Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome

Abstract  Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted ( P  <   0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms ( P  <   0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls ( P  <   0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.     

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.     

Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior

Interferon (IFN)-alpha has been used to investigate pathways by which innate immune cytokines influence the brain and behavior. Accordingly, the impact of IFN-alpha on diurnal secretion of hypothalamic-pituitary-adrenal (HPA) axis hormones was assessed in 33 patients eligible for treatment with IFN-alpha plus ribavirin for hepatitis C. In addition, the relationship between IFN-alpha-induced HPA axis changes and proinflammatory cytokines and behavior was examined. Plasma ACTH and cortisol as well as tumor necrosis factor (TNF)-alpha, interleukin-6 and their soluble receptors, were measured hourly between 0900 and 2100 hours at baseline and following approximately 12 weeks of either no treatment (n=13) or treatment with IFN-alpha/ribavirin (n=20). Plasma IFN-alpha was also measured at each visit. Depression and fatigue were assessed using the Montgomery-Asberg depression rating scale and the multidimensional fatigue inventory. Compared to no treatment, IFN-alpha/ribavirin administration was associated with significant flattening of the diurnal ACTH and cortisol slope and increased evening plasma ACTH and cortisol concentrations. Flattening of the cortisol slope and increases in evening cortisol were correlated with increases in depression (r=0.38, P<0.05 and r=0.36, P<0.05, respectively) and fatigue (r=0.43, P<0.05 and r=0.49, P<0.01, respectively). No relationship was found between immune and HPA axis measures, although increases in plasma IFN-alpha, TNF-alpha and soluble TNF-alpha receptor2 were independently correlated with behavioral endpoints. These data indicate that chronic exposure to innate immune cytokines may contribute to the altered diurnal HPA axis activity and behavior found in medically ill individuals. However, given the lack of correlation between HPA axis and immune measures, the mechanism by which chronic cytokine exposure influences HPA axis function remains to be determined.     

Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome

OBJECTIVE: Enhancement of negative feedback control of the HPA axis in patients with chronic fatigue syndrome (CFS) has been reported using the low dose dexamethasone suppression test. We have developed the use of prednisolone (5mg) as a more physiologically appropriate alternative to dexamethasone in the investigation of mild degrees of glucocorticoid resistance or supersensitivity. The objective of the study was to use this test to look for alterations in negative feedback control of the HPA axis in CFS patients. METHODS: Fifteen patients with CFS were recruited after fulfilling strict criteria including the absence of comorbid psychiatric diagnosis. They collected urine between 0900 and 1800h and saliva at 0900h pre-prednisolone. At midnight, they took prednisolone (5mg) orally and then collected urine and saliva at the same intervals the following day. RESULTS: Salivary cortisol was lower in CFS subjects pre-prednisolone than controls. Urinary cortisol metabolites were lower in CFS subjects pre-prednisolone, but did not reach significance. Both measures were significantly lower in CFS subjects post-dose. Mean percentage suppression of both salivary cortisol and urinary cortisol metabolites was significantly higher in CFS compared to controls. CONCLUSION: There is enhanced sensitivity of the HPA axis to negative feedback in CFS as demonstrated using the prednisolone suppression test. This provides further evidence of alterations in the control of the HPA axis in patients with established CFS.     

Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome

The objective of this study was to evaluate and compare the basal circadian and pulsatile architecture of the HPA axis in groups of patients with FMS, CFS, or both syndromes with individually matched control groups. Forty patients with either FMS (n = 13), FMS and CFS (n = 12), or CFS (n = 15) were matched by age (18-65), sex, and menstrual status to healthy controls. Subjects were excluded if they met criteria for major Axis I psychiatric disorders by structured clinical interview (SCID). Subjects were admitted to the General Clinical Research Center where meals and activities were standardized. Blood was collected from an intravenous line every 10 min over 24 h for analysis of ACTH and cortisol. Samples were evaluable for ACTH in 36 subject pairs and for cortisol in 37 subject pairs. There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P <.01). Elevation of cortisol in the late evening quiescent period was evident in half of the FMS patients compared with their control group, while cortisol levels were numerically, but not significantly, lower in the overnight period in patients with CFS compared with their control group. Pulsatility analyses did not reveal statistically significant differences between patient and control groups. We conclude that the pattern of differences for basal circadian architecture of HPA axis hormones differs between patients with FMS and CFS compared to their matched control groups. The abnormalities in FMS patients are consistent with loss of HPA axis resiliency.     

