Neuroendocrine Challenge Research Articles

Neuroendocrine challenges and clinical outcomes in men with chronic traumatic brain injury: a cross-sectional study.

Marked changes in the hypothalamic-pituitary axis have been documented in patients with traumatic brain injury (TBI). These enduring endocrine challenges could significantly influence the physical and psychological outcomes thereby impacting overall recovery. This study aimed to determine the prevalence and types of endocrine dysfunction in men with chronic TBI and to determine the association of endocrine dysfunction with clinical outcomes. A cross-sectional study that included male participants of 25-45 years (N = 66) with moderate to severe TBI within 6-24 months of injury. Serum Cortisol, Free T4, TSH, Luteinizing hormone, Testosterone, ACTH, Prolactin and IGF-1 were assessed. Glasgow Outcome Scale Extended (GOS-E) and Modified Barthel Index (MBI) scores were also assessed in them. The study cohort comprised male patients with a mean ± age of 32.8 ± 5.7 years. Low IGF-1 levels were most commonly encountered, followed by hypogonadism. Hypopituitarism was present in 56.1%. The proportion of hypogonadism was significantly higher in the group with moderate-total dependence (13/26) as compared to the functionally independent (8/40) group (50% vs. 20%; P = 0.011). Univariate and multivariate logistic regression analysis was used to determine the factors associated with hypopituitarism, revealing that severity of injury (OR = 2.6;) and GOS-E (OR = 3.1) were significant (P < 0.10) on univariate analysis. This study emphasizes the need to screen TBI patients for neuroendocrine dysfunction during the chronic phases and to establish screening criteria.

Citalopram Neuroendocrine Challenge Shows Altered Tryptophan and Kynurenine Metabolism in Migraine

Altered tryptophan (TRP) metabolism may have an important role in migraine susceptibility through its main metabolites, serotonin and kynurenine (KYN). Both affect pain processing and stress response by interfering with neural and brain hypersensitivity and by interacting with chemokines and cytokines that control vascular and inflammatory processes. The involvement of these pathways in migraine has been widely studied, but acute citalopram neuroendocrine challenge on TRP metabolism and cytokine profile has not been investigated yet. In our study, females with episodic migraine without aura and healthy controls were studied before and after acute citalopram or placebo in a double-blind setting. At baseline, increased TRP/large neutral amino acid (LNAA) ratio and decreased RANTES chemokine concentration were detected in migraine patients compared to controls. The challenge induced a significant increase in TRP, KYN, and TRP/LNAA in healthy controls, but not in migraine patients. Furthermore, migraine attack frequency negatively correlated with KYN/TRP ratio and positively correlated with the neuroendocrine-challenge-induced KYN concentration increase. Our results support a decreased breakdown of TRP via KYN pathway and a failure to modulate TRP–KYN pathway during citalopram-induced acute stress together with an increased vascular sensitivity in migraine. These mechanisms may provide useful drug targets for future drug development.

Current Status of Surgery in Management of Prolactinomas.

Prolactinomas are a complex neuroendocrine challenge for the neurosurgeon. Management of prolactinoma patients requires centres that include neuroendocrinologists, neurosurgeons, neuroradiologists. Although dopamine agonists are the current mainstay of management of prolactinomas, surgery was often preferred management option prior to 1980, before the advent of dopamine agonists. Importantly, all patients with neurologic symptoms suspected due to the lesion, and those risk of adverse effects of medical management, treatment failure, resistance to dopamine agonists and those planning pregnancy, should be referred to a neurosurgeon at the earliest possible. When selected after meticulous evaluation, in patients with neurological deficits like acute visual loss, intolerance to medical therapy, or treatment failures, surgical intervention could come to rescue. Encouragingly, when carefully selected, surgical remission rates are high. In the current review, we review the existing literature and share the experience at our centre in the surgical management of prolactinomas.

