Delayed effects of chronic cortisol treatment on brain and plasma concentrations of corticotropin (ACTH) and beta-endorphin

The effects of 2-day and 7-day cortisol treatment on immunoreactive corticotropin (ACTH) and beta-endorphin concentrations were measured in the cerebral cortex, hippocampus, hypothalamus, and cerebellum in male rats. Plasma ACTH, beta-endorphin, corticosterone, and cortisol levels were also measured in parallel. Cortisol administration by osmotic minipumps (25 mg/kg/day) maintained a constant, moderately high concentration (23.0 +/- 2.7 micrograms/100 ml) of this glucocorticoid in plasma. Two-day cortisol treatment suppressed the plasma concentration of ACTH and corticosterone, and also decreased, to a lesser degree, concentrations of beta-endorphin. ACTH and beta-endorphin levels in the brain remained unchanged after 2 days of cortisol treatment. After 7-day treatment, however, plasma concentrations of ACTH and beta-endorphin further decreased, while ACTH and beta-endorphin concentrations in the cortex and beta-endorphin concentrations in the cerebellum were also significantly decreased. Peptide concentrations in other brain areas did not change significantly with either 2-day or 7-day cortisol treatment. These data suggest that there are delayed effects of glucocorticoids on pro-opiomelanocortin peptide secretion and/or metabolism in the central nervous system. These findings are consistent with the impaired cognitive functions of patients with diseases, such as Cushing's syndrome and depression, that have long-lasting elevated cortisol secretion.     

Corticotropin releasing factor: basic studies and clinical applications

Corticotropin releasing factor (CRF) is a newly sequenced peptide first isolated from sheep hypothalami and thought to be an important modulator of both the pituitary-adrenal axis and the sympathetic nervous system. We administered intravenous, intramuscular, and intracerebroventricular CRH to non-human primates and measured plasma ACTH, beta endorphin, cortisol, GH and PRL responses to CRF. In addition, we determined the pharmacokinetic properties of I125 in these primates. We administered CRF as an intravenous bolus or as a continuous infusion to normal volunteers and as an intravenous bolus to patients with disorders of the hypothalamic-pituitary-adrenal axis, such as Cushing's syndrome and adrenal insufficiency, and patients with endogenous depression and mild hypercortisolism, and assessed their plasma ACTH, cortisol, GH and PRL responses. In addition, we determined the pharmacokinetic properties of CRF in man by measuring CRF immunoreactivity in plasma. CRF given intravenously to primates or man is a slowly metabolized, long-acting, secretagogue of ACTH, beta-endorphin and cortisol. When given intracerebroventricularly to primates it stimulates the hypothalamic-pituitary-adrenal axis without escaping into the plasma and it is actively cleared in the CNS. It does not cross the blood brain barrier appreciably when given intravenously. CRF given to primates and men as an intravenous continuous infusion has only mild ACTH stimulating effects and this may be due to an intact cortisol negative feedback system. Finally, CRF causes characteristic plasma hormone responses in patients with Cushing's disease, adrenal insufficiency and depression.     

Impaired reduction of enhanced levels of dehydroepiandrosterone by oral dexamethasone in anorexia nervosa

Allopregnanolone and dehydroepiendrosterone (DHEA) have been supposed to be involved in some psychiatric disorders including anorexia nervosa (AN). The secretion of DHEA and allopregnanolone occurs in both the brain and the adrenal gland, where it is under the control of the corticotrophin-releasing factor (CRF)/adrenocorticotrophin hormone (ACTH) system, and, according to the increased CRF/ACTH drive found in AN, we previously reported enhanced morning levels of both DHEA and allopregnanolone in underweight anorexic patients. To further characterize the physiology of these neurosteroids in AN, we measured plasma levels of cortisol, DHEA and allopregnanolone after the oral administration of 1 mg dexamethasone at 800h in six underweight AN women and ten age-matched healthy females. We found that, before dexamethasone administration, both cortisol and DHEA plasma concentrations were significantly increased in anorexic patients as compared to controls, whereas plasma allopregnanolone levels although increased in the former did not reach a statistical significance. Moreover, while cortisol levels after dexamethasone administration were suppressed in AN to values similar to normal controls, DHEA concentrations, although significantly decreased, remained higher than in normal controls. These data support the view that in AN, the increased production of DHEA may be linked to mechanisms other than the enhanced CRF/ACTH drive.     

