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To explore the integrity of the hypothalamic-pituitary-adrenal (HPA) system in major depressive disorder, 12 patients and normal controls matched for sex, age, and body weight received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an i.v. bolus dose. Compared to controls, depressed patients showed an elevation in baseline cortisol and a significant attenuation of net adrenocorticotropin (ACTH) responses, while cortisol secretion in response to hCRH was normal. These abnormalities in HPA axis function and apparent discordances in the interrelationships of ACTH and cortisol baseline and net stimulation responses between depressed patients and normal controls indicate, at least in part, a derangement of the glucocorticoid-dependent negative feedback circuitry and support the hypothesis that HPA hyperactivity in depression involves neurotransmitter-mediated hypothalamic hypersecretion of CRH.

Plasma growth hormone (GH) release after injection of 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) was investigated in 11 patients with major depressive disorder and normal controls matched for gender, age, body weight and ovarian status. In contrast to controls, who exhibited no significant GH response to CRH, depressed patients showed a significant net increase in GH secretion following CRH administration. The abnormal GH response to CRH was not correlated with baseline corticotropin (ACTH) and cortisol nor with CRH-induced ACTH and cortisol response. The implications of these findings are discussed with reference to such factors as alpha-adrenergic hyperactivity, hypothalamic-pituitary system dysregulation, drug interference, non-specific stress responses and abnormal neuroendocrine circadian rhythms in major depression.

In order to evaluate the possible effect of glucocorticoids as neuromodulators of the hypothalamic-pituitary-somatotropic system in depression, cortisol, growth hormone (GH), and insulin-like growth factor I (IGF-I) concentrations were studied before and after oral administration of 1 mg dexamethasone at 11 p.m. in 16 patients during depression and after recovery and in 28 healthy controls. While there were no significant differences in GH and IGF-I levels between depressed, recovered and control subjects, GH and IGF-I concentrations of cortisol non-suppressors were significantly elevated compared to suppressors. Moreover, post-dexamethasone cortisol, GH, and IGF-I levels were positively correlated. Dexamethasone had a stimulating effect on GH and IGF-I values in patients during depression and in cortisol non-suppressors only; this effect was absent in recovered and in control subjects and in cortisol suppressors. Thus, hypercortisolemia may be of great importance for the dysregulation of the hypothalamic-pituitary-somatotropic system reported in depression.

To explore the growth hormone-releasing hormone (GHRH)-GH-somatomedin axis in major depressive disorder, 12 patients and 12 normal controls matched to the patients on age, sex, ovarian status and body weight received synthetic human GHRH-44 amide (1 microgram/kg) as an intravenous bolus. Compared to controls, the depressed patients showed a reduction in baseline plasma GH and a significant attenuation of net plasma GH responses to GHRH. The blunted GH responses occurred along with significantly increased somatomedin C (Sm-C) concentrations. The impairment of GH responses to GHRH and the increased Sm-C concentrations in patients with depression could have resulted from episodic hypersecretion of GH during the daytime, indicating integrity of the negative feedback circuitry. Normal feedback regulation suggests that diurnal episodic hypersecretion of GH reflects an abnormality at or above the level of the hypothalamus, so that the GHRH-GH-somatomedin axis hyperactivity observed in certain patients with major depressive disorder may be due, at least in part, to hypersecretion of hypothalamic GHRH. Our failure to demonstrate a difference in plasma prolactin (PRL) responses to GHRH between controls and depressed patients indicates that GHRH is not a PRL releaser in patients with major depression and that the altered GH secretory dynamics may not be directly related to the altered circadian PRL secretion linked to depression.

The rapid growth of fundamental research in neuroendocrinology includes advances in our understanding of the role of neurotransmitters in the control of hypophysiotropic neurons, the concept of neurosecretion, the portal circulation chemotransmitter hypothesis of anterior pituitary regulation, and the chemical structures of the hypophysiotropic hormones. These advances correspond to the emergence of psychoneurobiology, with the appreciation of the roles of neuropeptides, such as hypothalamic releasing and inhibiting hormones, their relevance to brain function and possible involvement in psychiatric disease, and their introduction into psychoneuroendocrinological studies. The subject of the present review is to summarize and integrate current knowledge of the neuroendocrinology of hypothalamic releasing and inhibiting hormones, to apply it to the understanding of the pathogenesis of depression, and to evaluate their relevance as psychoneuroendocrine research tools.

