Cerebrospinal fluid neuropeptides in dementia.

Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH) and somatostatin (SRIF) were measured in 77 female inpatients with moderate to extreme dementia and in 17 elderly female controls. Both multi-infarct (MID) and Alzheimer-type (SDAT) demented patients had equally elevated CSF CRH and TRH but not SRIF levels as compared with the controls. This elevation was, however, not seen in patients with simple dementia while it was most prominent in those exhibiting marked depressive symptoms. It is concluded that depression rather than dementia itself may be associated with CSF CRH and TRH elevation in elderly patients with cognitive impairment.     

CSF somatostatin in anorexia nervosa and bulimia: relationship to the hypothalamic pituitary-adrenal cortical axis

The eating disorders, anorexia nervosa and normal weight bulimia, are associated with disturbances of hypothalamic-pituitary-adrenal cortical (HPA) and growth hormone function. Because somatostatin (SRIF) is one of the neuropeptides known to modulate feeding behavior and neuroendocrine systems, we measured cerebrospinal fluid (CSF) concentrations of this peptide in patients with eating disorders. CSF SRIF concentrations in patients with anorexia nervosa, both at low weight and after weight recovery, were similar to those in controls. When normal weight bulimic women stopped binging, they had a modest but significant increase in CSF SRIF. CSF SRIF was not related to plasma growth hormone concentrations but did show relationships to HPA axis hormones. Healthy volunteer women had a significant positive relationship between CSF SRIF and CSF corticotropin releasing hormone (CRH). In underweight anorectics, CSF SRIF was negatively related to both 24-hr urinary free cortisol and plasma cortisol concentrations after dexamethasone, but it was not significantly related to CSF CRH. These relationships more closely resembled those of healthy controls after weight correction. In bulimics, CSF SRIF was positively related to CSF CRH and negatively related to plasma cortisol. Our findings support a previously described relationship between CSF SRIF and HPA axis activity. The differences in SRIF-HPA relationships in anorectics and bulimics may constitute or reflect pathophysiological distinctions between these disorders.     

Thyroid stimulating hormone response after thyrotropin releasing hormone in depressed, schizophrenic and normal women.

(1) Thyroid stimulating hormone (TSH) response after injection of thyrotropin releasing hormone (TRH) was studied in 23 depressed, 9 schizophrenic and 40 normal women. (2) In no group was TSH response correlated with age. (3) In the depressed patients, no relationship was found between TSH response and (i) severity of illness, (ii) clinical subtypes (unipolar/bipolar) and (iii) clinical remission. (4) There were no statistically significant differences in TSH baseline values between the groups. (5) Neither of the two patient groups showed reliable differences from controls regarding TSH response. However, depressed patients tended to show lower values than controls, while schizophrenic patients tended to show higher values than normal controls. (6) Significant differences were found between depressed and schizophrenic patients in regard to TSH response. In three depressed patients a TSH response below 5 μU/ml was found. This deficient TSH response occurred in unipolar depressed patients and was not seen in bipolar depressed patients, schizophrenic patients or normal controls. (7) These data provide evidence for a fault in hypothalamic pituitary regulation in some depressed patients but not in schizophrenic patients.     

改良电抽搐治疗对精神分裂症患者下丘脑激素(CRH和TRH)水平影响的临床对照分析

目的 观察改良电抽搐治疗对精神分裂症患者下丘脑促肾上腺皮质释放激素(CRH)和促甲状腺激素释放激素(TRH)的影响。方法 将符合CCMD-3精神分裂症诊断标准的精神分裂症患者57例随机分为治疗组(30例)与对照组(27例)进行观察。用放射免疫分析法分别对两组治疗前、后的CRH和TRH水平进行测定。结果 在治疗后TRH水平治疗组较对照组有明显的降低，而CRH在治疗前后变化不明显。结论 改良电抽搐治疗对TRH的影响大于CRH。     