Lithium induced hypothyroidism in patients with bipolar disorder

In psychiatry, neuroendocrine techniques were initially considered a potential “window into the brain” by indirectly marking central nervous system limbic dysfunction. At present this conception has evolved, owing to significant progress over the last decades demonstrating direct involvement of neuropeptides and neurohormones in psychiatric diseases. In a synchronic perspective, neuroendocrine investigations evaluate a functional status at a given moment in the evolution of the disease, which results from both etiopathogenic processes and compensatory homeostatic mechanisms. These vital physiological changes appear to be potential targets for novel hormonally based pharmacotherapies. However, in the past few years, the interest for the study of neuroendocrine dysregulations in psychiatric patients has declined. In order to better understand this relative disinterest, this article will attempt to shed light on strengths and limitations of the neuroendocrine approaches in psychiatry. It is necessary to bear in mind that the usefulness of these techniques in the clinical, pathophysiological and therapeutic fields depends largely on the selectivity of stimuli and the appropriateness of the methodologies used. Owing to the complexity of the clinical phenomena, multifactorial approaches (combining several neuroendocrine challenge tests to imaging, immunological, neurophysiological, neurochemical and/or genetic techniques) are to be privileged in psychiatric investigations. Despite the inherent limitations of these approaches, due to their technical and ethical constraints, the neuroendocrine strategy can inform modern clinical practice and lead to new breakthroughs in future science and practice.

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Methadone

The Relationships between Thyroid Hormones and the Brain Serotonin (5-HT) System and Mood: Of Synergy and Significance in the Adult Brain- A Review

The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been conformed repeatedly. Interaction of the thyroid and monoamine neurotransmitter systems has been suggested as a potential underline mechanism of action. While catecholamine and thyroid interrelationships have been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal of this article is to review the literature on the relationship between thyroid hormones and the brain serotonin (5-HT) system. In humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-HT responsiveness that is reversible with replacement therapy. In the majority of the studies, the effects of thyroid hormone administration in animals will experimentally-induced hypothyroid sates include an increase in cortical 5-HT concentrations and a desensitization of auto inhibitory 5-HT1A receptors in the rap he area, resulting in disinhibition of cortical hippocampal 5-HT release. Furthermore, there is some indication that thyroid hormones may increase cortical 5-HT2 receptor sensitivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact in the brain serotonin system. Thus it is postulated that one mechanism, among others, through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission, specifically by reducing the sensitivity of 5- HT1A auto receptors in the raphe area, and by increasing 5--HT2 receptor sensitivity.Faridpur Med. Coll. J. 2014;9(2): 98-101

Brain metastasis: The impact of surgical stress, immune stimulation, and NK cells

Brain metastasis (BrM) have poor prognosis, and prophylactic approaches are scarce. Surgical stress responses have been shown to promote metastasis in peripheral organs through their immune-suppressive impacts and through direct effects on the malignant tissue and host physiology. However, BrM have not been studied in these respects, and the unique brain immune milieu, blood supply, and BBB, may react differently to such neuroendocrine challenges. Thus, we studied the effect of laparotomy, role of NK cells, and CpG-C immune-stimulation – a TLR-9 agonist having minimal adverse effects in humans – in early stages of brain and lung metastasis. Two syngeneic animal models were used: 3LL/D122 in C57BL/J6 mice, and MADB106 mammary adenocarcinoma in F344 rats. Tumor cells were injected either through the tail vein or employing a novel internal carotid injection approach we have developed, which generates BrM with high efficacy and minimal injection-related interferences to cerebral blood flow. Employing both models and inoculation approaches in naive and NK-depleted animals, our results indicate that NK cells surprisingly have no impact on BrM, while profoundly controlling lung metastases. On the other hand, laparotomy significantly enhanced brain and lungs tumor infiltration, and CpG-C reduced it, overcoming the effects of laparotomy. Thus, surgery is a significant risk factor for BrM through yet unknown mechanisms, and CpG-C treatment may be used prophylactically in cancer patients.

