Hypothalamic-pituitary-adrenal Axis Dysfunction Research Articles

State and Trait Abnormalities in Serotonin Function in Major Depression

Background Neuroendocrine studies of brain serotonin (5-HT) function in depression generally show evidence of impaired 5-HT function but it is disputed whether or not this impairment resolves with clinical recovery. Aims To use the endocrine response to the selective 5-HT reuptake inhibitor, citalopram, to study brain 5-HT function in acute and recovered depressed subjects relative to healthy controls. Method We used a double-blind, placebo-controlled design to measure the prolactin and cortisol responses to citalopram (10 mg intravenously) in patients with major depression, in unmedicated subjects recovered from depression and in healthy controls. Results The prolactin responses to citalopram were blunted similarly in both acutely depressed and recovered subjects. The cortisol responses were blunted in the acutely depressed patients but not in the recovered subjects. Conclusions Our data support the proposal that some aspects of impaired 5-HT neurotransmission may be trait markers of vulnerability to depression. The recovery of the cortisol response to citalopram may indicate resolution of hypothalamic—pituitary—adrenal axis dysfunction.

HPA Axis Dysfunction in Major Depression: Relationship to 5-HT1A Receptor Activity

Major depression is associated with a dysfunction of the serotonergic activity and the hypothalamic-pituitary- adrenal (HPA) axis. Moreover, a reciprocal relationship between the serotonergic and HPA axis systems has been hypothesized. The purpose of the present study was to assess the relationship between sensitivity of 5-HT_1A receptors as measured by hormonal (ACTH, cortisol and PRL) and temperature responses to flesinoxan and HPA axis activity as measured by the dexamethasone suppression test. The sample included 21 inpatients with major depression. Dexamethasone nonsuppressors exhibited lower ACTH responses to flesinoxan as compared with dexamethasone suppressors. The results showed that a dysfunction in 5-HT_1A receptor activity could be due to a hypersecretion of cortisol.

Long term neurodevelopmental and behavioral effects of perinatal life events in rats.

Modern neurosciences are now able to open new avenues concerning an experimental approach to clinical neurosciences and psychiatry. Detection and prediction of potential vulnerabilities such as behavioral disturbances and neurodegenerative diseases, are urgent tasks leading to prevention that must be encouraged in parallel to the enormous efforts displayed for treatments. Besides possible genetic origins of diseases, environmental factors are now coming under scrutiny, and especially deleterious and challenging life events and stress occurring during prenatal and postnatal critical periods may orient brain functions towards deleterious developments. The hypothesis that will be examined is that early events might be at the origin of pathological transformations and symptoms after long periods of apparent normal abilities and behavioral homeostasis. We used models of prenatal stress and postnatal manipulations such as cross-fostering. It will be demonstrated that such events induce long-term changes, cognitive and emotional modifications appearing first, when offspring are adults, followed by cognitive defects later in life. Increased sensitivity of the hypothalamic pituitary-adrenal axis (HPA), the endocrine system controlling the secretion of stress hormones (corticoids), appears to be a major element of pathogenesis. HPA axis dysfunction appears very early after birth (3 days) and lasts for months. Cumulative exposure to high levels of hormones seems to be detrimental for some brain regions, especially the hippocampus and major neurotransmitter systems such as dopamine neurons. We evidenced that neuronal modifications in hippocampal region are correlated with behavioral and cognitive defects, relating environment, stress in early life, hormonal changes, long-term neuropathological processes and impaired cognition in aging. Moreover appears in offspring, when adults, a proneness to engage in drug dependence. These data emphasize the need to consider early environmental life events as etiological factors for delayed neuropsychiatric disturbances, neurodegenerative defects included. Moreover, they strengthen the interest for a longitudinal approach to promote experimental psychopathology.

