Hypothalamic-pituitary-adrenal Axis Disturbance Research Articles

Nutraceutical Interventions for Post-Traumatic Stress Disorder in Animal Models: A Focus on the Hypothalamic-Pituitary-Adrenal Axis.

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the hypothalamic–pituitary–adrenal (HPA) axis are involved in the pathogenesis of mood disorders, including anxiety, PTSD, and major depressive disorders. Studies have demonstrated the relationship between the HPA axis response and stress vulnerability, indicating that the HPA axis regulates the immune system, fear memory, and neurotransmission. The selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, are the only drugs that have been approved by the United States Food and Drug Administration for the treatment of PTSD. However, SSRIs require long treatment times and are associated with lower response and remission rates; therefore, additional pharmacological interventions are required. Complementary and alternative medicine therapies ameliorate HPA axis disturbances through regulation of gut dysbiosis, insomnia, chronic stress, and depression. We have described the cellular and molecular mechanisms through which the HPA axis is involved in PTSD pathogenesis and have evaluated the potential of herbal medicines for PTSD treatment. Herbal medicines could comprise a good therapeutic strategy for HPA axis regulation and can simultaneously improve PTSD-related symptoms. Finally, herbal medicines may lead to novel biologically driven approaches for the treatment and prevention of PTSD.

The co-chaperone FKBP51 modulates HPA axis activity and age-related maladaptation of the stress system in pituitary proopiomelanocortin cells

Glucocorticoid (GC)-mediated negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, the body’s physiological stress response system, is tightly regulated and essential for appropriate termination of this hormonal cascade. Disturbed regulation and maladaptive response of this axis are fundamental components of multiple stress-induced psychiatric and metabolic diseases and aging. The co-chaperone FK506 binding protein 51 (FKBP51) is a negative regulator of the GC receptor (GR), is highly stress responsive, and its polymorphisms have been repeatedly associated with stress-related disorders and dysfunctions in humans and rodents. Proopiomelanocortin (Pomc)-expressing corticotropes in the anterior pituitary gland are one of the key cell populations of this closed-loop GC-dependent negative feedback regulation of the HPA axis in the periphery. However, the cell type-specific role of FKBP51 in anterior pituitary corticotrope POMC cells and its impact on age-related HPA axis disturbances are yet to be elucidated. Here, using a combination of endogenous knockout and viral rescue, we show that male mice lacking FKBP51 in Pomc-expressing cells exhibit enhanced GR-mediated negative feedback and are protected from age-related disruption of their diurnal corticosterone (CORT) rhythm. Our study highlights the complexity of tissue- and cell type-specific, but also cross-tissue effects of FKBP51 in the rodent stress response at different ages and extends our understanding of potential targets for pharmacological intervention in stress- and age-related disorders.

Chronopharmacology of glucocorticoids.

Glucocorticoids influence a wide array of metabolic, anti-inflammatory, immunosuppressive, and cognitive signaling processes, playing an important role in homeostasis and preservation of normal organ function. Synthesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is the primary glucocorticoid in humans. Synthetic glucocorticoids are important pharmacological agents that augment the anti-inflammatory and immunosuppressive properties of endogenous cortisol and are widely used for the treatment of asthma, Crohn's disease, and rheumatoid arthritis, amongst other chronic conditions. The homeostatic activity of cortisol is disrupted by the administration of synthetic glucocorticoids and so there is interest in developing treatment options that minimize HPA axis disturbance while maintaining the pharmacological effects. Studies suggest that optimizing drug administration time can achieve this goal. The present review provides an overview of endogenous glucocorticoid activity and recent advances in treatment options that have further improved patient safety and efficacy with an emphasis on chronopharmacology.