纤维肌痛患者血清中三种促激素释放激素含量的改变

目的 探讨纤维肌痛患者血清中促肾上腺皮质激素释放激素(CRH)、促甲状腺激素释放激素(TRH)和促性腺激素释放激素(GnRH)含量变化及其临床意义。方法 选取2009年6月至2010年10月在安徽医科大学附属第一医院神经内科就诊的纤维肌痛患者26例及同期健康体检者29名,分别作为患者组及对照组,用汉密尔顿抑郁量表-17评估患者的抑郁状况。采取ELISA方法检测两组血清中CRH、TRH和GnRH含量,所得数据分别采用独立样本t检验(正态分布)与MannWhitney Test检验(非正态分布),同时用受试者工作特征(ROC)曲线分析3种激素对纤维肌痛诊断的特异度和敏感度,并采取Spearman相关性分析探讨3种激素含量与患者年龄、性别、压痛点个数、疼痛程度及抑郁程度的相关性。结果 与对照组[70.0(48.7,78.0) ng/L]相比,纤维肌痛患者血清中CRH含量明显升高[271.9(210.9,326.5)ng/L,x2=6.408,P＜0.01],TRH[分别为(82.7±6.9)、(87.2±6.8)ng/L,t =2.560,P＜0.05]及GnRH[分别为(18.2±0.9)、(19.9±1.6) ng/L,t=5.324,P＜0.01]含量也显著性升高。三者均与疼痛程度和压痛点个数正相关,CRH和GnRH含量还与患者抑郁程度正相关。血清中3种激素含量的诊断敏感度和特异度ROC曲线下面积分别为1.000、0.684与0.854。结论 纤维肌痛患者CRH、TRH和GnRH分泌增多,其中CRH的值可能可以作为诊断纤维肌痛的参考指标。     

Endocrine responses to growth hormone releasing hormone and corticotropin releasing hormone in early-onset Alzheimer's disease

In a study of the hypothalamic-pituitary-somatotropic (HPS) and the hypothalamic-pituitary-adrenal (HPA) systems in early-onset Alzheimer's disease (AD), 10 drug-naive patients and matched controls were given 50 micrograms growth hormone releasing hormone (GHRH) at 9 a.m. and 100 micrograms corticotropin releasing hormone (CRH) at 6 p.m. as an i.v. bolus dose. Compared with controls, patients with AD showed attenuated GHRH-induced growth hormone (GH) responses and decreased adrenocorticotropic hormone (ACTH) but normal cortisol secretion following CRH. GH responses to GHRH were negatively correlated with the plasma insulin-like growth factor (IGF-I) concentrations and the severity of dementia. A positive correlation was found between GHRH-evoked GH release and ACTH responses to CRH. The results suggest a pathological process at the level of the pituitary or the hypothalamus, possibly involving a cholinergic, monoaminergic, or peptidergic imbalance in AD, and support the view that altered HPS and HPA secretory dynamics in AD are related to the underlying brain dysfunction.     

CSF diazepam-binding inhibitor concentrations in panic disorder.

Diazepam-binding inhibitor (DBI) is a neuropeptide that has been detected in the brain and cerebrospinal fluid (CSF). Previous studies have suggested the possible role of DBI as a potential endogenous anxiogenic ligand modulating GABAergic transmission at the benzodiazepine-GABA receptor complex. The measurement of DBI immunoreactivity (DBI-IR) in CSF of panic-disorder patients and normal controls was undertaken to assess whether there were differences in the CSF concentration of this peptide to assess possible relationships with other monoamines and peptides. Lumbar CSF was obtained from 18 panic patients (4 men, 14 women) and 9 controls (5 men, 4 women). As a group, no significant differences were found between panic patients' CSF concentration of DBI-IR (1.12 +/- 0.27 pmol/mL) and normal volunteers (1.23 +/- 0.27 pmol/mL). No gender differences were demonstrated. However, we did find a positive correlation between CSF levels of DBI and CSF corticotropin releasing hormone (CRH) in our panic patients.     