Dopaminergic activity in transgenic mice underexpressing glucocorticoid receptors: effect of antidepressants

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used to investigate the long-term effect of hypothalamic–pituitary–adrenal axis dysfunction on brain dopamine transmission. Compared to control mice, the transgenic animals showed increased amphetamine-induced locomotor activity and increased concentrations of striatal dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Binding of [ 3H]SCH 23390 and [ 3H]spiperone to, respectively, D1 and D2 dopamine receptors was increased in transgenic mice. In contrast, autoradiography of striatal [ 3H]GBR 12935 binding to the dopamine transporter was decreased and the mRNA levels of this transporter, measured by in situ hybridization, remained unchanged in the substantia nigra pars compacta. The effect of chronic treatment for two weeks with amitriptyline or fluoxetine was compared in control and transgenic mice. No significant changes were observed in control mice following antidepressant treatment, whereas in transgenic mice both antidepressants reduced striatal [ 3H]SCH 23390 and [ 3H]raclopride specific binding to D1 and D2 receptors. Amitriptyline, but not fluoxetine, increased striatal [ 3H]GBR 12935 binding to the dopamine transporter, whereas its mRNA level in the substantia nigra pars compacta was decreased in fluoxetine, compared to vehicle- or amitriptyline-treated transgenic mice. From these results we suggest that hyperactive dopaminergic activity of the nigrostriatal pathway controls motor activity in the transgenic mice. Furthermore, antidepressant treatment corrected the increased striatal D1 and D2 receptors and decreased dopamine transporter levels in the transgenic mice.

The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke.

The hypothalamic-pituitary-adrenal (HPA) axis, the mediator of cortisol, plays a central role in the homeostatic processes. In this study, we addressed the potential impact of HPA axis activity on established anthropometric, metabolic and haemodynamic risk factors for cardiovascular disease (CVD), type 2 diabetes mellitus and stroke. A cross-sectional study. A subgroup of 284 men from a population sample of 1040 at the age of 51 years. Anthropometric measurements included body mass index (BMI, kg m-2), waist/hip circumference ratio (WHR) and abdominal sagittal diameter (D). Overnight fasting values of blood glucose, serum insulin, triglycerides, total, low (LDL) and high density (HDL) lipoprotein cholesterol, as well as resting heart rate and blood pressure, were also determined. By using repeated diurnal salivary cortisol measurements during everyday conditions, methods were developed to characterize the status of the HPA axis, and set in relation to the anthropometric, metabolic and haemodynamic measurements. In bivariate analyses, risk factors intercorrelated in clusters of anthropometric (BMI, WHR, D), metabolic (insulin, glucose and their ratio, triglycerides, cholesterol [total and LDL], HDL cholesterol [negative]) and haemodynamic (systolic and diastolic blood pressure and heart rate) measurements. This was also the case in the two-dimensional scaling analysis, where, however, HDL separated out. A normal HPA axis status, characterized by high variability and morning cortisol values, as well as a clear response to a standardized lunch and dexamethasone suppression test, was then introduced by a statistical weighting procedure. This did not essentially change the results of either the bivariate correlation matrix or the two-dimensional scaling analysis. A similar introduction of a pathological HPA axis, characterized by low variability and morning cortisol values, a poor lunch-induced cortisol response and a blunted dexamethasone suppression of cortisol, changed the results markedly. Now strong and consistent correlations were found not only within but also between different clusters of risk factors, which also congregated into one distinct cluster, again except for HDL cholesterol. These results disclose the prospect of an overriding function of a pathological HPA axis on other, established risk factors for CVD, type 2 diabetes and stroke. Its close association to HPA axis dysfunction may explain the previously reported powerful risk indication of abdominal obesity for the diseases mentioned. The HPA axis abnormality has been reported to be a characteristic consequence of frequently repeated or chronic environmental stress challenges.

