Gender differences in hypothalamic-pituitary-adrenal (HPA) axis reactivity

The present study was designed to determine whether there are gender differences in hormonal response patterns to HPA axis activation. To this end, two methods of activating the HPA axis were employed: a standardized psychological stress test and a pharmacological challenge. Healthy subjects (mean age 23.4 years, SD 7.0 years) completed a naloxone challenge and/or the modified Trier Social Stress Test (TSST). For the naloxone challenge, two baseline blood samples were obtained. Placebo was then administered (0 min), followed by increasing doses of intravenous naloxone (50, 100, 200 and 400 microg/kg) at 30-min intervals. Post-placebo blood samples were collected at 15-min intervals for 180 min. The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn. Eighty subjects (53 male, 27 female) underwent the TSST. Following the psychological stressor, adrenocorticotropin (ACTH) and cortisol responses were significantly greater in male subjects compared to female subjects (z=-2.34, p=0.019 and z=-2.12, p=0.034, respectively). Seventy-two subjects (52 male, 20 female) underwent HPA axis activation induced by naloxone. In contrast to the TSST, cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=4.11, p<0.001). Forty-one subjects (25 male, 16 female) completed both the TSST and naloxone challenge. In this subset, ACTH and cortisol responses to the TSST did not differ significantly by gender, although the effect size was moderate to large. Adrenocorticotropin and cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=2.29, p=0.022 and z=4.34, p<0.001, respectively). In summary, male subjects had greater HPA axis responses to a psychological stressor than female subjects, and females had greater hormonal reactivity than males to pharmacological stimulation with naloxone. Such differences are of interest as potential contributors to gender differences in health risks.     

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.     

Interaction of brain noradrenergic system and the hypothalamic-pituitary-adrenal (HPA) axis in man

BACKGROUND: Numerous interactions between the brainstem locus coeruleus system and the HPA axis have been shown in experimental animals. This relationship is less well characterized in humans and little is known about the influence of psychiatric disorders, which disturb one of these systems, on this relationship. METHODS: Untreated subjects with pure MDD (n = 13), MDD with comorbid anxiety disorders (n = 17), and pure anxiety disorders (n = 15) were recruited by advertising. Age and sex matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 45). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for ACTH assay. These same subjects also underwent a clonidine challenge study for assessment of growth hormone release as a marker of tonic noradrenergic activation. RESULTS: Examining log transformed area under the curve response for each hormone, a significant negative relationship (simple regression) was observed between systems in normal subjects. This relationship was preserved in anxiety subjects. However, both pure depressed and comorbid depressed and anxiety subjects demonstrated disruption of this relationship. CONCLUSIONS: Under normal circumstances, noradrenergic systems can influence the magnitude of the HPA axis response to stress. However, in subjects with major depression, HPA axis activation appears autonomous of noradrenergic influence.     

Sleep deprivation effects in older endogenous depressed patients

In a drug-free group of 15 older endogenous depressed inpatients, all-night sleep deprivation (SD) was associated with a significant decrease in Hamilton depression scores and in Profile of Mood States self-ratings of depression. Six of 15 patients (40%) were responders to SD, as evidenced by greater than or equal to 30% improvement in Hamilton ratings. While symptomatic improvement was short-lived (8 of 15 patients worsened after 1 night of recovery sleep), five patients showed further improvement after 1 night of recovery sleep. The final two patients had an increase in Hamilton ratings after sleep deprivation, with a return to baseline values after 1 night of recovery sleep. Responders (but not nonresponders) showed significant improvement in sleep latency, sleep efficiency, and slow wave sleep during recovery sleep (as did controls). The SD Hamilton depression rating (at 9 a.m. after all-night sleep deprivation) showed a significant inverse correlation with the increase in slow wave sleep (SWS) minutes and in SWS % from baseline to first recovery night. Responders also had significantly larger increases in SWS minutes than did nonresponders (53.8 vs. 7 minutes). Similarly, the % change in Hamilton depression ratings was predicted by baseline Stage 4 sleep. These findings suggest that there is a mutual interaction between the process of sleep regulation and the symptoms of depression. They also confirm a prediction from the two-process model of sleep regulation--namely, that improved sleep initiation and maintenance and increased SWS, attained by SD, are associated with clinical improvement.     

Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids

Reduced fetal growth has been closely associated with an increased risk for the development of chronic disease in later life. Accumulating evidence indicates that fetal exposure to excess glucocorticoids represents a critical mechanism underlying this association. Approximately 7% of pregnant women are at risk of preterm delivery and these women are routinely treated with synthetic glucocorticoids (sGC) between 24 and 34 of weeks gestation to improve neonatal outcome. Animal studies have demonstrated that maternally administered sGC crosses the placenta, affecting fetal hypothalamic–pituitary–adrenal (HPA) development, resulting in changes in HPA axis function that persist throughout life. These changes appear to be modulated at the level of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in the brain and pituitary. As the HPA axis interacts with many other physiological pathways, the changes in endocrine function are also sex-specific and age-dependent. Alterations in behavior, particularly locomotion, in animals exposed to sGC in utero have also been demonstrated. Consistent with the finding in animal models, emerging human data are indicating attention deficit-hyperactivity disorder (ADHD)-like symptoms in children exposed to repeated courses of sGC in utero. This behavioral phenotype is likely linked to alterations in dopamine (DA) signaling, suggesting that sGC are able to permanently modify or ‘program’ this system. Finally, it is emerging that changes in HPA axis function and behavior following antenatal exposure to sGC are transgenerational and likely involve epigenetic mechanisms. A comprehensive understanding of the acute and long-term impact of sGC exposure in utero is necessary to begin to develop recommendations and treatment options for pregnant women at risk of preterm delivery.     

Update on stress and depression: the role of the hypothalamic-pituitary-adrenal (HPA) axis

Over the past 50 years, relationships between stress and the neurobiological changes seen in psychiatric disorders have been well-documented. A major focus of investigations in this area has been the role of the hypothalamic-pituitary-adrenal (HPA) axis, both as a marker of stress response and as a mediator of additional downstream pathophysiologic changes. This review examines the emerging literature concerning the relationship between stress, HPA axis function, and depression, as well as the role of early life stress as an important risk factor for HPA axis dysregulation. The more recent studies reviewed suggest that the prominence of HPA axis hyperactivity in adults with depressive and anxiety disorders may constitute a link between the occurrence of adversity in childhood and the development of adult psychopathology.     

HPA axis abnormalities in depressed patients with normal response to the DST

In order to identify depressed patients with hypothalamic-pituitary-adrenal (HPA) axis abnormalities who have a normal response to the dexamethasone suppression test (DST), the authors administered a series of neuroendocrine tests including insulin-induced hypoglycemia, arginine vasopressin challenge, and a DST. Using standard sensitivity measures, as well as logistic regression, they concluded that many patients with HPA abnormalities are not identified by the DST. These findings suggest that other neuroendocrine tests, which are sensitive to HPA axis abnormalities, may be helpful in subtyping depression on the basis of HPA axis functioning.     

Sleep deprivation and imipramine binding sites in depressed patients and healthy subjects

The influence of sleep deprivation on 3H imipramine binding was investigated in blood platelets of 32 depressed patients and 15 healthy subjects. The effect of sleep deprivation was not statistically different in either group. Changes of Bmax associated with sleep deprivation were compensated for by reciprocal changes of Kd in the group of patients, suggesting altered regulatory mechanisms. A comparison of binding characteristics of responders and nonresponders to sleep deprivation revealed no difference between groups. If the patients were divided by a biological criterion (number of binding sites), a prediction of clinical response to sleep deprivation was possible.     

Effects of hyperactivity of the maternal hypothalamic-pituitary-adrenal (HPA) axis during pregnancy on the development of the HPA axis and brain monoamines of the offspring

Offspring of mothers with adrenal hyperactivity during pregnancy have been reported to have changes in brain monoamines and altered emotional, reactive, sexual and maternal behavior. Since the hypothalamic-pituitary-adrenal (HPA) axis is known to be involved in the expression of such behaviors and is itself under monoaminergic control, we examined the development of the HPA axis and brain monoamines in pups whose mothers had adrenal hyperactivity, reflecting administration of ACTH during the last third of their pregnancy. The adrenals of the experimental animals weighed less and had aberrant morphology. The abnormal histology was more pronounced in the adrenals of the experimental females than of the males, suggesting that females were more vulnerable to the prenatal treatment. In both experimental males and females, basal plasma corticosterone levels were higher compared to the controls, while after exposure to stress, experimental animals attained lower plasma corticosterone levels than the controls. In the brain of the experimental animals, dopaminergic activity appeared to be decreased, while serotonergic activity increased. Our results indicate that the prenatal treatment affected brain development in the offspring and as a consequence programmed the developing HPA axis in such a way as to hyperfunction under basal conditions, leading to its exhaustion and its inability to react properly to stress.     

