Genetic variation of the mineralocorticoid receptor gene (MR, NR3C2) is associated with a conceptual endophenotype of "CRF-hypoactivity".

Recently, the "conceptual endophenotype" approach has been proposed as a means to identify subgroups of patients affected by stress-related psychiatric disorders. Conceptual endophenotypes consist of patterns of psychological, biological, and symptomatic elements. We studied a sample of patients seeking help for psychosomatic and stress-related disorders (total N = 469), who were evaluated with a diagnostic instrument that integrates psychological and biological data to derive 13 endophenotypes, or Neuropattern.

Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress.

The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects.

A common mineralocorticoid receptor polymorphism (I180V) interacts with life events in relation to perfectionism in eating disorders: a pilot study.

The stress response is regulated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). When the balance between GR and MR signalling is disturbed, one's capacity to cope with a stressful event is diminished. In this pilot study, we tested the hypothesis that an interaction between common variants in the MR (rs5522) or GR gene (rs41423247) and stressful life events influences perfectionism levels in a group of patients with an eating disorder (ED; n = 113).

Salivary cortisol levels and the 2-year course of depressive and anxiety disorders.

Introduction: Depression and anxiety disorders have been associated with hyperactivity of the hypothalamic-pituitary adrenal (HPA) axis. However, lower cortisol levels have also been observed in depressed patients. Whether cortisol level predicts the course of these disorders has not been examined in detail.

Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder.

Appropriate signaling in the brain by the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) is critical in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, emotional arousal and cognitive performance. To date, few data exist on MR (and GR) expression in the brain of patients suffering from major depressive disorder (MDD). With the help of quantitative PCR we assessed MR and GR mRNA expression, including the splice variants MRα and MRβ, in tissue samples from the hippocampus, amygdala, inferior frontal gyrus, cingulate gyrus and nucleus accumbens.

Mineralocorticoid receptor gene variants as determinants of HPA axis regulation and behavior.

We tested if common mineralocorticoid receptor (MR) gene variants contribute to the variability in neuroendocrine control and behavioral reactivity as observed in humans. For that purpose we screened for genetic variability and tested functionality of the identified human MR gene variants in vitro. Four haplotypes were tested for transactivational capacity in vitro and showed profound significant differences when stimulated with cortisol.

Human mineralocorticoid receptor (MR) gene haplotypes modulate MR expression and transactivation: implication for the stress response.

Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in secretion of corticosteroids which facilitate behavioural adaptation. These effects exerted by corticosteroids are mediated by two brain corticosteroid receptor types, the mineralocorticoid receptor (MR), with a high affinity already occupied under basal conditions and the glucocorticoid receptor (GR), with a low affinity only activated during stress. Here, we studied MR gene haplotypes constituted by the two single nucleotide polymorphisms MR-2G/C (rs2070951) and MRI180V (rs5522).

C-reactive protein polymorphisms are associated with the cortisol awakening response in basal conditions in human subjects.

Cortisol affects the acute-phase response, but it is unknown whether C-reactive protein (CRP), an acute-phase reactant, also affects hypothalamus?pituitary?adrenal axis activity. In the present study, associations were explored between CRP haplotypes with plasma CRP concentrations and basal salivary cortisol level. We included 266 physically healthy Caucasian subjects (103 females and 163 males) aged between 18 and 65 years of whom 94 had a psychiatric disorder in a genetic association study.

Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response: Interaction with SSRIs.

Background: Cortisol controls the activity of the hypothalamic-pituitary-adrenal (HPA) axis during stress and during the circadian cycle through central mineralocorticoid (MR) and glucocorticoid receptors (GR). Changes in MR and GR functioning, therefore, may affect HPA axis activity. In this study we examined the effect of common functional MR gene variants on the cortisol awakening response (CAR), which is often disturbed in stress-related disorders like depression.

The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels.

The mineralocorticoid receptor (MR) is essential in the regulation of volemia and blood pressure. Rare mutations in the MR gene cause type 1 pseudohypoaldosteronism and hypertension. In this study we characterized the common MR polymorphism c.

Basal cortisol levels in relation to dimensions and DSM-IV categories of depression and anxiety.

The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification may fail to adequately distinguish neuroendocrine factors involved in the etiology of depressive and anxiety disorders. Continuous phenotypic dimensions may correlate better with underlying neuroendocrine dysregulations. We compared the categorical DSM-IV diagnoses with a dimensional approach in the same group of outpatients with depressive (n=36), anxiety (n=18), and comorbid depressive and anxiety (n=19) disorders, who were free of psychotropic medication, and in 36 healthy controls.

Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities.

Context: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood.

Objective: We examined the relationship between two main str systems, the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, with the metabolic syndrome and its components.