Estrogens Normalize the Hypothalamic- Pituitary-Adrenal Axis Response to Stress and Increase Glucocorticoid Receptor Immuno- reactivity in Hippocampus of Aging Male Rats

Aging is associated with a disturbance in the regulation of the hypothalamic-pituitary-adrenal axis (HPA) and reduced levels of glucocorticoid receptors (GR) in the hippocampus. To compensate for these effects, we have investigated whether estrogen therapy normalized the HPA response to stress and GR in hippocampus and paraventricular (PVN) nucleus. Young (3–4 months) and old (20 months) male Sprague-Dawley rats were bled by tail cut in the basal state and following ether stress. While basal and ether-stimulated levels of plasma corticosterone (CORT) were similar in the two groups, old animals presented a delayed termination of the response to ether stress. A dexamethasone inhibition test carried out in old animals, showed a failure to completely block plasma CORT after ether stimulation. Furthermore, in old rats GR-immunoreactive levels were reduced in CA1-CA2 hippocampal subfields and subiculum, while normal levels were obtained in CA3-CA4 and PVN. We observed that prolonged estrogen treatment (6 weeks) of old rats normalized the termination of the stress response, restored dexamethasone inhibition of plasma CORT, and increased GR immunoreactivity in CA1 and CA2 hippocampal subfields and subiculum. The results suggest that estrogen treatment enhanced the glucocorticoid feedback signal by increasing GR in hippocampus, and corrected the disturbances in HPA axis regulation. These animal experiments may be important to elucidate the effects of estrogenic on the hippocampal and HPA dysfunction associated with aging and Alzheimer’s disease in humans.

Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is characterized by profound fatigue and an array of diffuse somatic symptoms. Our group has established that impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis is an essential neuroendocrine feature of this condition. The relevance of this finding to the pathophysiology of CFS is supported by the observation that the onset and course of this illness is excerbated by physical and emotional stressors. It is also notable that this HPA dysregulation differs from that seen in melancholic depression, but shares features with other clinical syndromes (e.g., fibromyalgia). How the HPA axis dysfunction develops is unclear, though recent work suggests disturbances in serotonergic neurotransmission and alterations in the activity of AVP, an important co-secretagogue that, along with CRH, influences HPA axis function. In order to provide a more refined view of the nature of the HPA dusturbance in patients with CFS, we have studied the detailed, pulsatile characteristics of the HPA axis in a group of patients meeting the 1994 CDC case criteria for CFS. Results of that work are consistent with the view that patients with CFS have a reduction of HPA axis activity due, in part, to impaired central nervous system drive. These observations provide an important clue to the development of more effective treatment to this disabling condition.

Hypothalamic-pituitary-adrenal axis dysfunction in Alzheimer's disease: lack of association between longitudinal and cross-sectional findings.

The authors examined longitudinal hypothalamic-pituitary-adrenal (HPA) axis function in Alzheimer's disease. Cortisol levels of 30 patients with Alzheimer's disease and 17 healthy elderly subjects were measured before and after administration of dexamethasone. These measures were repeated at 9-month intervals in the patients with Alzheimer's disease. At baseline, cortisol levels were higher in the Alzheimer's disease group before and after dexamethasone administration. Although only two of the four patients whose cortisol levels were not suppressed by dexamethasone also had high cortisol levels before dexamethasone administration, basal and postdexamethasone cortisol levels were correlated. HPA axis dysfunction correlated with severity of dementia at baseline but was not stable longitudinally and did not increase with follow-up. There was no association between longitudinal and cross-sectional findings. The longitudinal data were not consistent with a role for the glucocorticoid cascade hypothesis (that hippocampal cell loss in Alzheimer's disease results in hypercortisolism, which in turn acts as a co-factor in further degeneration) in the pathophysiology of mild and moderate Alzheimer's disease.

Enhanced Dexamethasone Suppression of Plasma Cortisol in Adult Women Traumatized by Childhood Sexual Abuse

A study was undertaken to determine if female survivors of childhood and/or adolescent sexual abuse (CSA) would exhibit hypothalamic–pituitary–adrenal (HPA) axis abnormalities characteristic of patients with combat-related posttraumatic stress disorder (PTSD)—i.e., enhanced cortisol suppression to low-dose dexamethasone and increased density of lymphocyte glucocorticoid receptors. Nineteen women who reported experiencing severe CSA and 21 nonvictimized women participated in a low-dose (0.5 mg) dexamethasone suppression test and donated blood for measurement of lymphocyte glucocorticoid receptor binding. Women with CSA had significantly enhanced suppression of plasma cortisol in response to 0.5 mg dexamethasone compared to the nonvictimized women. These observations are consistent with findings in male veterans with combat-related PTSD. They suggest that this pattern of HPA axis dysfunction may be a characteristic sequel of psychiatric disorders that occur following a range of traumatic experiences. This HPA axis profile is different than that associated with acute stress or with major depressive disorder.

