Hypothalamic-pituitary-adrenal axis interaction with prostaglandins

1. The major PGE2 plasma metabolite, 15-keto-13, 14-dihydro-PGE (PGEM) was measured during metyrapone, dexamethasone and ACTH tests in order to elucidate if plasma PGE was affected by short term changes of the hypothalamic-pituitary adrenal axis function in man. 2. Plasma PGEM, serum cortisol and serum 11-deoxycortisol were determined by RIA. 3. Metyrapone (an inhibitor of adrenal 11 beta-hydroxylase), 250-1000 mg was given orally at 4 hour intervals for 20 hours. PGEM, cortisol and 11-deoxycortisol were measured before and 10 and 22 hours after the start of metyrapone in 10 patients evaluated for pituitary disease. 4. Dexamethasone, 1 mg orally, was given at 23 hours on day one and 25 IU (1-24) ACTH were given iv at 8 hours on day two. Blood was drawn for determination of PGEM and cortisol at 8 hours day one, and 8 hours day two. After the ACTH injection, blood was drawn at 90 minutes (for PGEM) and at 120 minutes (for PGEM and cortisol). 10 subjects aged 21-62 years were studied. 5. Plasma PGEM levels were significantly increased after metyrapone, concomitantly with the lowering of serum cortisol levels. 6. No difference in the PGEM increase between patients with normal or subnormal 11-deoxycortisol response was found. 7. A significant increase in plasma PGEM levels was found when serum cortisol was suppressed 9 hours after dexamethasone administration. 8. Glucocorticoids inhibit synthesis of eicosanoids and the present results suggest that short term decrease in cortisol may stimulate PG synthesis.     

Hypothalamic-pituitary-adrenal axis and bipolar disorder.

There is robust evidence demonstrating abnormalities of the HPA axis in bipolar disorder. Hypercortisolism may be central to the pathogenesis of depressive symptoms and cognitive deficits, which may in turn result from neurocytotoxic effects of raised cortisol levels. Manic episodes may be preceded by increased ACTH and cortisol levels, leading to cognitive problems and functional impairments. Identification and effective treatment of mood and cognitive symptoms of mood disorders are clinical goals, but currently available treatments may fall short of this ideal. Manipulation of the HPA axis has been shown to have therapeutic effects in preclinical and clinical studies, and recent data suggest that direct antagonism of GRs maybe a future therapeutic strategy in the treatment of mood disorders.     

Hypothalamic-pituitary-adrenal axis function during perinatal depression

Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis is an important pathological finding in pregnant women exhibiting major depressive disorder. They show high levels of cortisol pro-inflammatory cytokines, hypothalamic-pituitary peptide hormones and catecholamines, along with low dehydroepiandrosterone levels in plasma. During pregnancy, the TH2 balance together with the immune system and placental factors play crucial roles in the development of the fetal allograft to full term. These factors, when altered, may generate a persistent dysfunction of the HPA axis that may lead to an overt transfer of cortisol and toxicity to the fetus at the expense of reduced activity of placental 11β-hydroxysteroid dehydrogenase type 2. Epigenetic modifications also may contribute to the dysregulation of the HPA axis. Affective disorders in pregnant women should be taken seriously, and therapies focused on preventing the deleterious effects of stressors should be implemented to promote the welfare of both mother and baby.     

Hypothalamic-pituitary-adrenal axis disregulation in PrPC-null mice

As manifestations of prion diseases include disturbances of hypothalamic and pituitary functions, we tested the hypothesis that the cellular prion protein (PrPC) has a role as modulator of the hypothalamic-pituitary-adrenal axis. The level of corticosterone and adrenocorticotropic hormone were compared in PrPC null (PrP 0/0) and wild-type (PrP+/+) mice. PrP 0/0 showed hypercorticism during the dark part of day. After acute stress, corticosterone and adrenocorticotropic hormone increased similarly in PrP+/+ and PrP 0/0 mice. Adrenocorticotropic hormone, however, remained elevated in PrP+/+ 0/0 mice at corticosterone levels that are inhibitory in PrP mice. Pretreatment with corticosterone or dexamethasone inhibited stress-induced elevation of adrenocorticotropic hormone in PrP+/+ but not in PrP 0/0 mice. Thus, PrPC may play a role in the negative feedback regulation of axis.     

Hypothalamic-pituitary-adrenal axis abnormality and ECT response

Response to electroconvulsive therapy (ECT) was assessed in 42 depressed patients grouped by dexamethasone suppression test (DST) response. Patients with initially abnormal DST results had better outcomes according to global ratings that did patients with initially normal DST results; final Hamilton Rating Scale scores did not distinguish these two groups, however. No group had an outcome that was clearly poor; only three (14.3%) patients with initially normal DST results were rated as unimproved at discharge. The results of this and other studies attempting to predict response to ECT are sensitive to the heterogeneity of patients referred for ECT, the timing and type of outcome assessment, and the differential action of placebo effects.     

Hypothalamic-pituitary-adrenal axis,neuroendocrine factors and stress

The stress system coordinates the adaptive responses of the organism to stressors of any kind.(1). The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing "low turnover" osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.     

Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome

There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.     

Hypothalamic-pituitary-adrenal axis, glucocorticoids, and neurologic disease

Neurologic diseases often are accompanied by significant life stress and consequent increases in stress hormone levels. Glucocorticoid stress hormones are known to have deleterious interactions with neurodegenerative processes and are hypersecreted in neurologic disorders and comorbid psychiatric conditions. This review highlights the current state of knowledge of mechanisms controlling activation and inhibition of glucocorticoid secretion, outlines signalling mechanisms used by these hormones in neural tissue, and describes how endogenous glucocorticoids can mitigate neuronal damage in models of neurologic disease. This review highlights the importance of controlling stress and consequent stress hormone secretion in the context of neurologic disease states.     

Hypothalamic-pituitary-adrenal axis activity and age in major depression

The authors assessed hypothalamic-pituitary-adrenal axis activity in 28 endogenously depressed patients. Postdexamethasone serum cortisol values were found to be positively correlated with age but not sex or severity of depression.     

抑郁症患者下丘脑-垂体-肾上腺轴功能与自杀行为

目的：了解抑郁症患者自杀行为与下丘脑－垂体－肾上腺（ＨＰＡ）轴的关系。方法：对２５例抑郁症患者行地塞米松抑制试验（ＤＳＴ）,其中伴有自杀行为的１２例,不伴自杀行为的１３例,并进行为期１年的随访。结果：自杀组和无自且的ＤＳＴ脱抑制率无明显差异。血有皮质醇水平与汉密尔顿抑郁量（ＨＡＭＤ）评分有明显相关。随访期间所有受试者均未发生新的自杀行为。结论：抑随症患者的ＨＰＡ轴功能失调与自杀行为有关,但并不增加     

Hypothalamic-pituitary-adrenal axis function and suicidal behavior in depression.

Hypothalamic-pituitary-adrenal (HPA) axis function was examined in relation to suicidal behavior in depression. There were no significant differences between depressed patients who had or had not attempted suicide for either cerebrospinal fluid concentrations of corticotropin-releasing hormone, plasma cortisol levels predexamethasone or postdexamethasone, or for urinary-free cortisol outputs. However, depressed patients who had made a violent suicide attempt had significantly higher 4 PM and maximum postdexamethasone plasma cortisol levels, and significantly more of them were cortisol nonsuppressors than patients who had made nonviolent suicide attempts. A 5-year follow-up was carried out. There were no significant differences on indices of HPA function between depressed patients who did or did not reattempt suicide during the follow-up or who had never attempted suicide. These results suggest the possibility that dysregulation of the HPA axis may be a determinant of violent suicidal behavior in depression.     

Hypothalamic-pituitary-adrenal axis function in children with attention-deficit hyperactivity disorder

Examined hypothalamic-pituitary-adrenal axis (HPA axis) function in 30 children with attention-deficit hyperactivity disorder (ADHD) by measuring the diurnal variation and response to the dexamethasone suppression test (DST) of saliva cortisol. Normal diurnal saliva cortisol rhythm was found in only 43.3% of the ADHD children. DST showed suppression in 46.7% of the ADHD children. An abnormal diurnal rhythm and nonsuppression to the DST were more frequent in the severely hyperactive group than in the mildly hyperactive group of children with ADHD. These results suggest abnormalities in HPA axis function in some children with ADHD, especially those exhibiting severe hyperactivity.     

Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior

Activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to elevations in gamma-aminobutyric acid (GABA)-ergic neuroactive steroids that enhance GABA neurotransmission and restore homeostasis following stress. This regulation of the HPA axis maintains healthy brain function and protects against neuropsychiatric disease. Ethanol sensitivity is influenced by elevations in neuroactive steroids that enhance the GABAergic effects of ethanol, and may prevent excessive drinking in rodents and humans. Low ethanol sensitivity is associated with greater alcohol consumption and increased risk of alcoholism. Indeed, ethanol-dependent rats show blunted neurosteroid responses to ethanol administration that may contribute to ethanol tolerance and the propensity to drink greater amounts of ethanol. The review presents evidence to support the hypothesis that neurosteroids contribute to ethanol actions and prevent excessive drinking, while the lack of neurosteroid responses to ethanol may underlie innate or chronic tolerance and increased risk of excessive drinking. Neurosteroids may have therapeutic use in alcohol withdrawal or for relapse prevention.     

Hypothalamic pituitary gonadal axis dysregulation in depressed women

In order to examine HPG axis regulation in women with major depression, luteinizing hormone (LH) pulsativity was studied in 26 depressed and 24 normal women. Blood was sampled every 10 min for an 8-h period during the first week of their menstrual cycle. LH pulsatile release was analyzed using the computerized cluster analysis algorithm of Veldhuis and Johnson and spectral analysis. Compared to control women, depressed women had slower frequency dysrhythmic LH pulsatility. These results are consistent with a previously published pilot study which reported results of the first 23 subjects [Am. J. Psychiat. 154 (1997) 1454].     