Linking disease symptoms and subtypes with personalized systems-based phenotypes: A proof of concept study

A dynamic systems model was used to generate parameters describing a phenotype of Hypothalamic-Pituitary-Adrenal (HPA) behavior in a sample of 36 patients with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) and 36 case-matched healthy controls. Altered neuroendocrine function, particularly in relation to somatic symptoms and poor sleep quality, may contribute to the pathophysiology of these disorders. Blood plasma was assayed for cortisol and ACTH every 10min for 24h. The dynamic model was specified with an ordinary differential equation using three parameters: (1) ACTH-adrenal signaling, (2) inhibitory feedback, and (3) non-ACTH influences. The model was "personalized" by estimating an individualized set of parameters from each participant's data. Day and nighttime parameters were assessed separately. Two nocturnal parameters (ACTH-adrenal signaling and inhibitory feedback) significantly differentiated the two patient subgroups ("fatigue-predominant" patients with CFS only versus "pain-predominant" patients with FM and comorbid chronic fatigue) from controls (all p's<.05), whereas daytime parameters and diurnal/nocturnal slopes did not. The same nocturnal parameters were significantly associated with somatic symptoms among patients (p's<.05). There was a significantly different pattern of association between nocturnal non-ACTH influences and sleep quality among patients versus controls (p<.05). Although speculative, the finding that patient somatic symptoms decreased when more cortisol was produced per unit ACTH, is consistent with cortisol's anti-inflammatory and sleep-modulatory effects. Patients' HPA systems may compensate by promoting more rapid or sustained cortisol production. Mapping "behavioral phenotypes" of stress-arousal systems onto symptom clusters may help disentangle the pathophysiology of complex disorders with frequent comorbidity.     

Progressive dysregulation of autonomic and HPA axis functions in HIV-1 clade C infection in South India

