoms in patients with diabetes mellitus and treating them at the earliest.

Chronic hypothalamic-pituitary-adrenal axis disruption alters glutamate homeostasis and neural responses to stress in male C57Bl6/N mice

It is now well-established that stress elicits brain- and body-wide changes in physiology and has significant impacts on many aspects of health. The hypothalamic-pituitary-adrenal (HPA) axis is the major neuroendocrine system mediating the integrated response to stress. Appropriate engagement and termination of HPA activity enhances survival and optimizes physiological and behavioral responses to stress, while dysfunction of this system is linked to negative health outcomes such as depression, anxiety, and post-traumatic stress disorder. Glutamate signaling plays a large role in the transmission of stress-related information throughout the brain. Furthermore, aberrant glutamate signaling has negative consequences for neural plasticity and synaptic function and is linked to stress-related pathology. However, the connection between HPA dysfunction and glutamate signaling is not fully understood. We tested how HPA axis dysfunction (using low dose chronic corticosterone in the drinking water) affects glutamate homeostasis and neural responses under baseline and acute stress in male C57BL/6N mice. Using laser microdissection and transcriptomic analyses, we show that chronic disruption of the HPA axis alters the expression of genes related to glutamate signaling in the medial prefrontal cortex (mPFC), hippocampus, and amygdala. While neural responses to stress (as measured by FOS) in the hippocampus and amygdala were not affected in our model of HPA dysfunction, we observed an exaggerated response to stress in the mPFC. To further probe this we undertook in vivo biosensor measurements of the dynamics of extracellular glutamate responses to stress in the mPFC in real-time, and found glutamate dynamics in the mPFC were significantly altered by chronic HPA dysfunction. Together, these findings support the hypothesis that chronic HPA axis dysfunction alters glutamatergic signaling in regions known to regulate emotional behavior, providing more evidence linking HPA dysfunction and stress vulnerability.

Early developmental stage glucocorticoid exposure causes DNA methylation and behavioral defects in adult zebrafish

Post-traumatic stress disorder (PTSD) is a psychiatric disorder caused by genetic and environmental factors. It is closely related to a dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, in which the epigenetic modification of the nr3c1 plays an important role. It is well known that nr3c1 methylation in offspring is reportedly related to early adverse life experiences, prenatal stress response, and early nursing conditions; however, the methylation location and extent of the nr3c1 are not sufficiently elucidated. In order to study the internal mechanism of PTSD caused by early adverse life experience, we used zebrafish to construct a psychopathological model. We found that early developmental stage prednisolone exposure caused HPA axis negative feedback dysfunction and hormone secretion disorder in adult male zebrafish. By analyzing nr3c1 promoter, we found that cytosine-guanine island (CpGI) 2 was highly methylated in adult male zebrafish, which affected the expression of glucocorticoid receptor, resulting in abnormal behavior and anxiety like phenotype of adult male zebrafish. Therefore, we believed that an early exposure of zebrafish larvae to prednisolone may be recorded through a change of CpGI 2 methylation in the nr3c1 promoter region, causing abnormal adult male zebrafish behavior. Moreover, the establishment of the zebrafish psychopathological model may facilitate the study of the clinical management of patients with PTSD.

Examining the Relationship Between Hair Cortisol With Stress-Related and Transdiagnostic Subclinical Measures.

Background: Hair cortisol concentrations (HCC) provide a retrospective examination of long-term cortisol production as a measure of the hypothalamic-pituitary-adrenal (HPA) axis functioning, one of the major neural systems implicated in mediating the effects of stress on mental illness. However, evidence about the relationship between HCC with stressors and symptoms is scattered. In the present study, we aimed to examine the association between HCC and a wide range of stress-related and transdiagnostic subclinical measures in a sample of non-clinical young adults with a wide distribution of schizotypy.Methods: A total sample of 132 non-clinical young adults recruited at college and technical schools oversampled for schizotypy scores were assessed on distal and proximal stressful experiences, appraisals of stress, traits and symptoms of the affective, psychosis and dissociation spectrums, as well as stress-buffering measures, and provided 3 cm-hair samples.Results: No significant associations were found between HCC and any of the stress-related and subclinical measures. Only suspiciousness and disorganization showed a trend for a positive association with HCC but the magnitude was small.Conclusions: The present findings support previous studies indicating an overall lack of concordance between a broad range of stress-related and (sub)clinical phenotypic measures with hair cortisol. This study examined for the first time the relationship of HCC with the non-clinical expression of the psychosis spectrum, that is, schizotypy, which complements previous studies on clinical high risk and established psychosis and offers a promising strategy for studying possible HPA dysfunctions characterizing the subclinical psychosis continuum without the confounds associated to clinical psychosis.