The dynamics of the hypothalamic-pituitary-adrenal axis during maternal deprivation

A close contact between the dam and the litter is essential for the normal development of the hypothalamic-pituitary-adrenal (HPA) axis in rats and mice. Maternal signals, as licking and feeding, have been shown to sustain the HPA axis of the pups in a hypo-responsive state. Disruption of this mother-pup interaction by 24 h of maternal deprivation activates the otherwise quiescent stress system of the neonates, resulting in an enhanced adrenal sensitivity to adrenocorticotropic hormone (ACTH) and a decreased expression of central HPA markers, such as corticotropin-releasing hormone (CRH). However, the dynamics of these central and peripheral changes over the 24h period are largely unknown. In this study, we examined the time course of some of the central and peripheral indices of HPA activity during 24 h of maternal deprivation. We measured corticosterone and ACTH in the blood as well as CRH, mineralocorticoid and glucocorticoid receptor expression in the brain. Our results demonstrate that each of the components of the HPA axis responds to maternal deprivation at different time points following removal of the mother and with a very specific time course. The main activation of the HPA axis occurred between 4 h and 8 h of maternal absence. By contrast, during the second half of the deprivation period, negativefeedback mechanisms restrained the further increase in ACTH and corticosterone release. We conclude that maternal deprivation triggers a cascade of sequential changes at the various levels of the stress system, and that measuring only one aspect of the system at one time point does not accurately reflect the dynamic alterations of the HPA axis.     

Motor activity in depressed patients during therapeutic sleep deprivation

ProblemBoth sleep and motor activity have a bidirectional relationship with depression. The existing literature on motor activity during therapeutic sleep deprivation in depressed patients is inconsistent and fragmentary. In the present study we measured motor activity continuously during 40 hours of sleep deprivation in depressed patients.MethodThirty-four inpatients suffering from a major depression (DSM-IV) underwent sleep deprivation with a continuous waking period of 40 hours. Motor activity of the patients was continuously recorded using an actigraph on the non-dominant wrist. The effect of sleep deprivation was assessed by the Hamilton Depression Scale (six-item version), thus separating the group into responders and non-responders to sleep deprivation.ResultsWe found no significant differences in motor activity between responders and non-responders on the day before sleep deprivation. During the night, responders to sleep deprivation exhibited a higher motor activity and less periods of rest. On the day after sleep deprivation, responders exhibited a higher activity, too.ConclusionsMotor activity levels differ between the two groups, thus giving more insight into possible mechanisms of action of the therapeutic sleep deprivation. We suggest that higher motor activity during the night prevents naps and leads to better response to sleep deprivation.     

Basal activity of the hypothalamic-pituitary-adrenal axis in patients with depersonalization disorder

Depersonalisation disorder may occur during severe anxiety or following a traumatic event, suggesting a possible role of stress hormones. This study investigated basal activity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with depersonalisation disorder. Salivary cortisol levels were measured at four time points over 12 h in patients with depersonalisation disorder (N=13), major depressive disorder (MDD, N=14) and healthy controls (N=13). Beck Depression Inventory scores were significantly higher in depersonalised subjects than controls, while MDD subjects demonstrated higher scores than both groups. Basal cortisol levels of depersonalised subjects were significantly lower than those of MDD subjects but not healthy controls. These results point to reduced basal activity of the HPA axis in depersonalisation disorder. This pilot study supports the distinction between depersonalisation disorder and major depressive disorder which should be examined in a larger sample.     

Chronic cannabis use does not affect the normalization of hypothalamic-pituitary-adrenal (HPA) axis induced by methadone in heroin addicts

The hypothalamic-pituitary-adrenal (HPA) axis activity is usually altered by heroin use. In the present study we evaluated in one hundred twenty-one heroin addicts the effects of marijuana smoking on the normalization of HPA axis upon methadone treatment. The study showed that in heroin addicts who are chronic cannabis smokers a treatment with methadone lasting 12 months was able to normalize both plasma corticotropin (ACTH) and cortisol levels, as well as to control both heroin withdrawal symptoms and opioid craving. As expected in the same group of patients marijuana smoking and its craving were not reduced by methadone treatment. Our data confirm that methadone treatment outcomes are not modified by cannabis use and they add in the literature the evidence that chronic cannabis use is not able to affect the normalization of HPA axis upon methadone treatment in heroin addicts.     