Growth hormone response to growth hormone releasing hormone in depression and schizophrenia

Growth hormone releasing hormone, a 44-amino acid peptide (GHRH-44), was administered (1 micrograms/kg i.v.) to 6 normal controls, 10 schizophrenic subjects, and 7 depressed subjects. A significantly lower growth hormone (GH) response was found in the schizophrenic and depressed groups. Two molecular forms of GH, 22K GH and 20K GH, were also measured but did not further differentiate the three groups of subjects.     

Postmortem stability and characterization of immunoreactive luteinizing hormone releasing hormone and thyrotropin releasing hormone in human brain tissue

PARKER, C. R., JR. AND J. C. PORTER. Postmortem stability and characterization of immunoreactive luteinizinghormone releasing hormone and thyrotropin releasing hormone in human brain tissue. BRAIN RES. BULL. 8(6) 623–630, 1982.—The content and concentration of immunoreactive luteinizing hormone releasing hormone (LHRH) and of thyrotropin releasing hormone (TRH) were evaluated in hypothalamic tissue of 52 cadavers of adult humans (33 males, 18 to 70 years of age, and 19 females, 17 to 74 years of age). Autopsy was performed between 2.5 and 21 hr after death. When the data were subjected to linear regression analysis, it was found that neither the concentration nor content of LHRH or TRH varied significantly between 2.5 and 21 hr postmortem. The stability of LHRH or TRH in hypothalamic fragments that included the pituitary stalk was similar to the stability of these peptides in hypothalamic fragments that did not include the pituitary stalk. The concentration as well as content of LHRH and TRH in specimens analyzed 2.5 to 12 hr postmortem was similar to that in specimens analyzed 13 to 21 hr postmortem. When aliquots of a homogenate or a synaptosomal fraction of hypothalamic tissue were incubated at 4° or 37°C prior to the analysis of endogenous LHRH and TRH, it was found that the concentration of each peptide remained constant for several hours. However, when synthetic LHRH or TRH was mixed with aliquots of homogenates or subcellular fractions of hypothalamic tissue and incubated at 37°C, each exogenous peptide was rapidly degraded. Based upon the results of gel filtration chromatography, high performance liquid chromatography, biological activity (LHRH), and susceptibility to degradation by serum (TRH), immunoreactive LHRH and TRH in extracts of human brain tissue appeared to be similar to synthetic LHRH and TRH. These findings support the view that, although human brain tissue has the capacity to degrade LHRH and TRH, the endogenous pools of these peptides are sequestered in such a manner that they are stable for several hours in the postmortem human brain. These data are suggestive that brain tissues obtained at autopsy may be useful in the study of peptidergic systems in the human.     

CSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture

Hypocretins/orexins are newly identified peptides of hypothalamic origin. Hypocretin deficiency is involved in the sleep disorder narcolepsy, suggesting the importance of hypocretin neurotransmission for the regulation of sleep. Hypocretin is known to excite midbrain dopaminergic neurons and to induce hyperactivity and stereotypy in animals. Altered hypocretin neurotransmission might therefore be involved in schizophrenia, since an involvement of dopaminergic mechanisms and an association with sleep disturbance are well demonstrated in patients with schizophrenia. Hypocretin is also known to affect the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH). In the current study, we measured CSF hypocretin levels in 12 controls and 13 patients with chronic schizophrenia associated with moderate sleep disturbance, such as longer sleep onset latency, decreased total sleep time and decreased sleep efficacy. No difference in CSF hypocretin levels between schizophrenia and control subjects was found. CSF hypocretin levels were positively correlated with CSF CRH levels in the patient, control and combined subject populations, but the correlation did not reach statistical significance in any population. The hypocretin levels in schizophrenic patients were, however, positively and significantly correlated with sleep latency, one of the most consistent sleep abnormalities seen in schizophrenia. This correlation was not significant in controls, and no other significant correlation between CSF hypocretin levels and any measure of sleep architecture in either patients or controls was observed. Further studies of whether CNS hypocretin neurotransmission is involved in sleep and neuroendocrine abnormalities seen in patients with schizophrenia and other psychiatric conditions are warranted.     