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Glucocorticoids influence a wide array of metabolic, anti-inflammatory, immunosuppressive, and cognitive signaling processes, playing an important role in homeostasis and preservation of normal organ function. Synthesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is the primary glucocorticoid in humans. Synthetic glucocorticoids are important pharmacological agents that augment the anti-inflammatory and immunosuppressive properties of endogenous cortisol and are widely used for the treatment of asthma, Crohn's disease, and rheumatoid arthritis, amongst other chronic conditions. The homeostatic activity of cortisol is disrupted by the administration of synthetic glucocorticoids and so there is interest in developing treatment options that minimize HPA axis disturbance while maintaining the pharmacological effects. Studies suggest that optimizing drug administration time can achieve this goal. The present review provides an overview of endogenous glucocorticoid activity and recent advances in treatment options that have further improved patient safety and efficacy with an emphasis on chronopharmacology.

Cushing's syndrome is associated with sleep alterations detected by wrist actigraphy.

The association between the hypothalamic-pituitary-adrenal (HPA) axis and sleep is well described. It is also known that HPA axis disturbances have an effect on sleep. In fact, patients affected by Cushing's syndrome (CS) often complain about poor sleep quality. Our aim was to evaluate objective sleep quality and duration in patients with Cushing's syndrome in active phase, using wrist actigraphy. In 12 patients with active CS without ongoing specific therapy (11F, 1M; age 40.0±10.9years; BMI 28.4±6.7kg/m(2)) and 12 healthy control subjects (HS) (11F, 1M; age 44.0±11.0years; BMI 23.9±4.2kg/m(2)) an actigraphic evaluation was performed on 3 consecutive days under free living conditions. Objective measurement of sleep duration and quality was estimated by an actiwatch, which is a wristwatch-like device used to detect motor activity. In CS patients, wrist actigraphy showed higher fragmented sleep (fragmentation index CS 16.2±4.2, HS 13.0±3.6; p=0.034) and increased nocturnal motor activity (total activity score CS 8318±4308, HS 4971±2372; p=0.020; mean activity score CS 8.7±4.2, HS 5.4±2.2; p=0.030; mean score in active time CS 104.8±39.2, HS 74.8±23.1; p=0.030). On the contrary, actual sleep time resulted similar in CS and HS. No correlation was found between sleep alterations and urinary free cortisol in patients. The impaired actigraphic parameters described in our study suggest that hypercortisolism is associated with sleep alterations, which could contribute to the worsening of life quality and metabolic comorbidities associated with CS. These results have to be confirmed in a larger cohort of patients, using more accurate instruments for sleep assessment.

Impact of N-acetylcysteine and sesame oil on lipid metabolism and hypothalamic-pituitary-adrenal axis homeostasis in middle-aged hypercholesterolemic mice.

Hyperlipidemia and stress are important factors affecting cardiovascular health in middle-aged individuals. We investigated the effects of N-acetylcysteine (NAC) and sesame oil on the lipidemic status, liver architecture and the hypothalamic-pituitary-adrenal (HPA) axis of middle-aged mice fed a cholesterol-enriched diet. We randomized 36 middle-aged C57bl/6 mice into 6 groups: a control group, a cholesterol/cholic acid diet group, a cholesterol/cholic acid diet group with NAC supplementation, a cholesterol/cholic acid diet enriched with 10% sesame oil and two groups receiving a control diet enriched with NAC or sesame oil. NAC administration prevented the onset of the disturbed lipid profile, exhibiting decreased lipid peroxidation and alkaline phosphatase (ALP) levels, restored nitric oxide bioavailability and reduced hepatic damage, compared to non-supplemented groups. High-cholesterol feeding resulted in increased hypothalamic glucocorticoid receptors (GR) levels, while NAC supplementation prevented this effect. NAC supplementation presented significant antioxidant capacity by means of preventing serum lipid status alterations, hepatic damage, and HPA axis disturbance due to high-cholesterol feeding in middle-aged mice. These findings suggest a beneficial preventive action of plant-derived antioxidants, such as NAC, on lipid metabolism and on the HPA axis.