Testing the hypothalamic-pituitary-adrenal axis in survivors of childhood brain and skull-based tumors.

The objective of this study was to determine whether a low dose of ACTH (0.2 microg/kg) improves the sensitivity of ACTH testing in detecting hypothalamic-pituitary-adrenal (HPA) axis abnormalities in survivors of childhood brain and skull-based tumors. Twenty-two children who had undergone treatment for brain or skull-based tumors were enrolled in a prospective study to extensively evaluate the HPA axis. Five tests of the adrenal axis were evaluated in each patient, including determination of basal serum cortisol, a standard ACTH test (250-microg i.v. bolus), a low dose ACTH test (0.2 microg/kg i.v. bolus), an insulin tolerance test, and a single dose metyrapone test. Cortisol responses to both ACTH tests were nearly identical. Two patients (9%) failed the low dose ACTH test, whereas three (14%) failed the standard ACTH test; five of the children (23%) failed the insulin tolerance test, and five (23%) had abnormal responses to metyrapone. One child who initially passed the metyrapone test failed the test 19 months later after becoming symptomatic. All children with abnormal metyrapone test results had low levels of basal cortisol secretion. In this study, the low dose ACTH test did not improve the sensitivity of ACTH testing for evaluation of the HPA axis. We conclude that a single morning basal cortisol level is a good screen for testing the HPA axis in children. We recommend confirming HPA axis dysfunction with the single dose metyrapone test, although this test also has limitations.

Glucocorticoid receptor mRNA in Alzheimer's diseased hippocampus

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a common finding in Alzheimer's dementia. Since there is loss of hippocampal corticosteroid receptors in animal models of aging, and since hippocampal cell loss occurs in Alzheimer's disease (AD), it has been suggested that a loss of hippocampal glucocorticoid receptors (GR) may underlie some aspects of HPA axis dysfunction in patients with AD. Levels of corticosteroid receptor protein are not reliably determined in postmortem human brain due to rapid lability. In contrast, levels of mRNA coding for GR are stable in postmortem tissue. We report here initial observations from in situ hybridization experiments which indicate that regional levels of glucocorticoid receptor mRNA in hippocampus, as determined by film autoradiography, are significantly higher in AD hippocampus than in controls. While neuronal levels of GR mRNA in AD, revealed by emulsion autoradiography, were equal in control and AD tissue. Taken together these results suggest that adrenal dysfunction in AD may relate to defects in receptor function rather than corticosteroid receptor loss in the hippocampus.

HPA axis function in depression and dementia: A review

AbstractThis article reviews recent advances in the understanding of hypothalamic‐pituitary‐adrenal (HPA) dysfunction in depression and dementia. Although the dexamethasone suppression test (DST) has proved disappointing as a diagnostic test, more recent tests of HPA axis function have not yet been adequately investigated in this regard. There is mounting evidence from both animal and human studies that a complex interrelationship exists between mood, age, cognitive function, brain structure and HPA axis dysfunction. To explore this relationship further, studies combining clinical, neuroimaging and neuroendocrine investigation are required.

Hypothalamic-pituitary-adrenal dysfunction in posttraumatic stress disorder

Neuroendocrine studies examining the hypothalamic-pituitary-adrenal (HPA) axis under baseline conditions and in response to neuroendocrine challenges have supported the hypothesis of altered HPA functioning in posttraumatic stress disorder (PTSD). However, to date, there is much debate concerning the nature of HPA changes in PTSD. Furthermore, in studies showing parallel findings in PTSD and major depressive disorder there is controversy regarding whether the HPA alterations suggest a specific pathophysiology of PTSD, or, rather, reflect comorbid major depressive disorder. This review summarizes findings of HPA axis dysfunction in both PTSD and major depressive disorder, and shows distinct patterns of HPA changes, which are probably due to different mechanisms of action for cortisol and its regulatory factors.