Does dehydroepiandrosterone sulfate have a role in COVID-19 prognosis and treatment?

The pathophysiology of COVID comprises an exaggerated pro-inflammatory response. Hypothalamic-pituitary-adrenal (HPA) axis has a crucial role in various inflammatory conditions and modulated immunological response. Limited evidence is available regarding the incidence and the effect of HPA dysfunction in COVID-19. Although the cortisol levels have only been estimated in a few studies, the dehydroepiandrosterone sulfate (DHEAS) release from the adrenal gland has not been explored yet. In this mini review, the authors discuss the role of dehydroepiandrosterone (DHEA) and DHEAS in the acute stress response and immunological modulation. Various effects of DHEAS have been demonstrated in different diseases. The specific inhibitory effect of DHEA on interleukin 6 (IL-6) could be of paramount importance in COVID-19. Further, DHEA supplementation has already been proposed in inflammatory conditions, like rheumatoid arthritis. DHEAS levels in COVID-19 may help to understand the HPA axis dysfunction as well as the possibility of repurposing DHEA as a drug for mitigating the pro-inflammatory COVID-19.

Secretagogin Mediates the Regulatory Effect of Electroacupuncture on Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Surgical Trauma.

Electroacupuncture (EA) improves hypothalamic-pituitary-adrenal (HPA) axis disorder by reducing corticotropin-releasing hormone (CRH) synthesis and release in the paraventricular nucleus (PVN). However, the potential mechanism underlying CRH regulation remains unclear. Secretagogin (SCGN) is closely related to stress and is involved in regulating the release of CRH. We hypothesized that SCGN in the PVN might trigger the HPA system and be involved in EA-mediated modulation of HPA dysfunction caused by surgical trauma. Serum CRH and adrenocorticotropic hormone (ACTH) and plasma corticosterone (CORT) levels at 6 h and 24 h after hepatectomy were determined by radioimmunoassay. CRH and SCGN protein levels in the PVN were detected by western blot and immunofluorescence, and CRH and SCGN mRNA levels in the PVN were determined by means of real-time polymerase chain reaction (RT-PCR) and in situ hybridization (ISH). Our studies showed that serum CRH, ACTH, and CORT levels and PVN CRH expression were significantly increased at 6 h and 24 h after hepatectomy in the hepatectomy group compared with the control group, and those in the EA+hepatectomy group were decreased compared with those in the hepatectomy group. The protein and mRNA levels of SCGN in the PVN were also increased after hepatectomy, and their expression in the EA+hepatectomy group was decreased compared with that in the hepatectomy group. When SCGN expression in the PVN was functionally knocked down by a constructed CsCI virus, we found that SCGN knockdown decreased the serum CRH, ACTH, and CORT levels in the SCGN shRNA+hepatectomy group compared with the hepatectomy group, and it also attenuated CRH expression in the PVN. In summary, our findings illustrated that EA normalized HPA axis dysfunction after surgical trauma by decreasing the transcription and synthesis of SCGN.

Maltreatment timing, HPA axis functioning, multigenic risk, and depressive symptoms in African American youth: Differential associations without moderated mediation.