Human immunodeficiency virus type 1 (HIV-1) infection causes a wide spectrum of abnormalities in neurological, neuropsychological, and neuroendocrinological functions. Several studies report disturbance in autonomic nervous system (ANS) and hypothalamic pituitary-adrenal (HPA) axis function in HIV-1B infected individuals. However, no such investigations on the effect of HIV-1 clade C infection, particularly during the initial phase of the disease progression, have been reported. The present investigations were carried out longitudinally over a 2-year period at 12 monthly intervals in clinically asymptomatic HIV-1 clade C seropositive patients (n=120) and seronegative control subjects (n=29). We determined both the basal levels and the dynamic changes in plasma levels of norepinephrine (NE), epinephrine (E), adrenocorticotrophic hormone (ACTH) and cortisol (CORT). Studies were also extended longitudinally (at three separate yearly visits of each participant), to evaluate the response of autonomic and HPA axis to mirror star tracing challenge test (MSTCT) and the values were determined as area under the curve (AUC, corrected for baseline levels of NE, E, ACTH, and CORT). The findings show that the values of basal plasma NE levels, as well as NE response to MSTCT (AUC) at the first visit of HIV-1 seropositive individuals did not differ from those found in the control subjects (NE, pg/ml, HIV-1C=313.5+/-12.7 vs. controls=353.0+/-21.3; p=NS; AUC, HIV-1C=225+/-14.75 vs. controls=232.7+/-19.34; p=NS, respectively). At the subsequent two visits of HIV-1 positive patients however, NE response to MSTCT challenge was progressively attenuated (AUC=235+/-19.5 and 162.7+/-13.6; p<0.01 and 0.05, respectively) compared to that found at the first visit. On the other hand, plasma levels of E as well as E response to MSTCT at the first visit were significantly lower in HIV-1C seropositive individuals compared to those in the control subjects (pg/ml, HIV-1C=77.30+/-5.7 vs. controls=119.1+10.5; p<0.05; AUC, HIV-1C =83.29+/-7.5 vs. controls=172.3+/-18.9; p<0.001), but no further change was observed in AUC of E in response to MSTCT at the two subsequent yearly visits. The basal plasma levels of ACTH in HIV-1C seropositives were not different than in the control subjects (pg/ml: HIV-1C=20.0+/-0.9 vs. controls=23.1+/-1.6; p=NS), but ACTH response to MSTCT in HIV-1C seropositive patients at the first visit was lower than in the controls (AUC, HIV-1C=23.57+/-1.5 vs. controls=30.94+/-3.5; p<0.05), and fluctuated between high and low at the second and third visits (AUC, 28.89+/-2.3 and 21.69+/-2.36, respectively). However, the baseline plasma levels of cortisol as well as the response of cortisol to MSTCT (AUC) in HIV-1C seropositive individuals were higher than in the control subjects at the first visit (mug/dl, HIV-1C=9.83+/-0.39 vs. controls=6.3+/-0.56; p<0.05; AUC, HIV-1C=12.31+/-0.7 vs. control=9.18+/-0.9; p<0.05), and remained high at the two subsequent yearly follow up visits of HIV-1C (AUC, 11.8+/-0.86 and 11.98+/-0.77, respectively). These findings demonstrate attenuated autonomic functions, a disconnection between response of ACTH and cortisol to the MSTCT challenge, and an inverse relationship between plasma levels of catecholamine(s) and cortisol. Since plasma catecholamines and cortisol are the peripheral mediators of the autonomic and HPA axis function, the findings of this study reflect the overall adverse effect of HIV-1C infection on autonomic as well as HPA axis functions. The findings, apart from being the first to demonstrate the progressive dysregulation of autonomic nervous system and HPA axis function among HIV-1C infected seropositive individuals much ahead of the onset of acquired immunodeficiency syndrome (AIDS), also suggest that MSTCT, involving visuoconstructive cognitive abilities, is an effective stressor for unraveling the underlying dysfunctions in the neuroendocrine functions in health and disease.     

Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis

BACKGROUND: Fatigue is a common and disabling symptom in patients with multiple sclerosis (MS). Underlying mechanisms postulated so far have involved localization of brain lesions and abnormalities of the neuroendocrine system and cytokine regulation. OBJECTIVE: To investigate the relationship between fatigue and the hypothalamo-pituitary-adrenal (HPA) axis in patients with MS. DESIGN: A prospective survey. SETTING: Outpatient and inpatient study at the Max Planck Institute of Psychiatry, Munich, Germany. PATIENTS: Thirty-one patients with clinically definite MS, a relapsing-remitting disease course, and without MS-specific treatment. INTERVENTIONS: Assessment of fatigue with 3 questionnaires: the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Visual Analog Scale. Assessment of HPA axis regulation with the combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test. RESULTS: The FSS score was significantly correlated with the MFIS score. Patients with fatigue had significantly elevated adrenocorticotropin (ACTH) levels in the combined Dex-CRH test. CONCLUSIONS: In contrast to results for chronic fatigue syndrome, where a hyporeactivity of the HPA axis has been shown, MS patients with fatigue exhibited a higher activity of the HPA axis than those without fatigue, as evidenced by significantly increased ACTH concentrations. Proinflammatory cytokines, known to be elevated in patients with MS, may cause both HPA axis alterations and fatigue.     

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.

BACKGROUND: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS: We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS: Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS: Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.     

Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome

OBJECTIVE: It has been suggested that a hypofunctional hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome could result in an exaggerated release of pro-inflammatory cytokines during stress. As pro-inflammatory cytokines are involved in the induction of sickness behavior and thus constitute a potential physiological correlate of stress-induced symptom exacerbation in chronic fatigue syndrome, we set out to evaluate the LPS-induced production of pro-inflammatory cytokines during psychosocial stress in CFS and healthy controls. METHOD: Twenty-one CFS patients and 20 healthy controls matched for age and gender underwent a standardized psychosocial stress test (Trier social stress test, TSST). Adrenocorticotropine hormone (ACTH), salivary cortisol and plasma cortisol levels were measured before and repeatedly following exposure to the stressor. Lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-alpha were assessed at baseline as well as 10 and 60 min after the stress test. RESULTS: CFS patients showed an inverse stress-induced response pattern of LPS-stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were significantly associated for TNF-alpha in controls and for both cytokines in CFS patients. Stress-induced changes in stimulated cytokine production were not associated with general fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines. However, partial correlations revealed that these results were due to the high correlations with basal LPS-induced cytokine levels. CONCLUSION: CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated pro-inflammatory Il-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-alpha.     

Cortisol and ACTH responses to psychosocial stress are modulated by corticosteroid binding globulin levels

The hypothalamus-pituitary-adrenal (HPA) axis is vital for an organisms' response to physiological and psychological stress. Cortisol, secreted upon activation of the HPA axis, impacts on physiological systems throughout the organism. Responses to cortisol are influenced and modified by a number of factors, including corticosteroid binding globulin (CBG) levels. A major part of circulating cortisol is bound to CBG and only the unbound fraction is thought to be biologically active. The aim of the present study was to examine the modulating effect of CBG levels on hormonal responses following psychosocial stress in women using oral contraceptives (n=115) and in medication-free men (n=93). In women, CBG levels were negatively associated with ACTH and salivary cortisol and positively with total cortisol levels following the TSST. In men, positive associations were observed between CBG and ACTH and total cortisol levels following the TSST. CBG is an important regulatory element of HPA axis response patterns; therefore, CBG levels have to be taken into account as a potential modifier of ACTH and cortisol responses to psychosocial and pharmacological stimulation. Investigations of the consequences of long-lasting OC intake on the neuroendocrine stress regulation in women might be warranted.     

Effect of repeat exposure on neuroendocrine and symptom responses to pentagastrin

The cholecystokinin (CCK-B) agonist pentagastrin stimulates dose-dependent release of adrenocorticotropin (ACTH) and cortisol in humans, likely via direct pharmacological action at pituitary CCK-B receptors. Pentagastrin also produces side effects, however, which may be experienced as novel or anxiety arousing and could contribute to ACTH release. Available data suggest that pentagastrin's activation of the hypothalamic-pituitary-adrenal (HPA) axis is unrelated to anxiety symptoms themselves, but novelty effects have not been examined in this model and do strongly activate this system in animals. To further explore the impact of novelty and anxiety symptoms on HPA responses, pentagastrin was administered twice to 12 subjects (six male, six female) under single-blind conditions. Repeat pentagastrin injection was associated with a slight habituation in the magnitude of symptom and HPA axis responses, but robust HPA and symptom responses were seen following both injections. No relationships were found between anxiety symptoms and HPA activity and the modest symptomatic and neuroendocrine habituation appeared to occur independently. Pentagastrin may release ACTH and cortisol through direct pharmacological action, perhaps enhanced on first exposure by psychologically mediated novelty effects. Novelty, per se, is not likely the primary mediator of the HPA response. This model may be useful for further study of cognitive-emotional modulators of HPA axis activity.     

Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers.