Design: The design was baseline data (yr 2004-2007) of a prospective cohort: the Netherlands Study of Depression and Anxiety (NESDA).

Salivary cortisol levels in persons with and without different anxiety disorders.

Objective: To examine the association between several subtypes of anxiety disorders and various cortisol indicators in a large cohort study. Anxiety disorders have been suggested to be linked to hypothalamic-pituitary-adrenal (HPA) axis activity, although results are scarce and inconsistent. No earlier studies have examined consistency of HPA axis findings across several anxiety subtypes and whether associations are state or trait dependent.

Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in major depressive disorder (MDD). Impaired HPA feedback may be due to the lower glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) levels in the forebrain. GR levels are transcriptionally controlled by multiple untranslated alternative first exons, each with its own promoter providing a mechanism for tissue-specific fine-tuning of GR levels.

Functional mineralocorticoid receptor (MR) gene variation influences the cortisol awakening response after dexamethasone.

Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and results in the secretion of corticosteroids, which facilitate behavioral adaptation and promote the termination of the stress response. These actions exerted by cortisol are mediated by two brain corticosteroid receptor types: the high affinity mineralocorticoid (MR) and the low affinity glucocorticoid receptor (GR). Dexamethasone is a potent GR agonist with affinity to MR.

Single nucleotide polymorphisms related to HPA axis reactivity.

A very important question in the neuroendocrinology of stress-related disorders is why some individuals thrive and others break down under similar adverse conditions. The hypothalamic-pituitary-adrenal (HPA) axis is the central component of the stress system, displaying extensive variability in reactivity among human subjects. Common gene variants have been associated with several changes in HPA axis reactivity.

Associations between sociodemographic, sampling and health factors and various salivary cortisol indicators in a large sample without psychopathology.

Background: Cortisol levels are increasingly often assessed in large-scale psychosomatic research. Although determinants of different salivary cortisol indicators have been described, they have not yet been systematically studied within the same study with a large sample size. Sociodemographic, health and sampling-related determinants of salivary cortisol levels were examined in a sample without potential disturbances because of psychopathology.

Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study.

Context: There is a central belief that depression is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in higher cortisol levels. However, results are inconsistent.

Objective: To examine whether there is an association between depression and various cortisol indicators in a large cohort study.

Salivary cortisol, serum lipids, and adiposity in patients with depressive and anxiety disorders.

Depressive and anxiety disorders are associated with an increased risk of cardiovascular disease. Chronic stress induces hypothalamus-pituitary-adrenal (HPA)-axis perturbations, which might subsequently induce atherogenic lipoprotein profiles and adiposity. The aim of the present study was to investigate the relationship between basal saliva cortisol levels and serum lipids and adiposity in psychiatric patients.

The influence of psychiatric comorbidity on the dexamethasone/CRH test in major depression.

Background: The outcome of the dexamethasone/corticotropin-releasing-hormone (DEX/CRH) test in depressed patients is heterogeneous. The present study investigated whether comorbidity of anxiety or somatoform disorders might be an explaining factor for this finding.

Methods: The DEX/CRH test was administered in 36 pure major depressive outpatients, 18 major depressive outpatients with a comorbid anxiety and/or somatoform disorder, and 43 healthy controls.

Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder.

Objectives: In affective disorders, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is a frequently observed phenomenon. Subtle changes in glucocorticoid receptor (GR) functioning caused by polymorphisms of the GR gene (NR3C1) may be at the base of the altered reaction of the HPA axis to stress and subsequently related to the development and course of affective disorders. The aim of our study is to evaluate associations between GR gene polymorphisms and bipolar disorder (BD).

Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health.

The stress-response, including autonomic and hypothalamic-pituitary-adrenal (HPA) axis reactivity, is essential for maintaining homeostasis during a challenge. Brain mineralocorticoid receptors and glucocorticoid receptors operate in balance to coordinate the stress-response. Genetic variants in both the human mineralocorticoid and glucocorticoid receptor-genes have been functionally characterized.

Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience.

Why some individuals thrive and others break down under similar adverse conditions, is a central question in the neuroendocrinology of stress related psychopathology. The brain mineralocorticoid (MR) and glucocorticoid receptors (GR) operate in balance to coordinate behavioural, autonomic and neuroendocrine response patterns involved in homeostasis and health. Genetic variants of both the MR and GR have been functionally characterized.

The coming out of the brain mineralocorticoid receptor.

Corticosteroids - secreted after stress - have profound effects on brain and behavior. These effects are mediated by mineralocorticoid and glucocorticoid receptors, which are abundantly expressed in limbic neurons. The role of mineralocorticoid receptors in higher brain functions has never been well understood.