Utilizing a large (N = 739), ancestrally homogenous sample, the current study aimed to better understand biological risk processes involved in the development of depressive symptoms in maltreated, African American children age 8-12 years. Maltreatment was independently coded from Child Protective Services records and maternal report. Self-reported depressive symptoms were attained in the context of a week-long, summer research camp. DNA was acquired from buccal cell or saliva samples and genotyped for nine polymorphisms in four hypothalamic-pituitary-adrenal (HPA)-axis-related genes: FKBP5, NR3C1, NR3C2, and CRHR1. Salivary cortisol samples were collected each morning (9 a.m.) and late afternoon (4 p.m.) throughout the week to assess HPA functioning. Results revealed that experiences of maltreatment beginning prior to age 5 were most predictive of depressive symptoms, whereas maltreatment onset after age 5 was most predictive of HPA axis dysregulation (blunted daytime cortisol patterns). Multigenic risk did not relate to HPA functioning, nor did it moderate the relationship between maltreatment and HPA activity. There was no mediation of the relationship between maltreatment and depressive symptoms by HPA dysfunction. Results are interpreted through a developmental psychopathology lens, emphasizing the principle of equifinality while carefully appraising racial differences. Implications for future research, particularly the need for longitudinal studies, and important methodological considerations are discussed.

FoxO3a suppresses neuropeptide W expression in neuronal cells and in rat hypothalamus and its implication in hypothalamic-pituitary-adrenal (HPA) axis.

FoxO3a, a forkhead family member of transcription factors, is involved in the regulation of cell metabolism, proliferation, differentiation and apoptosis. However, whether FoxO3a participates in the regulation of glucocorticoids induced-hypothalamic-pituitary-adrenal (HPA) dysfunction is still unknown. Our present results indicate that dexamethasone(DEX) increased FoxO3a expression in PC12 and hypothalamic neuronal cultures in correlation to reduced expression of NPW, a process that could be blocked by GR2 antagonist. DEX restrained the phosphorylation of Akt and FoxO3a, but not ERK1/2 phosphorylation, resulting with FoxO3a nuclear localization. Overexpression of FoxO3a inhibited NPW expression, while FoxO3a knockdown by siRNA had the opposite effect. The regulatory region of NPW promoter contains multiple FoxO3a binding sites, and FoxO3a bonding to these sites inhibited its transcriptional activity. In a rat model, chronic administration of corticosterone reduced animals' body weight and sucrose consumption and caused stress- depression like behavior. Corticosterone treatment induced a marked increase in FoxO3a levels, while decreased the expression of NPW protein in the hypothalamus. Immunofluorescent double labeling demonstrated that FoxO3a and NPW were collocated in the hypothalamus. Taken together, these data indicate that NPW is a new direct downstream target gene of FoxO3a. FoxO3a suppressed the transcription of NPW and modulated glucocorticoids-induced HPA dysfunction by directly regulating the expression of NPW. Thus, present findings suggest that FoxO3a and NPW may be potential therapeutic targets for endocrine and psychiatric disorders.

RELATIONSHIP OF HAIR CORTISOL CONCENTRATION WITH HISTORY OF PSYCHOSIS, NEUROPSYCHOLOGICAL PERFORMANCE, AND EVERYDAY FUNCTIONING IN REMITTED LATER-LIFE MAJOR DEPRESSIVE DISORDER