Combined dexamethasone suppression–corticotrophin-releasing hormone stimulation test in medication-free major depression and healthy volunteers

BackgroundThe hypothalamic–pituitary–adrenal (HPA) axis is dysfunctional in a subgroup of mood disorders. MethodsWe compared cortisol and adrenocorticotropic hormone (ACTH) responses in major depression and healthy volunteers to the combined dexamethasone suppression–corticotrophin-releasing hormone stimulation (DEX–CRH) test. Unlike other published studies, the study patients were medication-free and the healthy volunteers did not have first-degree relatives with a mood or psychotic disorder. Demographics, DSM-IV diagnoses and other clinical parameters were evaluated in major depressive disorder (MDD) and healthy control groups. Participants received an oral dose of 1.5mg dexamethasone at 11pm the day before CRH administration. On the following day, at 3pm, 100µg of ovine CRH was infused. Blood samples for determination of cortisol and ACTH were collected every 15min from 3pm to 4:15pm. Cortisol and ACTH responses were calculated as areas under the curve. ResultsControlling for age, baseline (i.e., post-dexamethasone) ACTH levels were higher in depressed patients compared to controls (p=0.01). There was a trend for higher ACTH responses in depressed patients compared to the control group (p=0.08). In depressed patients, cortisol and ACTH responses correlated positively with age, duration of illness and number of hospitalizations. LimitationsBecause of the cross-sectional study design we can only evaluate the nature of potential HPA axis disturbances that were present in patients when they are acutely depressed. ConclusionsFeedback inhibition of ACTH secretion by cortisol is compromised in MDD, and this is independent of an age effect on the HPA axis function.

The relationship between cortisol and verbal memory in the early stages of Huntington’s disease

Hypothalamic pituitary adrenal (HPA) axis hyperactivity has been linked to learning and memory difficulties in a range of neurodegenerative and neuropsychiatric conditions. In Huntington's disease (HD), both declines in learning and memory and HPA axis dysfunction are present early in the disease. However, the relationship between specific learning and memory deficits and HPA axis functioning in HD has not been examined. The aim of this study was to investigate cortisol levels in relation to verbal learning and memory in pre-diagnosed (pre-HD) participants and patients at the early stages of diagnosed HD (early-HD). Cortisol concentration was assayed in saliva samples from 57 participants (17 early-HD, 20 pre-HD, and 20 controls) at four time-points across a 24-h period. Verbal memory was assessed using the California Verbal Learning Test-Second Edition (CVLT-II). We focused statistical analyses on the late evening cortisol concentration, and examined cortisol levels and verbal memory function in relation to diagnostic group (control, pre-HD, early-HD), and in a separate set of analyses combining pre-HD and early-HD (and excluding controls) we also examined cortisol and verbal memory performance in relation to the severity of HD-related motor signs. Of these two classification approaches, HD motor sign severity was more strongly associated with high evening cortisol levels and both reduced information encoding and memory retrieval. Separately, there was also a trend of higher cortisol levels in pre-HD. The findings suggest hypercortisolism and the underlying pathological changes may begin many years before a clinical diagnosis is made, but the memory decline associated with HPA axis disturbance may only become detectable once motor signs become pronounced.

Associations between cognitive performance and cortisol reaction to the DEX/CRH test in patients recovered from depression

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in major depression (MDD) is one of the most reliably reported neurobiological characteristics of affective disorders. Whether these alterations in HPA axis regulation are limited to the acute stage of MDD or whether they persist after recovery, remains ambiguous. A relationship between hypercortisolemia and cognitive dysfunction in acutely depressed patients has been repeatedly observed and it was also demonstrated in a number of studies that a discrete cognitive impairment often persists in the remitted state of depression. In the present study we were interested, whether these subtle impairments in cognitive functioning observed in patients recovered from depression compared to healthy control subjects are associated with HPA axis feedback sensitivity. In 20 recovered patients and 20 matched healthy controls we assessed HPA axis feedback sensitivity with the combined dexamethasone suppression/corticotropin-releasing-hormone (DEX/CRH) challenge test. Furthermore cognitive performance was investigated with respect to the following domains: verbal memory (Auditory Verbal Learning Test, VLMT), attention and executive control (Trail Making Test, TMT-A/B) as well as verbal fluency (Controlled Oral Word Association Test, COWAT). Recovered patients showed a significantly poorer cognitive performance compared to healthy controls (all p<.05). With regard to HPA-axis activity, no overall difference was observed in the DEX/CRH test between recovered patients and controls. In recovered patients however, a significant association was observed between cortisol response and verbal memory (main effect VLMT trial 1-5: p=.046), attention (main effect TMT-A: p=.015) and executive functioning in terms of set shifting (interaction samples*TMT-B: p=.018). Poorer test performance was related to increased cortisol levels in response to challenge. The present findings suggest that patients recovered from MDD are especially vulnerable toward detrimental effects of subtle HPA axis disturbances on cognitive performance.