Stable adrenocorticotropin-stimulated 11-beta-hydroxylase activity but loss of age-related changes in patients with hypercortisolemia

Eleven-beta-hydroxylase activity was measured before and after acute adrenocorticotrophic hormone (ACTH) stimulation in 28 controls, 25 depressed Dexamethasone Suppression Test (DST) suppressors, 13 DST nonsuppressor patients, and 8 patients with Cushing's syndrome to investigate changes in states of cortisol hypersecretion. Eleven-beta-hydroxylase activity was equivalent among groups both before and after stimulation. Such 11-beta-hydroxylase stability, however, resulted in higher cortisol and 11-deoxycortisol poststimulation levels in both depressed DST nonsuppressors and Cushing's patients than in controls. Basal 11-beta-hydroxylase activity is positively correlated and 11-deoxycortisol is negatively correlated with age in controls and DST suppressors, but not in the patients tested with evidence of cortisol hypersecretion. These findings suggest that in vivo basal 11-beta-hydroxylase activity rises gradually with age, but does not rise after acute administration of exogenous ACTH. The age relationship is lost in states of cortisol hypersecretion, but the lack of response to acute exogenous ACTH is not affected.     

Suppressive action of ACTH on growth hormone secretion in patients with infantile spasms

The changes in insulin-induced growth hormone secretion and in serum cortisol level were studied in 3 cases of West syndrome. The ACTH therapy consisted of an eight weeks course with gradual tapering every two weeks. Daily administration of 12.5 or 25.0 micrograms per kg ACTH for two weeks suppressed an insulin-induced rise in serum GH. The patients who showed sharply suppressed responses as to serum GH had been exposed to high cortisol levels of over 50 micrograms per dl serum. When they were examined before starting the therapy and 72 or 96 hours after the last ACTH injection, all the subjects showed a normal rise in the level of serum GH. The clinical implications of the findings were discussed in terms of the possible adverse effect on the developing brain.     

Increased adrenocorticotropin responses to acute stress in Otsuka Long-Evans Tokushima Fatty (type 2 diabetic) rats

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new diabetic strain of rats whose disease closely resembles human type 2 diabetes. We measured plasma adrenocorticotropic hormone (ACTH) and corticostrone levels, and iodine-125-labeled ovine corticotropin-releasing factor ([125I]oCRF) binding in the anterior pituitary after ether-laparotomy stress in OLETF rats to examine the alteration of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, we examined ACTH secretion following CRF administration in vivo and in vitro to characterize the mechanisms regulating the HPA axis in OLETF rats. Body weight, plasma glucose and insulin levels in OLETF rats were significantly higher than that in Long-Evans Tokushima Otsuka (LETO) rats. Basal plasma ACTH levels tended to be higher in OLETF rats than in LETO but it did not reach statistical significance. Ether-laparotomy stress dramatically increased plasma ACTH levels at 2 h after the stress both in either OLETF and LETO rats; the peak plasma ACTH level in OLETF rats following the stress was significantly greater than in LETO rats. Plasma ACTH levels following CRF (2 microg/kg, i.v.) in OLETF and LETO rats showed statistically significant increases at 10 and 30 min after CRF administration compared to ACTH levels at 0 min, however, the peak plasma ACTH level in OLETF rats at 10 min after CRF administration was significantly greater than in LETO rats. In contrast to ACTH levels, no significant differences in corticosterone levels between OLETF and LETO were observed at any of the time points. CRF (10 ng/ml) significantly increased ACTH secretion in pituitary cultures from OLETF compared to LETO rats. These data reveal a complex regulation of the endocrine system in this diabetic condition and suggest that HPA axis may be more stimulated during acute stress in diabetes mellitus than in unaffected subjects.     