BACKGROUND: Corticotropin-releasing hormone (CRH) and vasopressin (VP) are the two principal neuropeptide regulators of the hypothalamic-pituitary-adrenal axis in man, with VP serving to augment CRH-induced adrenocorticotropic hormone (ACTH) release. Unlike VP, desmopressin (DDAVP), which is a synthetic analogue of VP, when administered alone, has not been shown in healthy subjects to have consistent ACTH-releasing properties. It has been suggested that chronic fatigue syndrome (CFS), characterized by profound fatigue and a constellation of other symptoms, may be caused by a central deficiency of CRH. METHODS: We administered 100 micrograms ovine CRH (oCRH) and 10 micrograms DDAVP, both alone and in combination, to a group of subjects with CFS, and to a group of healthy volunteers. Our aim was to establish the effect of DDAVP on CRH-induced ACTH release in these two groups. RESULTS: The delta-ACTH responses to oCRH were attenuated in the CFS (21.0 +/- 4.5 ng/L) compared to the control subjects (57.8 +/- 11.0 ng/L; t = 3.2, df = 21, p < .005). The delta-cortisol responses were also reduced in the CFS (157.6 +/- 40.7 nmol/L) compared to the healthy subjects (303.5 +/- 20.9 nmol/L; t = 3.1, df = 21, p < .01). The delta-ACTH and delta-cortisol responses to DDAVP alone did not differ between the two groups. On administration of both CRH and DDAVP no response differences between the two groups for either ACTH (p = .3) or cortisol output (p = .87) were established. Comparing the ACTH and cortisol responses to CRH and CRH/DDAVP in only those individuals from each group who had both tests, the cortisol output to the combination was significantly greater in the CFS compared to the healthy group. The ACTH output was also increased in the former group, though this was not significant. CONCLUSIONS: DDAVP augments CRH-mediated pituitary-adrenal responsivity in healthy subjects and in patients with CFS. That DDAVP was capable of normalizing the pituitary-adrenal response to oCRH in the CFS group suggests there may be increased vasopressinergic responsivity of the anterior pituitary in CFS and/or that DDAVP may be exerting an effect at an adrenal level.     

Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome

OBJECTIVE: The aim of this study was to obtain comprehensive information on basal hypothalamic-pituitary-adrenal (HPA) axis activity in chronic fatigue syndrome (CFS) patients who were not affected by medication or comorbid psychiatric disorder likely to influence the HPA axis. METHOD: Steroid analysis of urine collections from 0600 to 2100 h at 3-h intervals in CFS patients and in controls. RESULTS: Urinary free cortisol and cortisone concentrations showed a significant normal diurnal rhythm, but levels were lower across the cycle in CFS. In contrast, while urinary cortisol metabolites also showed a normal diurnal rhythm, levels were not significantly different between the CFS and controls at any time. Derived metabolite ratios were similar in both groups. CONCLUSION: This study provides further evidence for reduced basal HPA axis function in patients with CFS, based on lower free cortisol and cortisone levels, but this is not corroborated by cortisol metabolite data. The difference between these measures cannot be explained by an altered timing of the diurnal rhythm.     

The acute effects of a mineralocorticoid receptor (MR) agonist on nocturnal hypothalamic-adrenal-pituitary (HPA) axis activity in healthy controls

INTRODUCTION: Both glucocorticoid and mineralocorticoid receptors (GRs and MRs) help modulate cortisol feedback on the hypothalamic-adrenal-pituitary (HPA) axis. In brain, MRs inhibit the HPA axis and are thought to be fully occupied. Thus, prior studies of the effects of an MR agonist on HPA axis activity have first used metyrapone to inhibit cortisol production and to consequently deplete the receptors. Herein, we propose that an MR agonist may inhibit the HPA axis without first "unloading" receptors of endogenous cortisol. METHODS: Healthy subjects were admitted to the General Clinical Research Center. Blood was sampled for cortisol and adrenocorticotropic hormone (ACTH) from 16:00 to 24:00 h, when greatest MR activity is expected, on two consecutive nights. The first night established a baseline and the second night established response. On the second afternoon, all subjects were given 0.5mg fludrocortisone. Mean cortisol and ACTH were computed from 16:00 to 24:00 h. RESULTS: Fludrocortisone acutely decreased mean cortisol (p=0.003; effect size (ES) 1.65) and mean ACTH (p=0.000, ES 4.46). Additionally, post hoc analysis showed that fludrocortisone tended to decrease the cortisol/ACTH ratio (p=0.0686, ES 0.92) across the same time period. CONCLUSIONS: Fludrocortisone significantly inhibits nocturnal HPA axis activity without first depleting MR receptors with metyrapone. This suggests that brain MRs are not fully occupied by endogenous cortisol and can be further activated by an agonist. The decrease in cortisol/ACTH ratio suggests a possible role on adrenal sensitivity as well. The ability to lower nocturnal HPA axis activity has interesting implications in disorders of HPA axis excess, such as insomnia, depression and healthy aging.     