Cortisol secretary pattern and glucocorticoid feedback sensitivity in women from a Mediterranean area: relationship with anthropometric characteristics, dietary intake and plasma fatty acid profile

Chronic stress is associated with a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis consisting on disturbances on the cortisol response and lipid metabolism. To evaluate the HPA axis activity in women from a Mediterranean area, comparing three different measurements: daily cortisol secretory variability, postprandial cortisol secretion and glucocorticoid feedback sensitivity. In addition, HPA axis disturbance is correlated with dietary habits and plasma fatty acid profiles. The participants were 41 women born during the first 6 months of 1960 and living in a Mediterranean area (Murcia, Spain). They were of normal weight, with a waist circumference of 80.5 +/- 9.3 cm. Their salivary cortisol levels, 7-day dietary record and plasma fatty acid profile were evaluated. Daily cortisol variability and postlunch cortisol secretion were recorded and a dexamethasone suppression test is performed in order to detect possible HPA disturbance. Both the methods used for HPA axis evaluation were positively correlated (r = 0.448, P = 0.004). Subjects with normal diurnal curves (high cortisol variability) showed significantly higher cortisol values in the morning and postprandial cortisol secretion than women with pathological curves (medium and low variability). Cortisol variability was inversely correlated with waist circumference (r = -0.312, P = 0.047), suggesting that a disturbed HPA axis response may lead to an android pattern of body fat distribution. Dietary fat and saturated fatty acid intake were lower in the high cortisol variability group, while monounsaturated fatty acid intake was higher (P < 0.05). No major differences were reported in plasma fatty acid profile. A disturbed HPA axis is associated with abdominal fat distribution and a higher content of fat and saturated fatty acids in the diet. Women who chose a dietary pattern closer to the Mediterranean diet, with high monounsaturated fatty acid intake, showed lower levels on HPA axis disturbance.

Cognitive Modulation of the Endocrine Stress Response to a Pharmacological Challenge in Normal and Panic Disorder Subjects

The hypothalamic-pituitary-adrenal (HPA) axis may mediate the deleterious effects of stress on health. It is sensitive to cognitive and emotional aspects of organism-environment interactions, such as familiarity, control, and social support. Scientific study of how such factors moderate human HPA axis activity has been limited. Their relevance to HPA axis disturbances in psychiatric patients is largely unexplored. To determine whether cognitive manipulation can alter HPA axis activity in laboratory studies and whether patients with panic disorder are differentially sensitive to the manipulated factors. Pharmacological activation paradigm (cholecystokinin-B agonist pentagastrin) by which we examined symptom and endocrine effects on subjects randomly assigned to a standard introduction or a cognitive intervention. Clinical research center. Recruited from university clinic and newspaper advertisements. Fourteen patients with panic disorder and 14 controls, individually matched for age and sex. Intervention Half of each group received a 9-minute cognitive intervention designed to reduce novelty, increase cognitive coping, and provide a sense of control. Corticotropin (ACTH) and cortisol levels. The cognitive intervention significantly reduced cortisol (P = .02) and ACTH (P = .01) levels, despite pentagastrin's robust stimulation of both hormones (P<.001). The intervention effect was evident in patients and controls, who did not differ in basal HPA axis activity or response to pentagastrin. They did differ in panic symptom responses, which were unaffected by the intervention, and in ACTH effects of the intervention. Patients' exaggerated anxiety responses to pentagastrin were normalized by the intervention. Cognitive/emotional manipulation can substantially modulate HPA axis responses to pharmacological activation in humans, and HPA disturbances in panic disorder may be secondary to manipulable cognitive/emotional sensitivities. Further study of such factors as novelty, control, and coping may help clarify the origins of HPA axis disturbance in psychiatric disorders and the mediators linking psychosocial stress to disease.