Corticotropin-releasing factor (CRF)--a review

Corticotropin-releasing factor (CRF), a 41 amino acid polypeptide, has been isolated from ovine hypothalamic extracts, sequenced, and synthesized. It has a high potency for stimulating the secretion of corticotropin-like and beta-endorphin-like immunoactive substances in vitro and in vivo in laboratory animals and humans. The high concentration of CRF-like immunoactivity in hypophyseal portal plasma supports the hypothesis that CRF is the physiological hypothalamic factor. Human and rat CRF (rCRF) also have been purified and synthesized. They have an 83% sequence homology with ovine CRF (oCRF). oCRF-like activity has been found in human hypothalamus, pituitary stalk, posterior pituitary, thalamus, cerebral cortex, cerebellum, pons, medulla oblongata, spinal cord and in the adrenal, lung, liver, stomach, duodenum and pancreas. oCRF-like activity also has been found in the human placenta and in tissues producing ectopic ACTH. The action of CRF can be potentiated by vasopressin, oxytocin, epinephrine, norepinephrine, VIP, and angiotensin II. Intracerebroventricular administration of CRF in the rat produces prolonged elevations of plasma epinephrine, norepinephrine, glucose and glucagon; elevates mean arterial pressure and heart rate; increases motor activity and exploration in familiar surroundings and oxygen consumption; and decreases feeding and sexual behavior. Testing with CRF has enabled the separation of patients with hypothalamic and pituitary adrenal insufficiency. The CRF stimulation test has been useful in distinguishing pituitary from ectopic causes of Cushing's disease. The distribution of CRF within and beyond the hypothalamus provides an anatomical context for the observation that CRF can simultaneously activate and coordinate metabolic, circulatory and behavioral responses that are adaptative in 'stressful' situations. CRF not only stimulates the pituitary-adrenal axis in man, but it also influences several aspects of CNS function which may be of relevance to psychiatric illnesses.     

Corticotropin-releasing factor test in melancholic patients in depressed state versus recovery: a comparative study

PURPOSE: Basal adrenocorticotropin hormone (ACTH) and cortisol levels and their response to corticotropin-releasing factor (CRF) test were studied in melancholic depressive patients in depressed state and recovery, and compared with healthy controls. METHODS: Fifty-four outpatients diagnosed with unipolar depressive disorder with melancholic features according to DSM-IV and 23 healthy controls were included in the study. The Structured Clinical Interview for DSM-IV (SCID-IV) was used for diagnosis. Twenty-nine patients were in recovery, while 25 were in depressed state at the moment of the administration of the CRF test. FINDINGS: No differences were found between the recovered and depressed groups with respect to CRF test. Lower ACTH and higher cortisol levels with significant differences were shown in the neuroendocrine variables at 15, 30, and 60 min, and in peak response and increase, in the ACTH and cortisol response curves to CRF challenge between the groups of melancholic patients, both recovered and depressed, compared with the healthy control subjects. Moreover, recovered and depressed melancholic patients had a higher whole cortisol area under the curve with significant differences than the healthy control subjects. CONCLUSIONS: The crossover clinical status at the moment of the CRF test doesn't differentiate changes in the HPA axis in melancholic patients, while we did find significant differences in the group of healthy controls in comparison with the groups of melancholic patients both in depressive state and recovery. This supports the hypothesis that hypothalamic pituitary adrenal (HPA) axis shows alterations that remain in depressive patients even after recovery.     

Enhanced adrenal sensitivity to exogenous cosyntropin (ACTH alpha 1-24) stimulation in major depression. Relationship to dexamethasone suppression test results

ACTH alpha 1-24 (cosyntropin) (250 micrograms by intravenous bolus) was given to 38 medicated patients with major depressive disorder (MDD) and to 34 normal control subjects. Patients with MDD had significantly higher plasma cortisol concentrations and significantly higher increases in plasma cortisol levels 60 minutes after cosyntropin infusion than did control subjects. Patients who were nonsuppressors in the dexamethasone suppression test had significantly higher 60-minute cortisol concentrations and cortisol increases than did normal subjects and patients with MDD who were suppressors. There were significant, strongly positive correlations between cortisol secretory responses to cosyntropin and postdexamethasone cortisol concentrations in patients with MDD. These findings confirm that adrenal sensitivity to corticotropin (ACTH) is enhanced in MDD and suggest that this endocrine abnormality may be related pathophysiologically to the resistance of cortisol secretion to dexamethasone suppression.     