Introduction Psychotic features are more prevalent in older adults with depression than in younger depressed adults. Psychotic major depressive disorder (PMD) is associated with poorer neuropsychological performance and poorer everyday functioning, in both acute and remitted states, compared with non-psychotic major depressive disorder (NPMD). In addition, PMD is also associated with more pronounced dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including elevated cortisol levels, but it is not known whether this difference between PMD and NPMD persists in remission. The goal of this exploratory study was to test the hypothesis that a history of psychotic features, poorer neuropsychological performance, and poorer everyday functioning were associated with higher cortisol levels in sustained remission of major depressive disorder. If confirmed, it could suggest a possible mechanism for neuropsychological and functional impairment in remitted PMD. In order to examine the relationship between sustained HPA dysfunction in remission and the aforementioned variables, we measured hair cortisol concentration (HCC), a measure of longer-term cortisol exposure. Methods This study used a cross-sectional design and included 60 participants aged 50 years or older with a history of major depressive disorder (n = 17 with NPMD and n = 43 with PMD) in sustained remission and 36 non-psychiatric comparison participants. Hair samples were collected using standardized methods and cortisol concentrations were determined from the first 3-cm hair segment most proximal to the scalp, or from as much hair as was available for participants with shorter hair. This hair segment represents the hair growth over the 3-month period prior to the sampling. HCC was measured in a research laboratory with extensive experience in this analysis using a validated high sensitivity enzyme immunoassay (EIA) that is standard in the field. In order to examine the relationships between HCC and i) history of psychotic features, ii) neuropsychological performance (processing speed, executive function, and verbal memory), and iii) everyday functioning (participant-report general functioning and observer-rated IADL performance), we performed three sets of correlation analyses, one for each variable of interest (point biserial for psychosis history and HCC; Pearson's r for neuropsychological and functional measures). We calculated effect sizes and 95% confidence limits in order to compare HCC results between patient and non-psychiatric comparison groups. HCC data were highly skewed and were log transformed for all analyses. Results NPMD and PMD groups had mean (SD) HCCs of 18.86 (32.97) pg/mg and 12.48 (11.26) pg/mg, respectively. The correlation between HCC and history of psychosis was weak (r = -0.02), as were the correlations between HCC and the neuropsychological measures (r ranging between -0.11 and 0.1). The correlations between HCC and i) IADL performance (r = -0.04) and ii) general functioning (r = -0.074) were also weak. None of these correlations were statistically significant. The mean (SD) HCC for non-psychiatric comparison subjects was 13.86 (20.06) pg/mg. Both effect sizes for the difference between the clinical and non-psychiatric comparison groups were small (0.26 for NPMD versus Comparison group and 0.25 for PMD versus Comparison group). Conclusions This is the first study to assess HCC in PMD and to examine the relationship between HCC and cognition and between HCC and everyday functioning in MDD. We did not find a correlation between HCC and history of psychosis, neuropsychological performance, or functioning in later-life patients with MDD in sustained remission. Further, there was no substantial difference in mean HCC between the patient and non-psychiatric comparison group. There is variability in the literature regarding HCC in MDD and regarding the relationship between HPA-axis function and neuropsychological performance in remitted MDD. Our findings will be discussed in this context. This research was funded by This study was funded by a research grant from the University Health Network Centre for Mental Health ($14,000)

Association between Stress and the HPA Axis in the Atopic Dermatitis.

The hypothalamic–pituitary–adrenal (HPA) axis is one of the body’s neuroendocrine networks that responds to psychological stress (PS). In the skin, there exists a peripheral HPA axis similar to the central axis. Glucocorticoids (GCs) are key effector molecules of the HPA axis and are essential for cutaneous homeostasis. Atopic dermatitis (AD) is a condition typically characterized by a chronic relapsing course that often results in PS. HPA dysfunction is present in AD patients by the decreased response of GCs elevation to stress as compared to those unaffected by AD. Nevertheless, in skin, acute PS activates several metabolic responses that are of immediate benefit to the host. During the acute phase of PS, increased endogenous GCs have been shown to provide benefit rather than by aggravating cutaneous inflammatory dermatoses. However, a chronic T helper cell type 2 (Th2) predominant cytokine profile acts as a negative feedback loop to blunt the HPA axis response in AD. In this article, we reviewed the role of CRF, pro-opiomelanocortin (POMC)-derived peptides, GCs of the HPA, and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in AD, with a discussion of the pathogenetic mechanisms of inflammation and skin barrier functions, including antimicrobial defense, and their association with PS.

Neuroendocrine stress reactivity of male C57BL/6N mice following chronic oral corticosterone exposure during adulthood or adolescence

