Axis In Posttraumatic Stress Disorder Research Articles

Stress Across Generations: DNA Methylation as a Potential Mechanism Underlying Intergenerational Effects of Stress in Both Post-traumatic Stress Disorder and Pre-clinical Predator Stress Rodent Models.

Although most humans will experience some type of traumatic event in their lifetime only a small set of individuals will go on to develop post-traumatic stress disorder (PTSD). Differences in sex, age, trauma type, and comorbidity, along with many other elements, contribute to the heterogenous manifestation of this disorder. Nonetheless, aberrant hypothalamus-pituitary-adrenal (HPA) axis activity, especially in terms of cortisol and glucocorticoid receptor (GR) alterations, has been postulated as a tenable factor in the etiology and pathophysiology of PTSD. Moreover, emerging data suggests that the harmful effects of traumatic stress to the HPA axis in PTSD can also propagate into future generations, making offspring more prone to psychopathologies. Predator stress models provide an ethical and ethologically relevant way to investigate tentative mechanisms that are thought to underlie this phenomenon. In this review article, we discuss findings from human and laboratory predator stress studies that suggest changes to DNA methylation germane to GRs may underlie the generational effects of trauma transmission. Understanding mechanisms that promote stress-induced psychopathology will represent a major advance in the field and may lead to novel treatments for such devastating, and often treatment-resistant trauma and stress-disorders.

Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder

Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress-related alterations in corticotropin releasing factor (CRF), hypothalamic pituitary adrenal axis (HPA) regulation and glucocorticoid signaling. Overnight HPA axis response mediating sleep disturbances in men and women with PTSD was examined using a metyrapone challenge. Metyrapone blocks cortisol synthesis, removing negative feedback, and increases the release of hypothalamic CRF and pituitary adrenocorticotropic hormone (ACTH). Laboratory-based polysomnography was used to monitor the sleep of 66 medically healthy, medication-free men and pre-menopausal follicular phase women including 33 with chronic PTSD (16 women and 17 men) and 33 age- and sex-matched controls (14 women and 19 men) over 3 consecutive nights. Participants completed an overnight metyrapone challenge after an adaptation and baseline night of sleep and ACTH was obtained by repeated blood sampling. Metyrapone resulted in a greater increase in ACTH and greater decreases in cortisol and delta spectral power sleep in PTSD subjects compared to controls, and a greater increase in ACTH in women compared to men. There was no sex difference in metyrapone effects on delta power sleep, and no significant metyrapone by PTSD by sex interactions with either ACTH or delta power sleep. Regression analyses indicated that a greater increase in ACTH response was associated with a greater decrease in delta power sleep response in PTSD subjects, but no such relationship was found in controls. The PTSD group difference was similar in men and women. These results suggest that stress-related alterations of the HPA axis in PTSD may contribute to sleep difficulties. Therapeutics that target the HPA axis may offer promise as a potential future treatment for PTSD and related sleep difficulties.

Effect of current and lifetime posttraumatic stress disorder on 24-h urinary catecholamines and cortisol: Results from the Mind Your Heart Study

Posttraumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular disease and several other chronic illnesses. Alterations in the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis in PTSD might contribute to these associations but findings regarding SNS and HPA activity in PTSD are heterogeneous. We measured 24-h urinary catecholamines and cortisol in a large cohort of adult outpatients recruited from 2 Veterans Affairs medical centers. 24-h urinary norepinephrine, epinephrine, dopamine and cortisol were measured by tandem mass spectrometry. Lifetime and current PTSD were assessed with the Clinician Administered PTSD Scale using DSM-IV-TR criteria. Out of 613 participants, 199 (32.5%) had current PTSD, 100 (16.3%) had lifetime but not current PTSD, and 314 (51.2%) never had PTSD. Patients with current PTSD had significantly higher norepinephrine secretion compared to those without PTSD. Patients in the lifetime PTSD group exhibited lower cortisol values compared to those without PTSD. Participants who never had PTSD showed the lowest norepinephrine and the highest cortisol values. All results remained stable when controlling for potentially confounding variables. This study provides evidence for increased norepinephrine secretion and decreased cortisol in PTSD. Future longitudinal studies are needed to determine whether these changes contribute to adverse health outcomes in patients with PTSD.