Decreased corticotropin-releasing hormone (CRH) concentrations in the cerebrospinal fluid of eucortisolemic suicide attempters

Several lines of evidence suggest a dysregulation of the adrenocortical (HPA) system with hypersecretion of CRH is associated with suicidal behavior. However, controversial results have emerged from the determination of corticotropin-releasing hormone (CRH) concentrations in the lumbar cerebrospinal fluid (CSF) of suicide attempters probably due to methodological differences. We simultaneously measured CRH concentrations in the CSF and in the plasma of 41 psychiatric in-patients with different diagnoses (affective disorder, schizophrenia, personality disorders, adjustment disorder, substance abuse) and eight neurological control subjects. We also measured plasma cortisol concentrations because data from animal experiments suggest that cortisol may influence CSF CRH concentrations. The major finding was that patients who attempted suicide prior to admission had significantly lower CSF CRH concentrations than psychiatric patients without suicidal behavior. CRH concentrations were significantly higher in the CSF than in plasma in both, psychiatric patients and neurological control subjects. There was no significant difference between suicide attempters and patients with acute suicidal ideations. The latter group showed a trend towards lower CSF CRH concentrations compared with the neurological control subjects. Patients with affective disorder alone as well as patients with multiple diagnoses, but not schizophrenic patients, showed significantly lower CSF CRH concentrations than neurological control subjects. Plasma CRH and plasma cortisol concentrations did not differ among diagnostic groups or between suicide attempters vs. non-attempters. Further studies with more homogeneous samples, drug-free patients and with simultaneous assessment of various parameters of the HPA system are warranted.     

Abnormal thyroid stimulating hormone, prolactin, and growth hormone responses to thyrotropin releasing hormone in abstinent alcoholic men with cerebral atrophy

The thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) responses to thyrotropin releasing hormone (TRH), the Wechsler Adult Intelligence Scale (WAIS) for cognitive impairment, and computed tomographic scans were evaluated in 15 nondepressed alcoholic men after 4 weeks of abstinence and in 10 normal controls. Both cognitive impairment and cerebral atrophy were found in 13 of the alcoholics. Eight alcoholics (seven with cerebral atrophy) had blunted TSH and PRL responses to TRH and a TRH-induced paradoxical increase of GH. This study demonstrates that besides affecting the TSH response to TRH, alcoholism often induces alterations of the PRL and GH secretory patterns in response to TRH. The severe brain damage caused by long-term alcoholism might be involved in the pathogenesis of these neuroendocrine alterations.     

Enzymes involved in the degradation of thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LH-RH) in bovine brain

As part of an investigation of neuropeptide inactivation mechanisms, we have resolved an enzymatic activity in bovine brain which catalyzes the deamidation of thyrotropin releasing hormone (TRH) and the hydrolysis of the Pro9--Gly10--NH2 bond of luteinizing hormone releasing hormone (LH-RH) from a second LH-RH degrading activity which does not degrade TRH. The former activity is similar, if not identical to, the post-proline cleaving enzyme in kidney as it is active toward the post-proline cleaving enzyme substrate CbzGly--Pro--Leu--Gly and inhibited by CbzPro--Phe and diisopropylfluorophosphate. In addition, products derived from the degradation of TRH and LH-RH by this activity show a specific cleavage on the carboxyl side of a proline residue. The latter activity has not yet been characterized with respect to its site of cleavage of the LH-RH molecule due to the presence of other contaminating peptidases.     

Neocortical concentrations of neuropeptides in senile dementia of the Alzheimer and Lewy body type: comparison with Parkinson's disease and severity correlations.