Abnormal ACTH and cortisol responses to ovine corticotropin releasing factor in patients with primary affective disorder

To further explore hypothalamic pituitary adrenal regulation in patients with affective illness, we administered 1 microgram/kg of synthetic ovine corticotropin releasing factor at 2000h to 26 drug-free patients with this disorder and to 15 healthy controls. Compared to controls, depressed patients (N = 12) showed a significant elevation in baseline cortisol and significant reductions in the net ACTH and cortisol responses to corticotropin releasing factor. These findings were normal in manic (N = 6) and improved (N = 8) subjects. An additional finding was that baseline cortisol and net ACTH and cortisol responses to CRF were negatively correlated in the entire group of patients and controls as well as in the patients alone. These data indicate that the reduced ACTH and cortisol responses to CRF in depression reflect normal functioning of the pituitary corticotroph cell (i.e., that the negative feedback effect of cortisol on ACTH secretion in depression is physiologically intact, effectively serving as a brake on the ACTH response to exogenous CRF. Thus, the hypercortisolism of depression may be due to a hypothalamic defect, possibly involving hypersecretion of endogenous CRF. This possibility may be of particular interest in light of clinical observations that depression can often be precipitated by stress and by data in experimental animals that CRF may influence several processes known to be altered in the overall symptom complex of depression.     

Diminished cortisol levels in subordinate female marmosets are associated with altered central drive to the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Female marmosets offer a promising primate model of stress-related hypocortisolism, as they undergo chronic reductions in circulating cortisol after becoming subordinate in a social group. In this study, we treated dominant and subordinate female marmosets with the cortisol synthesis inhibitor metyrapone and corticotropin-releasing factor (CRF) to characterize the effects of subordination on central regulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Seven dominant and six subordinate female marmosets received CRF (6 microg/kg, intravenous [IV]), following pretreatment with metyrapone (75 mg/kg, by mouth [PO]) or water. Plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were determined before metyrapone or water treatment and before, 1 hour after, and 2 hours after CRF treatment. RESULTS: Following metyrapone treatment, subordinates had similar cortisol levels to dominants but significantly higher ACTH levels. During CRF challenges, cortisol concentrations were lower and ACTH concentrations higher in subordinates, although net integrated responses to CRF did not differ. Cortisol-to-ACTH ratios were consistently lower in subordinates. CONCLUSIONS: These results confirm previous findings of low cortisol concentrations and blunted adrenal responsiveness in subordinates and suggest that when differences in cortisol levels are eliminated, subordinates exhibit exaggerated hypothalamic drive to the pituitary. These neuroendocrine alterations in subordinate marmosets resemble those in posttraumatic stress disorder patients and adult survivors of child abuse.     

The involvement of serotonin in regulation of pituitary-adrenocortical function.

Adrenocorticotropin (ACTH) secretion from the anterior pituitary gland influences glucocorticoid secretion from the adrenal cortex and in turn is controlled mainly by corticotropin-releasing factor (CRF) release from the hypothalamus. CRF-containing neurons projecting from the paraventricular nucleus to the median eminence, which are involved in controlling pituitary-adrenocortical function, receive synaptic input from serotonin neurons projecting from the midbrain raphe nuclei. Serotonin stimulates the release of bio- or immunoassayable CRF from isolated rat hypothalamus in vitro. Corticosterone, ACTH, and CRF release in vivo is increased in rats by drugs that enhance serotonin function, including serotonin precursors, serotonin uptake inhibitors, serotonin releasers, and direct-acting serotonin agonists. Among the multiple serotonin receptors that exist in brain, at least two--5HT1A and 5HT2 or 5HT1C receptors--seem to mediate activation of pituitary-adrenocortical function. The physiological role of this stimulatory serotonergic influence on pituitary-adrenocortical function is still not well understood, but serotonin may play a role in circadian rhythmicity of adrenocortical secretion and in the activation of pituitary-adrenocortical function by certain types of stress. Measurement of ACTH or cortisol levels in humans after administration of a direct- or indirect-acting serotonin agonist provides one means of probing the functional state of brain serotonergic systems in disease or after drug treatment.     