Acute responsivity of the serotonergic system to S-citalopram and positive emotionality – The moderating role of the 5-HTTLPR

Considering, that the serotonergic system has a modulatory function on personality in general, we aimed to highlight its association with positive emotionality. In a placebo-controlled neuroendocrine challenge design (72 men) we investigated the association of serotonergic responsivity, 5-HTTLPR-genotype as well as their combined effects on positive emotionality. Regression analyses revealed an involvement of the serotonergic system in positive emotionality. There was no direct association between positive emotionality and cortisol responses to S-citalopram, rather 5-HTTLPR-genotype showed an association: positive emotionality scores increased with the number of s-alleles carried by the individuals. Most notable was the moderating role of 5-HTTLPR-genotype: only in ss-homozygotes serotonergic responsivity seems to additionally contribute to the level of positive emotionality. These findings are in line with research demonstrating that effects of 5-HTTLPR-genotype are not restricted to aspects of negative emotionality and temperament, and also support the idea of influences of the 5-HTTLPR-genotype on early neuronal development.

Variations in central serotonergic activity — Relevance of the 5-HTTLPR, life events and their interaction

The 5-HTTLPR and its interaction with adverse life events has been studied widely; especially with regard to depression. Few studies are available relating the respective association with acute serotonergic functionality.We examined the effects of the 5-HTTLPR, life events and their interaction on serotonergic responsivity using S-citalopram (10mg) in a placebo-controlled double-blind neuroendocrine challenge paradigm (n=59 healthy males). We considered positive and negative life events, life events experienced during the last year and accumulated over the whole life span and possible mediating effects of neuroticism, extraversion and openness to experience. We demonstrated associations of life events experienced during the last year: negative life events were positively associated with cortisol-responses in the challenge paradigm (β=0.28, p<0.05), while positive life events were inversely associated (β=−0.29, p<0.05).Neither the main effect of 5-HTTLPR-genotype nor its interactions with life events predicted the acute serotonergic functionality. In addition, openness for feelings significantly predicted the serotonergic responsivity, while no other personality traits measured in this study mediated the effect of life events. Our results question not only the stability of serotonergic activity but, importantly, add to the literature concerning the serotonergic system as a general threshold modulating system, i.e. being associated with the processing of positive as well as negative stimuli.

Psychological coping in depressed outpatients: Association with cortisol response to the combined dexamethasone/CRH test

BackgroundDepression is associated with dysfunctional coping styles and dysregulated hypothalamic–pituitary–adrenal (HPA) axis function. Studies have shown that maladaptive coping strategies relate to abnormal HPA axis function; however, such a relationship has been under-studied in patients with depression. We aimed to examine whether dysfunctional coping styles in depression would be associated with abnormal cortisol reactivity. MethodsSeventy-four outpatients with major depressive disorder and 133 age- and sex-matched healthy individuals were recruited. Coping was assessed by the Ways of Coping Checklist. Psychological distress was assessed by the Hopkins Symptom Checklist. Cortisol reactivity was measured by the combined dexamethasone/corticotropin-releasing hormone test. ResultsCompared to healthy individuals, depressed patients demonstrated significantly less use of problem-solving, positive reappraisal and social support coping styles and more use of self-blame and wishful thinking styles. Such a pattern of coping styles was significantly associated with patients' greater distress. Partial correlation analysis in patients, controlling for age and sex, revealed a significant correlation between more use of escape–avoidance coping and lower levels of reactive cortisol measures. A stepwise multiple regression analysis predicting cortisol reactivity from age, sex, distress, symptom severity and coping styles revealed that escape–avoidance coping was a significant predictor. LimitationsThe neuroendocrine challenge test was administered only once, based on a simple test protocol. ConclusionsMore use of escape–avoidance coping in depressed patients was associated with less cortisol reactivity. Our findings shed light on the heterogeneity of depression in terms of low and high levels of avoidance associated with exaggerated and blunted HPA axis reactivity, respectively.

Prolactin response to buspirone is not impaired in drug-naïve first episode patients with major depressive disorder