The neuroendocrinology of chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a common and disabling problem; although most likely of biopsychosocial origin, the nature of the pathophysiological components remains unclear. There has been a wealth of interest in the endocrinology of this condition, which will be reviewed in this article. Most studied has been the hypothalamic-pituitary-adrenal (HPA) axis; although the quality of many studies is poor, the overall balance of evidence points to reduced cortisol output in at least some patients, with some evidence that this is linked to symptom production or persistence. There is evidence for heightened negative feedback and glucocorticoid receptor function and for impaired ACTH and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis. Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication, and ongoing stress, it seems likely that HPA axis disturbance is heterogeneous and of multifactorial etiology in CFS. Studies assessing GH, dehydroepiandrostenedione and its sulfate, melatonin, leptin, and neuroendocrine-monoamine interactions are also reviewed. There is some evidence from these studies to suggest alterations of dehydroepiandrostenedione sulfate function and abnormal serotonin function in CFS, but whether these changes are of functional importance remains unclear. To obtain a clearer assessment of the etiological and pathophysiological relevance of endocrine changes in CFS, it is suggested that more prospective cohort studies be undertaken in groups at high risk for CFS, that patients with CFS are followed up into recovery, and that multidimensional assessments are undertaken to unravel the influence of the various confounding factors on the observed endocrine changes in CFS.

Personality disorders in relation to anthropometric, endocrine and metabolic factors.

Subjects with abdominal obesity show several signs of a perturbed regulation of the hypothalamic-pituitary-adrenal (HPA) axis. This is known to occur after chronic, submissive stress. Perceived environmental stress is depending on personality characteristics. Therefore, personality disorders (PD:s) were examined in relation to HPA axis status, other endocrine and metabolic variables as well as anthropometry. Men (no.=284) aged 51 years, recruited in similar subgroups of low, median and high waist/hip circumference ratio (WHR) from a sample of 1302 men. Measurements of personality disorders by Structured Clinical Interview for DSM-III-R, Axis II (SCID II), body mass index (BMI, weight, kg/height2, m2), WHR and abdominal sagittal diameter (D), dexamethasone suppression test (0.5 mg, salivary measurements of cortisol), insulin-like growth factor I (IGF-I), testosterone and metabolic variables. Men with cluster A (paranoid, schizotypal, schizoid) PD showed an increased BMI, WHR and D, independent of dexamethasone suppression. Testosterone was decreased in these men in relation to a blunted dexamethasone suppression. BMI, WHR and D were increased in men with cluster B (borderline, histrionic, narcissistic) and cluster C (avoidant, dependent, obsessive compulsive, passive aggressive) PD, only in relation to a blunted dexamethasone suppression. Furthermore, IGF-I was low in cluster B. Metabolic variables were differently associated to clusters of PD but generally followed obesity. Path-analytic models suggested that cluster B and C PD were followed by blunted dexamethasone suppression and obesity. Men with cluster A PD showed centralized body fat distribution, independently of dexamethasone suppression. In contrast, men with impulsive (cluster B) and anxious (cluster C) personality disorders seem often to have abdominal obesity only in combination with a blunted dexamethasone suppression test, suggesting a HPA axis disturbance. These results suggest that PD:s are involved in the development of abdominal obesity in men, with different endocrine and metabolic profiles depending on the type of PD. This might hypothetically be due to frequent exposure and/or an increased sensitivity to environmental stress factors, caused by aberrant personalities.

Visceral obesity and diabetes.