The low-dose dexamethasone suppression test in fibromyalgia

OBJECTIVE: Fibromyalgia syndrome (FMS) has been associated with decreased cortisol secretion. Patients with posttraumatic stress disorder (PTSD) exhibit similar hypocortisolism in the context of increased negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. Because trauma and PTSD have been associated with fibromyalgia, we evaluated whether patients with fibromyalgia demonstrate increased HPA feedback sensitivity. METHOD: Baseline blood samples were obtained at 0800 h, and 0.5 mg of dexamethasone was administered to 15 female patients with FMS and 20 normal controls at 2300 h. Adrenocorticotropin (ACTH), cortisol, and dexamethasone levels were measured at 0800 h after dexamethasone intake. RESULTS: There were no group differences in mean ACTH or cortisol levels or in ACTH/cortisol ratio at baseline. After dexamethasone intake, patients with FMS exhibited more pronounced suppression of cortisol but not of ACTH, as well as increased ACTH/cortisol ratios compared with controls. Percent cortisol suppression was associated with pain and fatigue, while ACTH/cortisol ratio and dexamethasone availability were associated with stress and anxiety measures. CONCLUSION: Our results suggest increased sensitivity to glucocorticoid feedback, manifested at the adrenal level, in FMS.     

Cushing's syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome

Twenty-three patients with pituitary adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome were studied before and after treatment. The relationship between the amelioration of the depressive syndrome and changes in cortisol and ACTH levels was investigated. There was a significant difference in mean change in 24-hour urinary free cortisol (UFC) excretion for changes in the depressed mood score from first to last visit. There were also significant correlations between decreases in UFC and decreases in both the depressed mood score and the modified Hamilton depression score. These relationships were not found for ACTH. Furthermore, with cortisol decreased to normal levels, continued high ACTH levels did not prevent improvement in depressed mood. The possibility that cortisol may also play a role in the pathogenesis and/or maintenance of the mood disorder in psychiatric patients is discussed.     

Stress sensitivity in metastatic breast cancer: analysis of hypothalamic-pituitary-adrenal axis function

The normal diurnal cortisol cycle has a peak in the morning, decreasing rapidly over the day, with low levels during the night, then rising rapidly again to the morning peak. A pattern of flatter daytime slopes has been associated with more rapid cancer progression in both animals and humans. We studied the relationship between the daytime slopes and other daytime cortisol responses to both pharmacological and psychosocial challenges of hypothalamic-pituitary-adrenal (HPA) axis function as well as DHEA in a sample of 99 women with metastatic breast cancer, in hopes of elucidating the dysregulatory process. We found that the different components of HPA regulation: the daytime cortisol slope, the rise in cortisol from waking to 30 min later, and cortisol response to various challenges, including dexamethasone (DEX) suppression, corticotrophin releasing factor (CRF) activation, and the Trier Social Stress Task, were at best modestly associated. Escape from suppression stimulated by 1mg of DEX administered the night before was moderately but significantly associated with flatter daytime cortisol slopes (r=0.28 to .30 at different times of the post DEX administration day, all p<.01). Daytime cortisol slopes were also moderately but significant associated with the rise in cortisol from waking to 30 min after awakening (r=.29, p=.004, N=96), but not with waking cortisol level (r=-0.13, p=.19). However, we could not detect any association between daytime cortisol slope and activation of cortisol secretion by either CRF infusion or the Trier Social Stress Task. The CRF activation test (following 1.5mg of DEX to assure that the effect was due to exogenous CRF) produced ACTH levels that were correlated (r=0.66, p<.0001, N=74) with serum cortisol levels, indicating adrenal responsiveness to ACTH stimulation. Daytime cortisol slopes were significantly correlated with the slope of DHEA (r=.21, p=.04, N=95). Our general findings suggest that flatter daytime cortisol slopes among metastatic breast cancer patients may be related to disrupted feedback inhibition rather than hypersensitivity in response to stimulation.     