BackgroundAn altered postsynaptic 5-HT1A receptor function along with hypercortisolemia has been associated with major depressive disorder (MDD). However, several methodological considerations related to data interpretation arise when subjects previously exposed to psychotropic medication are included in the study population. To address those issues we designed a study in a well defined cohort of first-episode, treatment-naïve MDD patients. MethodsThis cross-sectional case–control pharmacologic challenge study was designed to investigate the prolactin (PRL) response to buspirone in 21 non-late-life adult, treatment-naïve MDD patients with the first affective episode and in 20 age- and sex-matched healthy controls. Depressed patients showed a basal score in the Hamilton Rating Scale for Depression (HAMD-17) higher than 20. ResultsNo significant difference in PRL response to buspirone between first-episode, treatment-naïve patients with MDD and controls, was observed. The correlation between basal cortisol levels and PRL response was not observed in MDD group while significant negative correlation was found in healthy controls. The significantly higher PRL response to buspirone was observed in melancholic patients as compared to non-melancholic subjects. LimitationsThe current study is limited by its cross-sectional design, small sample size, factors related to neuroendocrine challenge methodology, and no placebo control. ConclusionThese results indicate no consistent changes in the hormonal response to the 5-HT1A agonist buspirone in major depression. Taken into account the interpretation of the buspirone test the present study does not support the hypothesis of an altered functional activity with down-regulation of the postsynaptic 5-HT1A receptor and/or in the postsynaptic receptor signal transduction in the hypothalamus in the pathogenesis of MDD.

What future for neuroendocrinology in psychiatry?

In psychiatry, neuroendocrine techniques were initially considered a potential "window into the brain" by indirectly marking central nervous system limbic dysfunction. At present this conception has evolved, owing to significant progress over the last decades demonstrating direct involvement of neuropeptides and neurohormones in psychiatric diseases. In a synchronic perspective, neuroendocrine investigations evaluate a functional status at a given moment in the evolution of the disease, which results from both etiopathogenic processes and compensatory homeostatic mechanisms. These vital physiological changes appear to be potential targets for novel hormonally based pharmacotherapies. However, in the past few years, the interest for the study of neuroendocrine dysregulations in psychiatric patients has declined. In order to better understand this relative disinterest, this article will attempt to shed light on strengths and limitations of the neuroendocrine approaches in psychiatry. It is necessary to bear in mind that the usefulness of these techniques in the clinical, pathophysiological and therapeutic fields depends largely on the selectivity of stimuli and the appropriateness of the methodologies used. Owing to the complexity of the clinical phenomena, multifactorial approaches (combining several neuroendocrine challenge tests to imaging, immunological, neurophysiological, neurochemical and/or genetic techniques) are to be privileged in psychiatric investigations. Despite the inherent limitations of these approaches, due to their technical and ethical constraints, the neuroendocrine strategy can inform modern clinical practice and lead to new breakthroughs in future science and practice.

Acute responsivity of the serotonergic system to S-citalopram and positive emotionality-the moderating role of the 5-HTTLPR.

According to the idea that the central serotonergic system has a modulatory function on behavior and personality in general, we aimed to highlight its association to habitual positive emotionality. In a placebo-controlled double-blind and randomized cross-over neuroendocrine challenge design (n = 72 healthy males) we investigated the association of the central serotonergic responsivity, 5-HTTLPR-genotype as well as their combined effects on positive emotionality. Regression analyses revealed an involvement of the serotonergic system in positive emotionality. There was, however, no direct association between positive emotionality and cortisol responses to S-citalopram; rather 5-HTTLPR-genotype showed an association (p < 0.05). That is, positive emotionality scores increased with the number of s-alleles carried by the individuals. Most notable was the moderating role of 5-HTTLPR-genotype (p < 0.05) on the association between acute serotonergic responsivity and positive emotionality. Indeed, this association was only found in ss-homozygotes, in which the acute responsivity of the serotonergic system additionally seems to contribute to the level of positive emotionality (r = 0.70, p < 0.05). The findings correspond to previous research demonstrating that the 5-HTTLPR is not only involved in the negative-emotional aspects of behavior and temperament, but is associated, moreover, with positive affectivity—supporting the assumption of its valence-neutrality. In addition, our data are in line with the idea of possible influences of the 5-HTTLPR-genotype on early neuronal development. They also indicate the need for further studies in order to clearly elucidate the role of the serotonergic system and its subcomponents in the regulation of positive emotionality.