Diurnal salivary cortisol in pediatric posttraumatic stress disorder

Background: The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). Additional information on basal cortisol levels in children exposed to trauma and experiencing PTSD symptoms may contribute to the understanding of the role of this axis in PTSD. Methods: Fifty-one children (30 boys and 21 girls, mean age 10.7 years) with a history of exposure to trauma and PTSD symptoms were compared with 31 age- and gender-matched healthy control subjects. Salivary cortisol was obtained from participants during home measurements and was collected four times a day (prebreakfast, prelunch, predinner, and prebed) for up to 3 consecutive days. Results: The clinical group demonstrated significantly elevated cortisol levels when compared with the control group. In addition, exploratory analyses revealed that girls with PTSD symptoms had significantly elevated cortisol levels when compared with boys with PTSD symptoms. Conclusions: The physiologic response of children with history of trauma and with PTSD symptoms may be characterized by heightened adrenal activity.

Marked lability in urinary cortisol levels in subgroups of combat veterans with posttraumatic stress disorder during an intensive exposure treatment program.

The objective of this study was to obtain longitudinal data on lability of cortisol levels in posttraumatic stress disorder (PTSD) because previous studies have largely been based on sampling at a single time point and have yielded varying results. This study measured urinary cortisol levels at admission, midcourse, and discharge during a 90-day hospitalization period in male Vietnam combat veterans with PTSD (N = 51). Although there were no significant differences in the mean +/- SEM urinary cortisol levels between the admission (59.4 +/- 3.0 microg/d), midcourse (55.6 +/- 3.9 microg/d), and discharge (53.4 +/- 3.4 microg/d) values, marked lability of cortisol levels in individual patients was observed over time, with changes ranging from +93 to -58 microg/d from admission to midcourse. In addition, this hormonal lability defined discrete subgroups of patients on the basis of the longitudinal pattern of cortisol change during exposure treatment, and there were significant psychometric differences in the level of social functioning between these subgroups. The findings do not support the concept of either a static "hypocortisolism" or "hypercortisolism" in PTSD, but rather suggest a psychogenic basis for cortisol alterations in PTSD in relation to psychosocial stress and indicate a central regulatory dysfunction of the hypothalamic-pituitary-adrenal axis characterized by a dynamic tendency to overreact in both upward and downward directions. The longitudinal findings fit with recent observations that cortisol elevations occur when acutely superimposed stressful conditions emotionally engage patients and overwhelm the usually dominating disengaging coping mechanisms associated with suppression of cortisol levels in PTSD. The findings emphasize the importance of longitudinal data in studies of the hypothalamic-pituitary-adrenal axis in PTSD.

Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder

Background: Decreased basal cortisol levels have been reported in individuals with posttraumatic stress disorder (PTSD). There is evidence for enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, which could account for this, but other possible mechanisms have not been ruled out. We examined the HPA axis employing a metyrapone-cortisol infusion protocol designed to study negative feedback sensitivity. Methods: Vietnam combat trauma-exposed subjects met DSM-IV criteria for PTSD. Exclusion criteria included substance abuse and most medications. Endogenous feedback inhibition was removed by blocking cortisol synthesis with oral metyrapone and reintroduced by intravenous infusion of cortisol. In a placebo condition, subjects received oral placebo and normal saline infusion. Serial blood samples drawn over 4 hours were assayed for adrenocorticotrophic hormone (ACTH), cortisol, and 11-deoxycortisol. Selected samples were assayed for cortisol binding globulin (CBG) and dehydroepiandrosterone (DHEA). Results: Basal plasma cortisol was significantly decreased in PTSD subjects ( n = 13) compared with control subjects ( n = 16). No significant difference in the ACTH response to cortisol infusion following metyrapone was observed; however 11-deoxycortisol was significantly decreased in PTSD subjects. In addition, CBG was significantly increased in PTSD subjects, and DHEA was significantly decreased in both PTSD and combat-exposed control subjects. Conclusions: These observations suggest decreased adrenocortical responsiveness may be an additional or alternative mechanism accounting for low cortisol in PTSD.

Altered hypothalamo-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD) and psoriasis

Altered hypothalamo-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD) and psoriasis

Sensitization of the hypothalamic-pituitary-adrenal axis in posttraumatic stress disorder.

Sensitization of the hypothalamic-pituitary-adrenal axis in posttraumatic stress disorder.

Increased pituitary activation following metyrapone administration in post-traumatic stress disorder.