Sex differences in ACTH pulsatility following metyrapone blockade in patients with major depression

Numerous studies suggest that increased central drive to the hypothalamic-pituitary adrenal (HPA) axis occurs in patients with major depression. To determine if increased central drive occurs throughout the 24 h, we evaluated ACTH secretion under metyrapone blockade of cortisol production. We collected blood every 10 min for measurement of ACTH and data were analyzed for ACTH pulsatility using the pulse detection algorithm deconvolution. We studied 28 patients with major depression and 28 age and sex-matched control subjects, of which 9 pairs were men and 19 pairs were women. We found a significant group x sex interaction with number of ACTH pulses (p=0.04); depressed men showed more ACTH pulses over 24h than matched control men (p=0.02). There was also a significant sex difference in AUC pulses with men showing a smaller AUC ACTH than women. Previous analyses of these data with RM-ANOVA showed a smaller ACTH response in depressed men compared to control men. These data suggest that pulsatility and mean ACTH levels are examining different aspects of HPA axis function, and that the types of HPA axis dysregulation in depression may differ between men and women.     

Slower cortisol response during ACTH stimulation test in autistic children

Autism is a hereditary, pervasive neurodevelopmental disorder that starts early in life. The main characteristics of the autism are impairment in social interactions, difficulties in adapting to novel environmental situations and improper reaction to stress. Since the Hypothalamic-Pituitary-Adrenocortical (HPA) axis plays a key role in the response to stress and because the previous research found abnormalities in HPA system, we conducted a study to test several elements of the HPA axis. Because autism is a heritable disorder, autistic subjects were studied as well as their parents. Cortisol circadian rhythm, cortisol daily secretion and its suppression response to dexamethasone had been measured from saliva or urine samples of the autistic children and their parents. Cortisol secretion response after ACTH stimulation was done with the autistic children only. The cortisol elevation after ACTH stimulation among the autistic individuals was slower (P = 0.017) than in healthy controls. No differences were found in salivary cortisol circadian rhythm or suppression response, as well as in cortisol daily excretion. These data indicate that, compared to healthy subjects, autistic individuals have fine differences in cortisol response to ACTH stimulation or possibly to other types of stress.     

The Insulin Hypoglycemia Test: Hypoglycemic Criteria and Reproducibility

The insulin hypoglycemia test (IHT) is widely regarded as the "gold standard" for dynamic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to investigate the temporal relationship between a rapid decrease in plasma glucose and the corresponding rise in plasma adenocorticotropic hormone (ACTH), and to assess the reproducibility of hormone responses to hypoglycemia in normal humans. Ten normal subjects underwent IHTs, using an insulin dose of 0.15 U/kg. Of these, eight had a second IHT (IHT2) and three went on to a third test (IHT3). Plasma ACTH and cortisol were measured at 15-min intervals and, additionally, in four IHT2s and the three IHT3s, ACTH was measured at 2.5- or 5-min intervals. Mean glucose nadirs and mean ACTH and cortisol responses were not significantly different between IHT1, IHT2 and IHT3. Combined data from all 21 tests showed the magnitude of the cortisol responses, but not the ACTH responses, correlated significantly with the depth and duration of hypoglycemia. All subjects achieved glucose concentrations of of < or = 1.6 mmol/l before any detectable rise in ACTH occurred. In the seven tests performed with frequent sampling, an ACTH rise never preceded the glucose nadir, but occurred at the nadir, or up to 15 min after. On repeat testing, peak ACTH levels varied markedly within individuals, whereas peak cortisol levels were more reproducible (mean coefficient of variation 7%). In conclusion, hypoglycemia of < or = 1.6 mmol/l was sufficient to cause stimulation of the HPA axis in all 21 IHTs conducted in normal subjects. Nonetheless, our data cannot reveal whether higher glucose nadirs would stimulate increased HPA axis activity in all subjects. Overall, the cortisol response to hypoglycemia is more reproducible than the ACTH response but, in an individual subject, the difference in peak cortisol between two IHTs may exceed 100 nmol/l.     