Cortisol, ACTH, and beta-endorphin after dexamethasone administration in Parkinson's dementia

The dexamethasone suppression test (DST) has been suggested as an effective tool for differentiating between depression and dementia. After administering 1 mg dexamethasone, we measured cortisol, ACTH, and beta-endorphin levels in 32 nondepressed patients with idiopathic Parkinson's disease (PD) (14 also with dementia) and 20 healthy, age-matched controls. Four of the 20 controls, 9 of the 18 with PD alone, and 8 of the 14 with PD and dementia were dexamethasone nonsuppressors (cortisol value greater than or equal to 5 micrograms/100 ml). PD patients without dementia (nonsuppressors) showed higher basal plasma values of cortisol (22.06 +/- 5.30 micrograms/100 ml) compared with the suppressors (13.38 +/- 3.30 micrograms/100 ml). Plasma ACTH and beta-endorphin responded in a coupled way to dexamethasone challenge. Higher basal levels of both peptides were found among PD patients (demented and nondemented), nonresponders to DST. Thus, the DST does not appear to be effective in differentiating between depression and dementia in PD. In addition, PD nonsuppressors showed higher basal values of plasma ACTH, beta-endorphin, and cortisol (similar to patients with major depression). This suggests that although the depression is clinically undetectable, both disorders may share some pathophysiological features at the hypothalamic hypophyseal adrenal level.     

Cortisol response to ACTH infusion in depressed patients: comparison with age-, sex-, and weight-matched normal subjects

Adrenal responsiveness to Cosyntropin (synthetic ACTH_1–24) was investigated in five patients with major depression and five individually matched normal subjects. Three hours following suppression of endogenous ACTH secretion with dexamethasone (1 mg orally), the adrenal response to a 10-min infusion of Cosyntropin (0.05 μg/kg body weight) was monitored for hr by plasma cortisol measured at 15-min intervals. The depressed patients had significantly higher baseline plasma cortisol, but not higher baseline ACTH, than the controls. During the 3-hr post-dexamethasone (and prior to Cosyntropin infusion), the depressed patients maintained significantly higher cortisol secretion, but not higher ACTH secretion, than the controls. After Cosyntropin infusion, there were no differences in ACTH and cortisol increases between the two groups. These findings stand in contrast to previous reports of enhanced adrenal responsiveness to the administration of much larger amounts of Cosyntropin in major depression.     

Long-Lasting Deficient Dexamethasone Suppression of Hypothalamic-Pituitary-Adrenocortical Activation Following Peripheral CRF Challenge in Socially Defeated Rats