Family history, early adversity and the hypothalamic-pituitary-adrenal (HPA) axis: Mediation of the vulnerability to mood disorders

The effect of early-life vulnerability factors on the subsequent pathophysiology of severe mood disorders has yet to be fully elucidated. This study examines the relationship between early adverse life experience, family history and hypothalamic-pituitary-adrenal (HPA) axis function. Childhood trauma questionnaire (CTQ) scores, family history data and the cortisol response to the dexamethasone/corticotrophin releasing hormone (dex/CRH) test were examined in 40 patients with severe mood disorder. Normative data for the CTQ was also obtained. The study demonstrated that mood disorder patients reporting high levels of childhood emotional neglect (n = 26) had an HPA axis response which did not differ from controls, whereas patients reporting low levels (n = 19) had an enhanced response (p = 0.011). A positive family history of mood disorder further enhanced this response. These data suggest that early adverse life events and genetic susceptibility have dissociable effects on glucocorticoid receptor-mediated negative feedback of the HPA axis in adult patients with severe mood disorders.     

Associations between hypothalamic-pituitary-adrenal axis function and facial emotion processing in depressed and control participants

Aim: The current study examined the relation between facial emotion processing accuracy and an aspect of hypothalamic–pituitary–adrenal axis function in 64 inpatients with major depression and 49 healthy controls over a 2‐week period. Methods: The Dexamethasone Suppression Test and a Facial Expression Recognition Task were completed at baseline and 10–14 days after baseline. Treatment response was determined 6 weeks after baseline by change in the Montgomery–Asberg Depression Rating Scale. Results: Increased cortisol response to dexamethasone was significantly correlated with reduced ability to recognize facial expressions of anger, sadness and disgust within the total sample, but these correlations did not remain significant at 10–14 days. Surprisingly, cortisol response to dexamethasone was comparable in acutely depressed inpatients and healthy controls, and did not change over time in relation to treatment response. Conclusion: The study findings provide preliminary evidence that hypothalamic–pituitary–adrenal axis functioning and processing threat‐related facial expressions are related, perhaps through involvement of the amygdala.     

Childhood trauma,HPA axis activity and antidepressant response in patients with depression

Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n = 42), treatment non-responder (n = 80) and untreated depressed (n = 41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment.     

抑郁障碍患者下丘脑—垂体—肾上腺轴的功能与自杀行为的关系(英文)

背景目前对抑郁障碍患者自杀行为的神经-内分泌研究仍较少,且结果多不一致。目的探讨国内抑郁障碍患者下丘脑-垂体-肾上腺(hypothalamus-pituitary-adrenal,HPA)轴释放功能与自杀行为的关系。方法比较14例2个月内有过自杀行为的抑郁障碍患者(抑郁研究组)和15例不伴自杀行为的抑郁障碍患者(抑郁对照组)的HPA轴功能。以地塞米松抑制试验(dexamethasone suppression test,DST)、一天中血浆皮质醇浓度的昼夜变化(在帕罗西汀治疗前及治疗6周后评估)以及治疗前和治疗后的24小时尿17-羟皮质醇和24小时尿游离皮质酮,评估HPA轴释放功能。同时以汉密顿抑郁量表(Hamilton Depression Rating Scale,HAMD)评定抑郁严重程度。另外测定15名无抑郁障碍的健康体检者的白天皮质醇浓度。结果抑郁研究组与抑郁对照组之间24h尿皮质醇浓度的差异无统计学意义,尿皮质醇浓度差异也无统计学意义。治疗前两组血浆皮质醇的午夜分泌低谷均不明显,而治疗后的分泌低谷变得明显。抑郁研究组DST阳性率显著高于对照组(57%对20%,χ2=4.24,p=0.039)。无论治疗前后,抑郁研究组患者血浆皮质醇水平与HAMD量表总分及绝望感和自杀观念的因子分呈显著正相关,但是抑郁对照组中这些相关系数无统计学意义。抑郁研究组早晨8点的血浆皮质醇浓度在治疗前后均显著高于健康对照组,而抑郁对照组的这一浓度并不比健康对照组高。结论本研究结果与先前关于抑郁症与HPA轴功能关系的研究结果大致相同。尽管如此,有自杀行为与无自杀行为的抑郁症患者之间还是存在某些差异。这些差异提示可能存在特定的自杀相关的HPA轴功能紊乱。有必要在大样本研究中进一步验证这些差异,以期能够在只报告有过自杀观念的人群中鉴别出实际有过自杀行为的个体。