Corticotropin releasing hormone (CRH), somatostatin (SRIF), and arginine vasopressin (AVP) concentrations were estimated using radioimmunoassay in the temporal and occipital cortices in postmortem brain from patients clinically and neuropathologically diagnosed as senile dementia of the Lewy body type (SDLT), senile dementia of the Alzheimer type (SDAT), and Parkinson's disease (PD) and from neurologically normal controls. The concentration of temporal and occipital neocortical CRH was diminished in both SDAT and SDLT compared to control values, whereas SRIF was reduced only in temporal cortex in both these conditions. In contrast, the concentrations of both CRH and SRIF were unaltered in PD. The concentrations of AVP in SDLT, SDAT, and PD were similar to those found in the control groups. The decrement in SRIF, but not CRH, was found to be correlated with some indices of severity of illness in SDAT; a similar but nonsignificant trend for SRIF was observed in SDLT.     

The influence of psychotropic drugs and releasing hormones on anterior pituitary hormone secretion in healthy subjects and depressed patients

Pharmacoendocrinological studies have shown that psychotropic drugs with different actions have different effects on anterior pituitary hormone secretion in man. Substances with different effects on the central nervous system are characterized by a different pharmacoendocrinological profile. Studies with various receptor blockers have shown varying influences on the DMI-induced growth hormone, prolactin, and ACTH/cortisol secretion. Growth hormone stimulation was shown to be mediated by alpha 2-receptors and inhibited by beta-receptors. Investigations in male and female endogenous depressive patients demonstrated a significantly blunted growth hormone response to DMI compared with age- and sex-matched healthy subjects. A comparative study in male endogenous depressive patients showed a significantly diminished growth hormone stimulation both after DMI and after growth hormone-releasing hormone compared to healthy male subjects. In further tests a simultaneous application of four releasing hormones (GHRH, CRH, GnRH, TRH) was used. These investigations showed a significantly lower GH stimulation in endogenous depressive patients compared with age- and sex-matched healthy subjects, but not in neurotic depressive or schizophrenic patients. Cortisol stimulation was similar in all groups of patients and healthy subjects. TSH stimulation was significantly lower in endogenous depressive and schizophrenic patients than in healthy subjects. Somatomedin-C concentrations were significantly elevated in endogenous depressed patients compared with healthy subjects. The blunted growth hormone response in endogenous depression could be explained by inhibitory influences such as increased somatomedin-C concentrations or a hyperactivity of central beta-adrenergic-receptors.     

Diazepam-binding inhibitor and corticotropin-releasing hormone in cerebrospinal fluid

Diazepam-binding inhibitor (DBI) is a neuromodulatory peptide for gamma-aminobutyric acid (GABA) neurotransmission. Cerebrospinal fluid (CSF) levels of DBI have been found to be elevated in depression. CSF levels of the peptide corticotropin-releasing hormone (CRH) have also been found to be elevated in depression. Therefore, we examined for a relationship between DBI and CRH in human CSF. We found significant positive correlations between CSF levels of DBI and CRH in depressed patients, pathological gamblers, and normal controls. These data, along with the elevated CSF levels of DBI in depression, suggest the possibility that DBI may have a role in coordinating responses to stress in humans in addition to its possible role in the pathophysiology of depression.     

Thyrotropin releasing hormone (TRH): a useful tool for psychoneuroendocrine investigation

(1) The hypothalamic tripeptide TRH was injected in normal controls and in schizophrenic, alcoholic and depressed patients. Behavioral and endocrine data were assessed and relationships between the two evaluated. (2) After TRH there was a brief and partial salutary behavioral change in all groups studied, suggesting that the behavioral effects of TRH are not disease specific. (3) A blunted TSH response after TRH was seen in some depressed and some alcoholic patients but not in schizophrenics, indicating that this fault is not simply a nonspecific attribute of mental illness. (4) In depression, but not in alcoholism, the blunting was accounted for by increased levels of serum cortisol. (5) In alcoholic patients, the TSH blunting was related to a favorable behavioral response to TRH. (6) While the relationship between ambient levels of serum cortisol and the TSH response was negative in normal subjects and depressed patients, it was positive in schizophrenic patients. The relative frequency of this finding in the various subtypes of schizophrenia is unknown. (7) The above data, taken together, suggest that both the behavioral and the endocrine effects of TRH render the tripeptide useful for psychoneuroendocrine investigation.     