Visceral obesity is a strong predictor of type 2 (non-insulin-dependent) diabetes and is associated with insulin resistance. In addition, research has indicated that the accumulation of visceral fat is regulated by endocrine mechanisms. Data suggest that progressive malfunction of the hypothalamic-pituitary-adrenal (HPA) axis, with elevation of levels of cortisol and reductions in levels of sex steroids and growth hormone, is associated with visceral accumulation of fat that contributes to circulating levels of free fatty acids, and that these factors are implicated in the development of insulin resistance. Furthermore, failure of central feedback control of the HPA axis by glucocorticoid receptors (GR) appears to be correlated with polymorphisms near the first exons of the GR gene. The HPA axis disturbances are similar to those seen after prolonged exposure to environmental stress. Psychosocial and socioeconomic factors, alcohol, depressive traits and anxiety are linked to HPA axis abnormalities.

Hypothalamic-pituitary-adrenal axis activity in panic disorder: prediction of long-term outcome by pretreatment cortisol levels

The authors sought to determine whether hypothalamic-pituitary-adrenal (HPA) axis activity in patients before their treatment for panic disorder can predict follow-up functional status. Although baseline HPA axis disturbances in patients with panic disorder appear to attenuate with treatment, there is evidence that they may be linked to poorer long-term outcomes. Follow-up clinical data were obtained for 18 of 20 patients with panic disorder who participated in a detailed study of HPA axis activity in panic, both before and during their treatment with alprazolam. HPA axis assessment included monitoring of adrenocorticotropin and cortisol over a full circadian cycle. The relationships between disability and clinical status at 2-year follow-up and HPA axis overactivity at entry were examined. Mean 24-hour cortisol levels before treatment provided a strong, positive predictor of disability scores at follow-up. Those patients who achieved the treatment goal of medication-free remissions had less evidence of HPA axis overactivity at entry than those who were not in remission. HPA axis activity before treatment did predict outcome 2 years later. This relationship appears robust and reproducible. Further work is needed to define the neuroendocrine mechanisms underlying the HPA axis markers that are linked to long-term functioning and to determine the biological, psychological, and social processes that link HPA axis disturbance to poorer outcomes.

Disturbances of hypothalamic-pituitary-adrenal axis functioning during ethanol withdrawal in six men

Excessive exposure to glucocorticoids can have neurotoxic effects. The behavioral, cognitive, and neurochemical changes observed following the cessation of heavy drinking, therefore, may be associated with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate HPA axis disturbances during the ethanol withdrawal syndrome, the authors examined diurnal changes in plasma cortisol in six alcohol-dependent men following the abrupt discontinuation of alcohol intake. Plasma cortisol concentrations were quantified every 30 minutes for 24 hours in the early stage (1 day after cessation) and the middle to late stage (3 days after cessation) of the ethanol withdrawal syndrome as well as after the resolution of acute symptoms (8 days or more after cessation). Plasma cortisol concentrations were almost twice as high during acute withdrawal as they were following recovery. The duration of the cortisol diurnal cycle on the first day of withdrawal was negatively correlated with the severity of withdrawal. There is a marked activation of the HPA axis associated with the ethanol withdrawal syndrome. The authors hypothesize that this activation may account for some of the signs and symptoms of acute and subacute withdrawal. They discuss the potential long-term physiological effects of the episodic increases in cortisol associated with repeated episodes of ethanol withdrawal. The alterations in cortisol rhythmicity during early withdrawal may also have clinical implications.

The dexamethasone suppression and metyrapone tests in depression

The dexamethasone suppression test (DST) and the metyrapone test (MT), a useful and reliable procedure for assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis, were performed in 28 patients suffering from major depressive illness with melancholia. The relationship between the DST and MT appeared to be complex. Patients who failed to suppress cortisol secretion after dexamethasone administration had higher postmetyrapone cortexolone levels and cortexolone/cortisol ratios than suppressors. However, there was a wide range of metyrapone responses in patients exhibiting abnormal DST results. This suggests that failure of adequate suppression after 1 mg of dexamethasone in depressed patients does not necessarily reflect homogeneity in the HPA axis disturbances of such patients.