Adolescence is associated with the maturation of the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroendocrine axis mediating the hormonal stress response. Adolescence is also a period in development marked by a variety of stress-related vulnerabilities, including psychological and physiological dysfunctions. Many of these vulnerabilities are accompanied by a disrupted HPA axis. In adult mice, a model of disrupted HPA function has been developed using oral chronic corticosterone administration via the drinking water, which results in various physiological and neurobehavioral abnormalities, including changes in stress reactivity and anxiety-like behaviors. In an effort to further complement and extend this model, we tested the impact of HPA disruption in adolescent mice. We also examined whether this disruption led to different outcomes depending on whether the treatment happened during adolescence or adulthood. In the current set of experiments, we exposed adult (70days of age) or adolescent (30days of age) male C57BL/6N mice to 4 weeks of either 0 or 25μg/ml oral corticosterone via their drinking water. We measured body weight during treatment and plasma corticosterone levels and activation of the paraventricular nucleus (PVN), as indexed by FOS immunohistochemistry, before and after a 30min session of restraint stress. Our data indicate that adolescent animals exposed to chronic corticosterone showed weight loss during treatment, an effect not observed in adults. Further, we found stress failed to elevate plasma corticosterone levels in treated mice, regardless of whether exposure occurred in adulthood or adolescence. Despite this reduced hormonal responsiveness, we found significant neural activation in the PVN of both adult- and adolescent-treated mice, indicating a dissociation between stress-induced peripheral and central stress responses following chronic corticosterone exposure. Moreover, stress-induced neural activation in the PVN was unaffected by chronic corticosterone treatment in adult animals, but led to a hyper-responsive PVN in the corticosterone-treated adolescent animals, suggesting an age-specific effect of corticosterone treatment on later PVN stress reactivity. Together, these experiments highlight the influence of developmental stage on somatic and neuroendocrine outcomes following chronic HPA disruption by noninvasive, oral corticosterone treatment. Given the substantial vulnerabilities to HPA dysfunctions during adolescence this model may prove useful in better understanding these vulnerabilities.

Attenuated DHEA and DHEA-S response to acute psychosocial stress in individuals with depressive disorders

BackgroundIn recent years, a relationship between depression and basal dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) levels has frequently been suggested, but responses of these adrenal steroids to psychosocial stress have not been examined in individuals with depressive disorders. In this study, we examined salivary DHEA, DHEA-S, and cortisol/DHEA response to the Trier Social Stress Test (TSST) in individuals with depressive disorders and in healthy controls to discover whether the responses of DHEA and DHEA-S to acute psychosocial stress could be a more sensitive marker of HPA dysfunction in depressive disorders. MethodsWe compared salivary cortisol, DHEA, DHEA-S, and cortisol/DHEA levels to the TSST tests between 38 individuals with depression and 43 healthy controls aged 18.4–25.9 years. Depression severity was assessed by the self-reported Beck Depression Inventory-II (BDI-II). Salivary samples were evaluated at four time points: the baseline (−10 time point), before the TSST started (0 time point), the end of the TSST (+20 time point), and the recovery (+50 time points). ResultsNo significant differences existed in the basal adrenal hormonal levels between subjects with depressive disorders and controls; however, at the end of TSST, attenuated DHEA and DHEA-S response was identified in subjects with depressive disorders compared to that found in healthy subjects. The differences in the DHEA and DHEA-S levels at the +20 time point, as well as the differences in the cortisol/DHEA at the +50 time point, exhibited negative correlations with depression severity. ConclusionAttenuated DHEA and DHEA-S response to acute psychosocial stress was identified in subjects with depressive disorders. These findings help us to discover the bi-directional relationship between depression and the hypothalamic-pituitary-adrenal (HPA) axis function, hence furthering our understanding of whether altered DHEA and DHEA-S response to psychosocial stress may be a more sensitive method than basal adrenal steroid analysis for detecting HPA axis dysfunction in depressive disorders. LimitationsAs this is a case control study, we could only draw the conclusion of the bi-directional relationship between the depression and the altered DHEA (S) response to stress, and could not identify whether depression was due to the HPA dysfunction, or vice versa. Prospective studies such as such as cohort studies or epidemiology experiments are needed to further test the cause of depression or HPA dysfunction; and the mechanisms responsible for altered DHEA and DHEA-S in response to acute psychosocial stress in individuals with depressive disorders are also needed to be clarified.

Effect of Exercise on Ovulation: A Systematic Review.