Relationship of temperament and character with cortisol reactivity to the combined dexamethasone/CRH test in depressed outpatients

BackgroundEvidence shows that depression is associated with hypothalamic–pituitary–adrenal (HPA) axis hyperactivation, although such findings are not entirely unequivocal. In contrast, various psychiatric conditions, including atypical depression, are associated with hypocortisolism. Another line of research has demonstrated that personality is associated with HPA axis alteration. It is thus hypothesized that different personality pathology in depression would be associated with distinct cortisol reactivity. MethodsEighty-seven outpatients with DSM-IV major depressive disorder were recruited. Personality was assessed by the temperament and character inventory (TCI). HPA axis reactivity was measured by the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. According to our previous studies, two subgroups were considered based on their cortisol responses to the DEX/CRH test: incomplete-suppressors whose cortisol response was exaggerated and enhanced-suppressors whose cortisol response was blunted. ResultsThe analysis of covariance, controlling for age, gender and symptom severity, revealed that incomplete-suppressors scored significantly higher on cooperativeness than enhanced-suppressors (p=0.002). A multivariate stepwise logistic regression analysis predicting the cortisol suppression pattern from the seven TCI dimensions, controlling for age, gender and symptom severity, revealed that lower cooperativeness (p=0.001) and higher reward dependence (p=0.018) were significant predictors toward enhanced suppression. LimitationsThe neuroendocrine challenge test was administered only once, based on a simple test protocol. ConclusionsOur findings suggest that (personality-related) subtypes of depression might be differentiated based on the different pattern of cortisol reactivity. Future studies are warranted to further characterize the HPA axis alteration in relation to various subtypes of depression.

A Steep Learning Curve: Decoding Epigenetic Influence on Behavior and Mental Health

Research on epigenetics has surged in the past two decades as it has become apparent that changes in gene function aside from those related to DNA mutations or natural variations may be integral factors in numerous perplexing health disorders. But much remains unknown about this relatively new field. Of the thousands of epigenetics studies published,1 a few hundred have addressed behavioral and mental health outcomes, but only a fraction of those have dealt with fetal or childhood exposures or outcomes. However, early results in the niche field of behavioral epigenetics suggest such studies could provide insights into behavioral and mental health conditions such as autism spectrum disorders (ASDs), attention deficit/hyperactivity disorder, schizophrenia, bipolar disorder, depression, and anxiety.

Serotonergic Function and Treatment of Behavioral and Psychological Symptoms of Frontotemporal Dementia

The purposes of this study were first, to evaluate the effectiveness of citalopram in treating behavioral disturbances in frontotemporal dementia (FTD) subjects and second, to determine whether an association exists between serotonergic function, as determined by a neuroendocrine challenge, and treatment response. Single-dose citalopram (30 mg per os) challenge followed by a 6-week open-label study. Outpatients referred to memory clinics. Fifteen patients suffering from FTD with severe behavioral and psychological symptoms of dementia. Following citalopram challenge, all patients were treated with citalopram titrated to a target dose of 40 mg once daily. Behavioral disturbances, using the Neuropsychiatric Inventory (NPI) (primary outcome) and Frontal Behavioural Inventory (secondary outcome), were assessed. Change in prolactin concentration following citalopram challenge was used as an index of central serotonergic response. Citalopram treatment was effective in treating behavioral symptoms, with significant decreases in NPI total score (F[2, 28] = 6.644, p = 0.004), disinhibition (F[2, 28] = 4.030, p = 0.029), irritability (F[2, 28] = 7.497, p = 0.003) and depression (F[2, 28] = 3.467, p = 0.045) scores over the 6 weeks. Significant improvement in Frontal Behavioural Inventory scores suggested that citalopram was also effective in the treatment ofbehaviors specific to FTD. A lower change score in concentration of prolactin was significantly positively correlated with greater improvement in the total NPI score from baseline to endpoint (r = 0.687, p = 0.005). A blunted response to a citalopram challenge, implying a dysfunctional serotonergic system, predicted a more positive treatment outcome. The results suggest that despite the endogenous serotonin deficiency of FTD, citalopram treatment may be effective in targeting the behavioral disturbances characteristic of FTD.