Thyrotropin releasing hormone uptake into serum and cerebrospinal fluid following intravenous or subcutaneous administration

Intravenous thyrotropin releasing hormone (TRH) was administered to 6 amyotrophic lateral sclerosis (ALS) patients at the dose rate of 10 mg/kg. Blood samples were obtained prior to and at 10, 20, 40, 60, and 120 min during the TRH infusions. Lumbar punctures were performed at 90 min following the start of infusion. The mean serum TRH concentration rose from 0.03 +/- 0.02 (SD) to 17 +/- 2 ng/ml by 60 min and remained constant to 120 min. The mean CSF TRH concentration rose 10-fold from 0.02 +/- 0.01 to 0.2 +/- 0.02 ng/ml at 90 min and increased further to 0.5 +/- 0.2 ng/ml at 120 min. Subcutaneous TRH was administered to 4 ALS patients at 2.5 mg/kg and to 5 ALS patients at 5.0 mg/kg. The mean serum TRH concentration increased to 1.4 +/- 0.6 ng/ml (2.5 mg/kg) and 3.2 +/- 1.1 ng/ml (5.0 mg/kg) by 60 min. The mean CSF TRH concentration at 60 min increased to 0.3 +/- 0.08 ng/ml following 2.5 mg/kg TRH and 0.8 +/- 0.04 ng/ml following 5.0 mg/kg TRH. TRH entry into the CSF is comparable following subcutaneous or intravenous administration.     

Cerebrospinal fluid levels of somatostatin, corticotropin-releasing hormone and corticotropin in alcoholism

Reduced brain and cerebrospinal fluid (CSF) levels of somatostatin, corticotropin-releasing hormone (CRH) and corticotropin (ACTH) have been reported among neuropsychiatric patients with cognitive dysfunction. Alcoholism is a disorder in which associated neuropsychiatric disorders occur. Therefore, we compared CSF levels of somatostatin, CRH and ACTH in alcoholics (n = 100) and normal controls (n = 30). There were no significant differences between the groups in concentrations of the 3 peptides. Moreover, there were no significant correlations between concentrations of the peptides in CSF and computed tomographic measures of the size of brain ventricles. There were, however, significant correlations between CSF concentrations of CRH and ACTH and between CSF concentrations of CRH and somatostatin in both the alcoholic and control groups.     

Abnormal growth hormone release following luteinizing hormone releasing hormone in anorexia nervosa

We studied the luteinizing hormone (LH), follicle stimulating hormone (FSH) and growth hormone (GH) secretion following an i.v. injection of 0.1 mg of luteinizing hormone releasing hormone (LHRH) in patients with anorexia nervosa, who showed the GH secretion after thyrotropin releasing hormone (TRH). Five out of 11 patients had an elevated plasma GH level in a fasting state. The administration of LHRH resulted in a significant increase in the plasma GH concentrations in 3 of the 11 patients. Three other patients also showed an elevation of the plasma GH concentration to 7.0, 18.4 and 29.6 ng/ml, which were 212, 175 and 191% of the preinjection levels, respectively. There is a positive correlation between the basal and peak plasma GH levels after LHRH. These increases, however, were related to neither the plasma gonadotropin responses to LHRH nor the plasma GH responses to TRH. The basal levels of plasma LH were reduced in 8 patients and normal responses to LHRH were observed in only one patient. Although plasma FSH was undetectable in 5 patients, the FSH response to LHRH appeared normal in 9 patients. These results indicate that an elevation of the plasma GH level after LHRH is not confined to patients with a GH secreting pituitary tumor but observed in subjects with anorexia nervosa and further suggest that the GH responsiveness to non-specific hypothalamic releasing hormones may be due to the impaired hypothalamic control in anorexia nervosa.