Infertility has been described as a devastating life crisis for couples, and has a particularly severe effect on women, in terms of anxiety and depression. Anovulation accounts for around 30% of female infertility, and while lifestyle factors such as physical activity are known to be important, the relationship between exercise and ovulation is multi-factorial and complex, and to date there are no clear recommendations concerning exercise regimes. The objective of this review was to systematically assess the effect of physical activity on ovulation and to discuss the possible mechanisms by which exercise acts to modulate ovulation in reproductive-age women. This was done with a view to improve existing guidelines for women wishing to conceive, as well as women suffering from anovulatory infertility. The published literature was searched up to April 2016 using the search terms ovulation, anovulatory, fertility, sport, physical activity and exercise. Both observational and interventional studies were considered, as well as studies that combined exercise with diet. Case studies and articles that did not report anovulation/ovulation or ovarian morphology as outcomes were excluded. Studies involving administered drugs in addition to exercise were excluded. In total, ten interventions and four observational cohort studies were deemed relevant. Cohort studies showed that there is an increased risk of anovulation in extremely heavy exercisers (>60min/day), but vigorous exercise of 30-60min/day was associated with reduced risk of anovulatory infertility. Ten interventions were identified, and of these three have studied the effect of vigorous exercise on ovulation in healthy, ovulating women, but only one showed a significant disruption of ovulation as a result. Seven studies have investigated the effect of exercise on overweight/obese women suffering from polycystic ovary syndrome (PCOS) or anovulatory infertility, showing that exercise, with or without diet, can lead to resumption of ovulation. The mechanism by which exercise affects ovulation is most probably via modulation of the hypothalamic-pituitary-gonadal (HPG) axis due to increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. In heavy exercisers and/or underweight women, an energy drain, low leptin and fluctuating opioids caused by excess exercise have been implicated in HPA dysfunction. In overweight and obese women (with or without PCOS), exercise contributed to lower insulin and free androgen levels, leading to the restoration of HPA regulation of ovulation. Several clear gaps have been identified in the existing literature. Short-term studies of over-training have not always produced the disturbance to ovulation identified in the observational studies, bringing up the question of the roles of longer term training and chronic energy deficit. We believe this merits further investigation in specific cohorts, such as professional athletes. Another gap is the complete absence of exercise-based interventions in anovulatory women with a normal body mass index (BMI). The possibly unjustified focus on weight loss rather than the exercise programme means there is also a lack of studies comparing types of physical activity, intensity and settings. We believe that these gaps are delaying an efficient and effective use of exercise as a therapeutic modality to treat anovulatory infertility.

Cortisol response patterns in depressed women and their healthy daughters at risk: Comparison with healthy women and their daughters

A dysfunctional hypothalamic pituitary adrenal (HPA) axis is widely accepted as a significant pathophysiological aspect of Major Depressive Disorder (MDD). Despite studies suggesting that a dysfunctional HPA axis might be present before the clinical syndrome becomes apparent, the functioning of the HPA axis in high–risk populations has not been well defined. The aim of the present study was to investigate the HPA axis functioning of mothers suffering from MDD and their healthy daughters compared to age- and sex-matched healthy controls. This design allowed a comparison of HPA axis functional differences among daughter and mother groups. HPA axis function was evaluated with a modified dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, which was performed after obtaining the diurnal adrenocorticotropic hormone (ACTH) and cortisol values at 8:00, 16:00, and 23:00 h. We found that MDD mothers and their daughters had low morning cortisol and the MDD mothers additionally had low-morning ACTH compared with controls. Dexamethasone suppressed both cortisol and ACTH in all groups and subsequent HPA axis stimulation by CRH-evoked a lower cortisol response but a higher ACTH response among subjects with MDD mothers. Although high-risk daughters had comparable cortisol levels after CRH infusion, the AUC for ACTH was greater than those of controls. These patterns of results suggest that multiple level HPA dysfunctions are present in both MDD patients and their high-risk carrying daughters. However, insufficient cortisol secretion was only present in MDD mothers, while the daughters could compensate cortisol levels during CRH challenge.

The Role of Stress Regulation on Neural Plasticity in Pain Chronification.