Our previous findings have demonstrated that individuals with post-traumatic stress disorder (PTSD) show lower basal cortisol levels, a larger number of lymphocyte glucocorticoid receptors, and an enhanced suppression of cortisol following the administration of dexamethasone compared to normals and patients with major depression. We have previously suggested that these alterations reflect an enhanced negative feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD. However, in the absence of direct knowledge of pituitary capability in this disorder, it has been equally likely that the alterations observed reflected either pituitary or adrenal insufficiency. In the present study, we examined ACTH release from the pituitary gland in PTSD following the administration of metyrapone. Metyrapone resulted in a significantly greater increase of ACTH and 11-deoxycortisol in combat veterans with PTSD (n = 11) compared with normal male volunteers (n = 8). When seen in the context of other abnormalities observed in PTSD, the present demonstration of increased pituitary activity in the absence of negative feedback provides unequivocal support for the hypothesis of enhanced negative feedback.

Dose-Response Changes in Plasma Cortisol and Lymphocyte Glucocorticoid Receptors Following Dexamethasone Administration in Combat Veterans With and Without Posttraumatic Stress Disorder

Our previous studies have suggested that combat veterans with posttraumatic stress disorder (PTSD) have alterations in hypothalamic-pituitary-adrenal axis functioning that are different from the well-documented biological changes observed in major depressive disorder and following exposure to stress. In the present study, we examined cortisol and lymphocyte glucocorticoid receptor number before and after the administration of 0.50 and 0.25 mg of dexamethasone in 14 combat veterans with PTSD, 12 combat veterans without PTSD, and 14 nonpsychiatric healthy men. All subjects were medication free at the time of testing and none met diagnostic criteria for major depression or substance dependence. Combat veterans with PTSD suppressed cortisol to a greater extent than did combat veterans without PTSD and normal controls in response to both doses of dexamethasone. Differences in cortisol suppression could not be attributed to substance dependence history or differences in dexamethasone bioavailability. Combat veterans with PTSD showed a larger number of baseline glucocorticoid receptors compared with normal men. Combat veterans without PTSD also had a larger number of baseline glucocorticoid receptors compared with normal men and in fact were comparable to combat veterans with PTSD on this measure. However, only veterans with PTSD showed a decrease in lymphocyte glucocorticoid receptor number following dexamethasone administration. The data support the hypothesis of an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal axis in PTSD.

Enhanced suppression of cortisol following dexamethasone administration in posttraumatic stress disorder.

The authors investigated the possibility of enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD) by using a low dose of dexamethasone. Baseline blood samples were obtained at 8:00 a.m., and 0.5 mg of dexamethasone was administered to 21 male patients with PTSD and 12 normal age-comparable men at 11:00 p.m. Cortisol and dexamethasone levels were measured 9 and 17 hours after dexamethasone administration. After correction for differences in dexamethasone levels, the PTSD patients showed greater suppression of cortisol in response to dexamethasone than did the normal subjects. This was true even in patients meeting concurrent diagnostic criteria for major depression. The data support earlier studies showing that HPA abnormalities in PTSD are different from those seen in depression and suggest that the low-dose dexamethasone suppression test may be a potentially useful tool for differentiating the two syndromes and further exploring differences in their pathophysiology.

Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder

The authors' objective was to investigate the possibility that glucocorticoid receptor changes may be involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD). They measured the number of lymphocyte cytosolic glucocorticoid receptors and plasma cortisol concentrations in 15 consecutively admitted male combat Vietnam veterans with PTSD and in a normal comparison group of 11 subjects. Both the patients and the normal comparison subjects showed a morning-to-afternoon decline in glucocorticoid receptor concentrations, paralleling the normal diurnal decline in cortisol levels. The number of glucocorticoid receptors was 63% greater in the morning and 26% greater in the afternoon in the patients with PTSD than in the normal subjects. No group differences in cortisol levels were observed, nor were glucocorticoid receptor number and cortisol levels correlated. The number of morning glucocorticoid receptors was positively correlated with symptoms of PTSD and anxiety. These results provide further evidence for a dysregulation of the HPA axis in PTSD. The finding that patients with PTSD had a substantially greater number of lymphocyte glucocorticoid receptors than normal comparison subjects is consistent with the authors' previous observations of low 24-hour urinary cortisol excretion in subjects with PTSD. Furthermore, the receptor changes observed are opposite of those reported in major depressive disorder. The present data, along with other findings of HPA abnormalities in PTSD, support the possibility of a greater negative feedback sensitivity at one or more levels of the HPA axis.