Hypothalamic-pituitary-adrenal axis function in chronic schizophrenia: association with clinical features.

The function of the hypothalamic-pituitary-adrenal axis (HPA-axis) and its association with clinical features in chronic schizophrenia were investigated. Twenty of 33 chronic schizophrenics exhibited an abnormal diurnal variation of the saliva cortisol level. The patients with abnormal diurnal variation gave higher scores for some negative symptoms than those with normal diurnal variation. On the dexamethasone suppression test (DST) of saliva samples, 13 of 34 chronic schizophrenics were abnormal. The patients with DST nonsuppression were more frequently classified into disorganized type and exhibited low scores of anxiety compared with the patients with normal suppression. The 9 patients who showed abnormal diurnal variation and DST nonsuppression were more frequently classified into disorganized type and showed higher scores of negative symptoms than the 9 patients who did not show any abnormal cortisol data. These results suggest that there might be some disturbance in the function of the HPA-axis in a group of chronic schizophrenics and that these patients might have severe negative symptoms.     

Hypothalamic-pituitary-adrenal axis function in patients with complex regional pain syndrome type 1

An exaggerated inflammatory process is considered an important pathophysiological feature of complex regional pain syndrome type 1 (CRPS-1). The hypothalamic-pituitary-adrenal (HPA) axis serves as a negative feedback mechanism for inflammatory processes. The present study examined the HPA axis function in patients with CRPS-1 by a determination of cortisol concentrations in saliva. Three sets of saliva samples were sequentially collected from 24 patients with CRPS-1 during medication (on-Med), 72 h after stopping medication (off-Med) and 8h after the oral administration of 1mg dexamethasone. One set of saliva samples was collected from healthy controls. The cortisol awakening response (CAR) and diurnal cortisol decline (DCD) were used as indices for HPA axis function. Cortisol levels during the post-awakening period in patients were increased following withdrawal of medications. The CAR during the off-Med condition was disappeared after administration of dexamethasone. Among the examined CRPS-related numerical variables, the frequency of spontaneous pain attacks showed relationships with the indices of HPA axis function. After classifying the patients into two subgroups, we observed that the CAR and DCD in patient who had a relatively high frequency of spontaneous pain attacks (subgroup 5 ≤) were lower and less steep than those in patient who had a relatively low frequency of spontaneous pain attacks (subgroup 0-4) for the on- and off-Med conditions. The CAR and DCD in subgroup 5 ≤ during their off-Med condition were comparable to those in controls. These results suggest that the increase in frequency of spontaneous pain attacks is associated with a reduced CAR and flattened DCD in patients CRPS-1.     

Hypothalamic-pituitary-adrenal axis function following a 35% CO2 inhalation in healthy volunteers

RATIONALE: The hypothalamic-pituitary-adrenal axis (HPA axis) is a central component of the brain's neuroendocrine response to stress. The extent of increase in cortisol secretion, provides an index of the HPA axis activity, and in this way, objectively reflects perceived stress. In healthy subjects, the 35% CO(2) inhalation does hardly induce stress, as expressed in anxiety. However, inconsistent results have been found in studies investigating the cortisol response following CO(2) inhalation. Clarity has to be reached about the normal reaction to this challenge, especially because this model is still a very valuable method to study central aspects of panic. OBJECTIVES: The present study aimed to test the hypothesis that a single breath of 35% CO(2) would not induce cortisol release in healthy volunteers. METHODS: In the current study, 20 healthy subjects underwent both a 35% CO(2) and a placebo inhalation in a randomised, single blind fashion. Cortisol levels were determined in saliva samples, taken at regular intervals. RESULTS: No differences were found between the CO(2) and the placebo condition. In both conditions a significant time effect was found, which can be subscribed to normal variation in the circadian rhythm. Furthermore, only modest subjective anxiety scores were found in the CO(2) condition. CONCLUSIONS: These results provide biological evidence for the hypothesis that healthy subjects are not affected by the 35% CO(2) challenge in a clinically significant way. Characteristic, PD patients react much stronger to the inhalation. Thus, in addition to psychological parameters, healthy subjects also constitute an ideal comparison group with regard to endocrinological parameters.     

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease mutation carriers compared with mutation-negative first-degree controls

Neurodegeneration in Huntington's disease (HD) occurs in various brain regions including the hypothalamus. In this cross-sectional study, hypothalamic-pituitary-adrenal (HPA) axis functioning was studied in 26 presymptomatic and 58 symptomatic HD mutation carriers, and 28 controls. HPA axis functioning was measured through salivary cortisol in the day curve, the cortisol awakening response (CAR), the area under the curve (AUC), the morning rise, and the dexamethasone suppression test (DST). Only the CAR was statistically different between the three groups, being explained by higher cortisol concentrations at 45 and 60 min post-awakening for presymptomatic mutation carriers compared to both symptomatic mutation carriers and controls. No differences were found for the AUC, evening and post-DST cortisol concentrations. Our study indicates a mild disturbance in morning cortisol secretion in HD mutation carriers that precedes the onset of motor symptoms.