Pain, especially chronic pain, is one of the most common clinical symptoms and has been considered as a worldwide healthcare problem. The transition from acute to chronic pain is accompanied by a chain of alterations in physiology, pathology, and psychology. Increasing clinical studies and complementary animal models have elucidated effects of stress regulation on the pain chronification via investigating activations of the hypothalamic-pituitary-adrenal (HPA) axis and changes in some crucial brain regions, including the amygdala, prefrontal cortex, and hippocampus. Although individuals suffer from acute pain benefit from such physiological alterations, chronic pain is commonly associated with maladaptive responses, like the HPA dysfunction and abnormal brain plasticity. However, the causal relationship among pain chronification, stress regulation, and brain alterations is rarely discussed. To call for more attention on this issue, we review recent findings obtained from clinical populations and animal models, propose an integrated stress model of pain chronification based on the existing models in perspectives of environmental influences and genetic predispositions, and discuss the significance of investigating the role of stress regulation on brain alteration in pain chronification for various clinical applications.

Neuroendocrine dysfunction and insomniain mild traumatic brain injury patients

Mild traumatic brain injury (mTBI) has been a growing public health concern in the worldwide. To investigate the subjective and objective characteristics of insomnia following mTBI and the association between insomnia and hypothalamic–pituitary–adrenal (HPA) function of mTBI patients, 59 patients with mTBI (mTBI group) were compared with 50 healthy participants (control group) in the present study. The subjective and objective measures of insomnia were respectively obtained from Pittsburgh Sleep Quality (PSQI) and polysomnography (PSG). HPA function was measured with low-dose short synacthen test (LDSST). According to the comparative and correlation analysis of the two groups, for PSQI, the scores of sleep syndrome, sleep latency, sleep efficiency, overall sleep quality and daytime dysfunction of mTBI patients were all higher, however only sleep efficiency and daytime dysfunction of mTBI patients were related with peak cortisol on lDSST; while for PSG, sleep efficiency (SE) was lower and wake after sleep onset (WASO) was longer in mTBI patients, moreover SE and WASO of mTBI patients were correlated with peak cortisol on LDSTT; for HPA function indexes, only peak cortisol on LDSST was lower in mTBI patients. These findings suggested that mTBI patients experienced more serious subjective insomnia symptoms than objective measurement, which were associated with HPA dysfunction. This study may contribute to identifying better treatment for mTBI patients with insomnia.

The performance of serum cortisol, plasma corticotropin and serum dehydroepiandrosterone sulfate levels in the diagnosis of hypothalamic pituitary adrenal dysfunction

Background:There is no single test can identify hypothalamic-pituitary-adrenal dysfunction (HPAD) perfectly. The study aimed to assess the performance of measuring serum cortisol, serum dehydroepiandrosterone sulfate (DHEA-S) and plasma corticotropin (ACTH) in comparison with standard-dose short cosyntropin (250 µg) testing for the diagnosis of HPAD.Methods:This is a cross-sectional study from Al-Faiha Specialized Diabetes, Endocrine, and Metabolism Center (FDEMC) in Basrah. For all patients with suspected HAD; baseline serum cortisol, serum dehydroepiandrosterone sulfate (DHEA-S) and plasma corticotropin (ACTH) and were measured, followed by a formal short cosyntropin test as the gold standard test.Results:The total number of the study participant was 169 patients. Of them, 134 (79.3%) were women. Their age ranges from 5-80 years. The cutoff serum cortisol that predicts abnormal short cosyntropin test was less than 5.31µg/dl with maximal sensitivity and specificity of 90.4 % and 92.3% respectively. The cutoff serum DHEA-S that predict abnormal short cosyntropin test was less than 31.11 µg/dl with a sensitivity of 89.2%and specificity of 62.7%.The least reliable parameter to predict the abnormal short cosyntropin was the plasma ACTH level with a cutoff of less than 5.30 pg/ml and lowest sensitivity of 89.2% and specificity of 62.7%.Conclusion:To exclude HPAD, serum cortisol at 9-11 am having the highest predictive value, DHEA-S has the midway function and plasma ACTH is the least reliable for that. Combination of serum cortisol and serum DHEA-S yield the best performance for combinations of test. Keywords: Hypothalamic pituitaryadrenal dysfunction, short cosyntropin test, dehydroepiandrosterone sulfate, corticotropin,cortisol.Â