Differences in Food Preference and Dietary Restraint between Young Adult Preterms versus Controls May Parallel Future Chronic Disease Risk

Individuals born prematurelymay have elevated risk of chronic conditions, such as metabolic and cardiovascular disease (CVD), and altered hypothalamic-pituitary-adrenal axis functionand the stresshormone, cortisol, responses. Presently, we added diet measures to a longitudinal study of 111 adult preterms (56 females, P-adults) and28 adult born full-term (18 females, F-adults), followed since birth and now at age 23 years, to examine dietary behaviors thatmay contribute to or be reflective of these chronic conditions. Each participant completed surveys to assess foodandnon-foodpreferences, dietary restraint (RevisedRestraint Scale), and food neophobia. Data were analyzed with analysis of covariance unless noted (significance criterion, p .05). P-adults reported least absolute liking for carrots, low-fat sugars, alcoholic beverages, and thrill seekingactivities. By chi square analysis and comparing relative preference ratings, P-adults were most likely toreporthigh-fatandsweet foodsas themostpreferredof foodornon-food category. P-adults only tended to have higher food neophobia, the effect of term status seen primarily in females. The P-adults reported lowest levels of dietary restraint, with greatest difference seen between the female groups for the restraint sub-category, Concern for Dieting. The birth-term groups did not vary significantly in adiposity. In summary, adult preterms reporteddietarybehaviors that can add to their prematurity and neuroendocrine challenges to increase metabolic and CVD risk, including less healthy food preferences and lower cognitive control of eating. Lower preference for alcoholic beverages and thrill seeking behaviors parallel findings of compensatory avoidance of stressful situations.

The response to sulpiride in social anxiety disorder: D2 receptor function

Some previous studies have suggested that patients with social anxiety disorder (SAD) have a hypoactive central dopaminergic system. Supporting this there have been reports from neuroimaging studies of reduced striatal D2 receptor binding in subjects with SAD. The aim of this study was to investigate D2 receptor sensitivity in patients with SAD compared with a group of matched, healthy controls using a neuroendocrine challenge with the selective D2 antagonist, sulpiride. D2 receptor function was assessed in 23 subjects with generalized SAD and 23 matched, healthy controls using a challenge with 400 mg of a selective D2 antagonist, sulpiride in a randomized, placebo-controlled, crossover design. Response to sulpiride was measured by the change in prolactin level and changes in self-rated measures of social anxiety, mood and the ability to experience pleasure. There was no significant difference in prolactin response to sulpiride between the two groups. Sulpiride resulted in no effect in either the SAD or healthy control group on measures of social anxiety, mood or the ability to experience pleasure. Contrary to our hypothesis, in this study we found no evidence of reduced D2 receptor function in subjects with SAD compared with healthy controls.

Altered Response to Neuroendocrine Challenge Linked to Indices of the Metabolic Syndrome in Healthy Adults

Metabolic syndrome (MetS) is characterized by central obesity, hypertension, insulin resistance, and hypercholesterolemia. Hypothalamic-pituitary-adrenal (HPA) axis activity is frequently abnormal in MetS, and excessive cortisol exposure may be implicated in metabolic derangements. We investigated the hypothesis that cortisol and adrenocorticotropic hormone (ACTH) responses to a standardized neuroendocrine challenge test would be associated with indices of MetS in a community sample of healthy adults. Healthy adults, 125 men and 170 women, without significant medical problems or chronic medications were recruited from the community. Participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, and anthropometric measurements, blood pressure, glycosylated hemoglobin (HbA1c), and cholesterol were measured. Participants reported on their history of early life stress and recent stress, as well as mood and anxiety symptoms. Cortisol and ACTH responses to the Dex/CRH test were negatively associated with measures of central adiposity (p<0.001) and blood pressure (p<0.01), and positively associated with HDL cholesterol (p<0.01). These findings remained significant after controlling for body mass index (BMI). Measures of stress and anxiety and depressive symptoms were negatively correlated with cortisol and ACTH responses in the Dex/CRH test but were not related to MetS indices. That altered HPA axis function is linked to MetS components even in a healthy community sample suggests that these processes may be involved in the pathogenesis of MetS. Identification of premorbid risk processes might allow for detection and intervention prior to the development of disease.

Childhood Adversity and Epigenetic Modulation of the Leukocyte Glucocorticoid Receptor: Preliminary Findings in Healthy Adults

BackgroundA history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans.MethodsWe examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test.ResultsDisruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05).ConclusionsThese findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.