Evidence of basal pituitary-adrenal overactivity in first episode, drug naïve patients with schizophrenia

BACKGROUND: Evidence for basal hypothalamic-pituitary-adrenal (HPA) axis dysfunction in schizophrenia is less consistent than that seen in major depression. Potential reasons include sampling procedures and the use of patients on antipsychotic medications which may suppress the HPA axis. Therefore, the objective of this study was to determine whether first episode, drug na?ve patients with schizophrenia have evidence of basal HPA axis dysfunction by measuring plasma levels of AVP, ACTH and cortisol from 13:00 to 16:00 h, a time frame which is believed to reflect 24 h concentrations of HPA axis activity. METHOD: In this cross-sectional study, plasma levels of AVP, ACTH and cortisol were measured in 12 (7 males and 5 females) (mean age +/-SD=33.6+/-12.6 years) patients with DSM-IV schizophrenia and compared with those found in age- and sex-matched healthy controls. RESULTS: Patients and controls did not differ in terms of their 13:00 h cortisol and AVP. However, patients with schizophrenia had higher levels of ACTH as compared to control subjects at 13:00 h (41.3+/-14.6 vs. 12.4+/-1.1 pg/ml respectively; t=1.99, df=11, p <0.05). In comparison to controls subjects, patients with schizophrenia, had higher mean (+/-SE) AUC of ACTH (26.3+/-6.2 vs. 13.9 nmol/l, respectively; t=2.86, df=11, p <0.02) and cortisol (279.4+/-26.0 vs. 213.1+/-18.4 nmol/l, respectively; t=3.72, df=11, p <0.01). Though, patients with schizophrenia, in comparison to control subjects, had lower mean (+/-SE) AUC of AVP (0.87+/-0.24 vs. 1.42+/-0.34 pmol/l, respectively; t=2.29, df=11, p <0.02). CONCLUSIONS: First episode, drug na?ve patients with schizophrenia show evidence of basal overactivity of the pituitary-adrenal axis.     

A preliminary study of dehydroepiandrosterone response to low-dose ACTH in chronic fatigue syndrome and in healthy subjects

Abnormalities of the production of dehydroepiandrosterone (DHEA), the adrenal androgen, have been linked with disorders such as obesity and psychological disorders such as major depression. Adrenocorticotropin (ACTH) is the primary stimulant of DHEA, and cortisol, from the adrenal. We chose to examine the DHEA and DHEA/cortisol response to the novel low-dose ACTH test in healthy subjects and a cohort with chronic fatigue syndrome (CFS): this test is useful in assessing subtle irregularities of pituitary-adrenal activity. Nineteen CFS subjects (diagnosed by CDC criteria) and 10 healthy subjects were examined. We demonstrated that 1 microg ACTH significantly elevates DHEA levels, with no difference in output between CFS and healthy subjects. The DHEA/cortisol ratio decreased in response to ACTH stimulation in healthy subjects but not in the CFS cohort. We suggest this divergence of response between the two groups represents an imbalance in the relative synthetic pathways of the CFS group which, if present chronically and if comparable to daily stressors, may manifest itself as an inappropriate response to stress. This difference may be important in either the genesis or propagation of the syndrome.