The present study focuses on the long-term changes in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis following two short-lasting episodes of intensive stress in the rat stress model of social defeat and the possible similarities with HPA functioning in human affective disorders. Male Wistar rats experienced social defeats on 2 consecutive days by an aggressive male conspecific. The long-term effect of these defeats on resting and ovine corticotropin-releasing factor (oCRF; intravenous (i.v.) 0. 5 microg/kg) induced levels of plasma ACTH and corticosterone (CORT) were measured 1 and 3 weeks later. In a second experiment the glucocorticoid feedback regulation of HPA function was tested in a combined dexamethasone (DEX)/CRF test (DEX; 25 microg/kg s.c., 90 min before oCRF injection, 0.5 microg/kg). The oCRF challenges were performed between 11.00 and 13.00 h (about three hours after start of the light phase). One week after defeat the ACTH response to CRF was significantly enhanced in defeated rats as compared to controls. Three weeks after defeat the ACTH response was back to control levels. The increased ACTH response 1 week after the stressor was not reflected in higher CORT levels. Neither were baseline ACTH and CORT levels affected by the prior stress exposure. DEX pretreatment inhibited pituitary adrenocortical activity, reflected both in reduced baseline and response values of ACTH and CORT. The ACTH response to CRF following DEX administration was significantly higher in defeated rats as compared to controls both at one and three weeks after defeat. A reduced DEX suppression of baseline secretion of ACTH appeared 3 weeks after defeat. The same tendency was apparent in response and baseline values of CORT. The differences in CORT between socially stressed and control treated rats, however, did not reach significance. The possible role of changes in glucocorticoid-(GR) and mineralocorticoid receptor (MR) binding in the altered regulation of HPA activity following defeat were studied in brain and pituitary of male Wistar rats 1 and 3 weeks after defeat. One week after defeat GR-binding decreased in hippocampus and hypothalamus. No changes were observed in GR-binding in the pituitary nor in MR-binding in any of the regions analysed. Three weeks after defeat GR-binding recovered in hippocampus and hypothalamus but at this time MR-binding in hippocampal tissue was seriously decreased. In a fourth experiment vasopressin (AVP) and CRF stores in the external zone of the median eminence (ZEME) were measured by quantitative immunocytochemistry one and three weeks after defeat and compared with controls. Social defeat failed to induce a change in the immunocytochemical stores of AVP or CRF. The present findings show that in rats short-lasting stressors like defeat induce long-lasting, temporal dynamic changes in the regulation of the HPA axis. Since these changes in time are reflected in GRs and MRs in different brain areas an altered corticosteroid receptor binding might play an important role in the affected HPA activity following defeat.     

Blunting of ACTH response to human CRH in depressed patients is avoided by metyrapone pretreatment

The current concept that blunted adrenocorticotropic hormone (ACTH) response to human corticotropin-releasing-hormone (h-CRH) in depression is primarily determined by elevated circulating plasma cortisol levels is still unproven. We tested this hypothesis by comparing ACTH release following intravenous administration of 100 micrograms h-CRH in 10 normal controls and in 21 inpatients with a major depressive episode. Eleven of these depressed patients were pretreated with an oral dose of 2 g metyrapone, which inhibits cortisol biosynthesis by blocking C-11 beta-steroid-hydroxylase. This intervention deprives the entire system of cortisol, which is the major feedback signal for the regulation of ACTH secretion at various pituitary and limbic sites. ACTH responses, assessed as areas-under-time-course-curves, were: in normal controls, 6.8 +/- 2.4 (SD) pg/ml/min x 10(3); in unmedicated patients, 2.6 +/- 1.1 pg/ml/min x 10(3); and in metyrapone pretreated patients, 9.0 +/- 6.7 pg/ml/min x 10(3). Thus, ACTH release in unmedicated depressed patients was significantly (p less than 0.001, Mann-Whitney U-test) blunted when compared with normal controls. In contrast, this blunting was completely avoided after metyrapone pretreatment, which resulted in net ACTH responses that were indistinguishable from those of the controls.     

The hypothalamic-pituitary-adrenal axis in chronic schizophrenic patients long-term treated with neuroleptics

PURPOSE: The authors investigated the hypothalamic-pituitary-adrenal (HPA) axis of regularly medicated schizophrenic patients. METHODS: The subjects were 53 patients who were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders--Fourth Edition (DSM-IV) criteria for schizophrenia. Each patients gave informed consent for the research. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Based on the dosages of neuroleptics (NLPs), the subjects were classified into two groups: those with lower dosages (LD) and those with higher dosages (HD). FINDINGS: (a) The medicated schizophrenic patients had significantly higher plasma corticotropin (ACTH) levels than the normals. (b) There was no significant difference in plasma cortisol levels between the schizophrenic patients and normals. (c) There was a significant difference in plasma ACTH levels between the HD and normal groups, but not between the LD and normal groups. (d) There was no significant difference in administration periods of NLPs, positive (POS) or negative symptoms (NES) between the HD and LD groups. (e) There was a positive correlation between the plasma ACTH and plasma cortisol levels in patients. CONCLUSIONS: Our results showed that, in chronic schizophrenic patients long-term treated with NLPs, ACTH secretion was elevated.