Since the discovery of CRH in 1981, several investigators have reported abnormalities of the hypothalamic-pituitary-adrenal (HPA) system in response to direct stimulation of the corticotroph cells in patients with psychiatric disorders. To further explore HPA system integrity in major depressive disorders, 13 drug-free patients and normal subjects matched for age, sex, ovarian status, and body weight received 100 micrograms synthetic human CRH as an iv bolus dose. Compared to that in the normal subjects, in the depressed patients a significant attenuation of the net ACTH release after CRH administration (772 +/- 597 vs. 263 +/- 286 pmol/min.L; P less than 0.02) was observed, while beta-endorphin and cortisol responses did not differ significantly between the groups. The magnitudes of ACTH and cortisol release were negatively correlated in the patient group only (r = -0.67; P less than 0.01). Thus, the blunted ACTH response to CRH in depression might be related to hypercortisolemia, while the implications of the apparent dissociation of ACTH and beta-endorphin after CRH administration still remain unclear. Our data support the hypothesis that the hyperactivity of the HPA system in depression most likely is a consequence of CRH hypersecretion, the origin of which may be explained by abnormal central glucocorticoid receptor or neurotransmitter regulation.

The existence of estrogen receptors in human meningiomas has long been a controversial issue. This may be explained, in part, by apparent heterogeneity of estrogen binding sites in meningioma tissue. In this study, estrogen receptors were determined in 58 meningiomas with an enzyme immunoassay using monoclonal antibodies against human estrogen receptor protein (estrophilin) and with a sensitive radioligand binding assay using 125I-labeled estradiol (125I-estradiol) as radioligand. Low levels of estrophilin immunoreactivity were found in tumors from 62% of patients, whereas radioligand binding activity was demonstrated in about 46% of the meningiomas examined. In eight (14%) tissue samples multiple binding sites for estradiol were observed. The immunoreactive binding sites correspond to the classical, high affinity estrogen receptors: the Kd for 125I-estradiol binding to the receptor was approximately 0.2 nM and the binding was specific for estrogens. The second, low affinity class of binding sites considerably influenced measurement of the classical receptor even at low ligand concentrations. The epidemiological and clinical data from patients with meningiomas, and the existence of specific estrogen receptors confirmed by immunochemical detection, may be important factors in a theory of oncogenesis.

Twenty-four subjects (12 patients with major depressive disorder and 12 controls matched for sex and age) received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an iv bolus dose. Healthy subjects exhibited a slight, but sustained, increase of plasma delta sleep-inducing peptide (DSIP) concentrations, whereas a marked reduction of DSIP levels was found in depressives. Compared to controls, depressed patients showed a significant attenuation of corticotropin (ACTH) responses, whereas cortisol secretion in response to hCRH was normal. Basal DSIP and cortisol concentrations were highly correlated and were higher in depressives than in controls. Both were negatively correlated with the DSIP responses to hCRH. These findings are compatible with the hypothesis that hypothalamic-pituitary-adrenal (HPA) overactivity in the depressive state is primarily due to central hypersecretion of CRH and support the view of a modulatory function of DSIP in the complex regulatory mechanism of the HPA system and of its pathophysiological significance for aberrant HPA axis function in major depressive disorder.

beta-Endorphin, leucine enkephalin and methionine enkephalin, were measured in 41 samples of human lumbar cerebrospinal fluid (CSF) of patients with different neurological diseases. beta-Endorphin-like immunoreactivity (beta-ELI) was present in concentrations between 10 and 150 fmol/ml CSF, and in 30 of the 41 samples studied the levels ranged from 10 to 40 fmol/ml. Methionine enkephalin-like immunoreactivity (MELI) measured 1-85 pmol/ml CSF, with 24 of the 41 samples having values between 3 and 4 pmol/ml. CSF concentrations of leucine enkephalin-like immunoreactivity (LELI) ranged from 0.1 to 12.5 pmol/ml, and in 31 of the 41 CSF samples studied LELI was present in concentrations of 0.1-0.25 pmol/ml. No significant relationship exists between the concentrations of beta-endorphin in CSF and sex and age of patients, CSF protein, CSF IgG and CSF leukocytes. No interrelationship could be found between beta-ELI, MELI and LELI concentrations.

Twenty subjects (10 patients with major depressive disorder and 10 controls matched for age, gender, and ovarian status) received 1 microgram/kg synthetic human growth hormone-releasing hormone (GHRH)-44 amide as an i.v. bolus dose. Compared to controls, depressed patients showed a significant attenuation of net growth hormone (GH) responses to GHRH associated with normal basal GH concentrations. The blunted GH responses occurred in the face of significantly higher somatomedin C (Sm-C) concentrations. Comparison of GH responses after GHRH with GH output following the alpha 2-agonist clonidine (CLON) revealed a significant positive correlation. The concordance between GH responses after specific challenges at different levels of the GHRH-GH-somatomedin axis indicates the integrity of the hypothalamic-pituitary-somatotropic system in depression and supports the view that altered GH secretory patterns in depression may primarily be due to a suprapituitary disturbance.