Psoriasis severity and hypothalamic-pituitary-adrenal axis function: results from the CALIPSO study

Psoriasis is a chronic inflammatory disease that significantly impacts life quality, being associated with stress and mental disorders. We investigated whether the activity of the hypothalamic-pituitary-adrenal (HPA) axis was associated with psoriasis severity, daily life stress and anxiety, and depressive symptoms. In this ancillary study, which was part of the CALIPSO (coronary artery calcium in psoriasis) study, saliva was collected from 102 patients with psoriasis immediately upon awakening, 30, and 60 min after awakening, at 2:00 pm and at bedtime (five time points) to determine salivary cortisol levels. We used Pearson's correlation coefficient to evaluate the association of clinical and psychopathological variables with HPA activity. We found a direct correlation between bedtime cortisol and psoriasis severity evaluated by the psoriasis area severity index (PASI; r=0.39, P<0.001). No correlations between other clinical and psychopathological variables or with other cortisol assessments were observed. The findings indicated that HPA dysfunction may be present in psoriasis, as bedtime cortisol was correlated with psoriasis severity. Our study is limited by the lack of a control group; therefore, we were not able to explore whether these cortisol values were different compared with a concurrent, healthy sample.

Hypothalamic-pituitary-adrenal (HPA) axis and aging.

Human aging is associated with increasing frailty and morbidity which can result in significant disability. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to aging-related diseases like depression, cognitive deficits, and Alzheimer's disease in some older individuals. In addition to neuro-cognitive dysfunction, it has also been associated with declining physical performance possibly due to sarcopenia. This article reviews the pathophysiology of HPA dysfunction with respect to increased basal adrenocorticotropic hormone (ACTH) and cortisol secretion, decreased glucocorticoid (GC) negative feedback at the level of the paraventricular nucleus (PVN) of the hypothalamus, hippocampus (HC), and prefrontal cortex (PFC), and flattening of diurnal pattern of cortisol release. It is possible that the increased cortisol secretion is secondary to peripheral conversion from cortisone. There is a decline in pregnolone secretion and C-19 steroids (DHEA) with aging. There is a small decrease in aldosterone with aging, but a subset of the older population have a genetic predisposition to develop hyperaldosteronism due to the increased ACTH stimulation. The understanding of the HPA axis and aging remains a complex area with conflicting studies leading to controversial interpretations.

A meta-analytic review of the impact of intranasal oxytocin administration on cortisol concentrations during laboratory tasks: moderation by method and mental health.

A large body of research has examined the acute effects of intranasal oxytocin administration on social cognition and stress-regulation. While progress has been made with respect to understanding the effect of oxytocin administration on social cognition in clinical populations (e.g. autism, schizophrenia), less is known about its impact on the functioning of the hypothalamic-pituitary-adrenal (HPA) axis among individuals with a mental disorder. We conducted a meta-analysis on the acute effect of intranasal oxytocin administration on the cortisol response to laboratory tasks. The search yielded eighteen studies employing a randomized, placebo-controlled design (k=18, N=675). Random-effects models and moderator analyses were performed using the metafor package for the statistical program R. The overall effect size estimate was modest and not statistically significant (Hedges g=-0.151, p=0.11) with moderate heterogeneity in this effect across studies (I(2)=31%). Controlling for baseline differences in cortisol concentrations, moderation analyses revealed that this effect was larger in response to challenging laboratory tasks that produced a robust stimulation of the HPA-axis (Hedges g=-0.433, 95% CI[-0.841, -0.025]), and in clinical populations relative to healthy controls (Hedges g=-0.742, 95% CI[-1.405, -0.078]). Overall, oxytocin administration showed greater attenuation of the cortisol response to laboratory tasks that strongly activated the HPA-axis, relative to tasks that did not. The effect was more robust among clinical populations, suggesting possible increased sensitivity to oxytocin among those with a clinical diagnosis and concomitant social difficulties. These data support the view that oxytocin may play an important role in HPA dysfunction associated with psychopathology.