Oestrogen receptor (ER) analysis was performed in 70 meningiomas with an enzyme immunoassay, using monoclonal antibodies against human oestrogen receptor protein (oestrophilin) and with a sensitive radioligand binding assay, using 125I-oestradiol as radioligand. Low levels of ER immunoreactivity were found in tumours from 51% of patients, whereas ER binding activity was demonstrated in 40% of the meningiomas examined. In 8 (11%) tissue samples multiple binding sites for oestradiol were observed. The immunoreactive binding sites corresponded to the classical, high-affinity ER. In ligand binding studies, however, measurement of classical ER was considerably influenced by a second low-affinity, high-capacity oestrogen binding component even at low ligand concentrations. 3H-methylpromegestone and 3H-methyltrienolone, a synthetic gestagen and androgen, were used for concurrent determination of the progesterone receptor (PR) and androgen receptor (AR) binding activity. High concentrations of PR were detected in 53 (76%), whereas moderate levels of AR binding sites were demonstrated in 33 (47%) tumours. A positive correlation between ER immunoreactivity and AR binding activity is indicative for an oestrogen regulation of AR via the ER system. The presence of gonadal steroid receptors in a large proportion of meningiomas and the tendency for a dependence of receptor concentrations on the histological subtype could have implications for tumour therapy.

Estrogen receptor (ER) analysis was performed in 70 meningioma samples by means of two assays: an enzyme immunoassay that used monoclonal antibodies against human ER protein (estrophilin), and a sensitive radioligand binding assay that used iodine-125-labeled estradiol as the radioligand. Low levels of ER immunoreactivity were found in tumors from 51% of patients, whereas ER binding activity was demonstrated in 40% of the meningiomas examined. In eight (11%) of the tissue samples, multiple binding sites for estradiol were observed. The immunoreactive binding sites corresponded to those of the classic high-affinity ER. In ligand binding studies, however, measurement of classic ER was considerably influenced by a second low-affinity high-capacity estrogen binding component, even at low ligand concentrations. Binding activity of the progesterone receptor (PR) and androgen receptor (AR) was determined concurrently using 17 alpha-methyl-3H-promegestone (3H-R 5020) and 17 alpha-methyl-3H-trienolone (3H-R 1881), a synthetic gestagen and androgen, respectively. High concentrations of PR were detected in 53 (76%) of the tumors, whereas a moderate number of AR binding sites were demonstrated in 33 (47%) of the tumors. A positive correlation between ER immunoreactivity and AR binding activity is suggestive of estrogen regulation of AR via the ER system. The presence of gonadal steroid receptors in a large proportion of meningiomas and the tendency toward a dependence of receptor concentrations on the histological subtype of the meningioma could have implications for tumor therapy.

To explore the role of the somatomedin-mediated long-loop negative feed-back mechanism in altered growth hormone (GH) secretory dynamics associated with depression, plasma IGF-I concentrations were measured in 34 patients with a major depressive episode and matched healthy subjects. Compared with controls, depressed patients exhibited significantly increased plasma IGF-I concentrations. In the patient group plasma IGF-I concentrations were positively correlated with the maximum post-dexamethasone plasma cortisol concentrations. Our data suggest that increased plasma IGF-I concentration may reflect diurnal GH hypersecretion, contribute to deficient GH responses to dynamic challenges, and indicate an interrelationship between the hypothalamic-pituitary-somatotropic (HPS) and -adrenocortical (HPA) system regulation in depression.

Analyses of gonadal steroid hormone receptor were performed using a monoclonal enzyme immunoassay for human estrogen receptor protein (estrophilin) for the first time and a conventional radioligand binding technique for progesterone and androgen receptors in 70 meningiomas. Low levels of estrogen receptor immunoreactivity (3.7 +/- 0.5 fmol/mg protein) were detected in 37 (53%) tumors, whereas moderate concentrations of androgen receptor binding activity (31.7 +/- 5.3 fmol/mg protein) and high concentrations of progesterone receptor binding activity (189 +/- 29.2 fmol/g protein) were demonstrated in 33 (47%) and 53 (76%) tumors, respectively. The estrophilin immunoreactivity was positively correlated with the androgen receptor binding activity (r = 0.634; p less than 0.001) but no relationship with the progesterone receptor binding activity was found. The presence of gonadal steroid receptors in a large proportion of meningiomas could have implications for diagnosis and tumor therapy.

Synthetic human corticotropin-releasing hormone (hCRH) was administered as an intravenous bolus (100 micrograms) to 13 patients suffering from endogenous depression and to 12 healthy volunteers. Compared with controls, depressed patients showed a significant amelioration of mood and well-being 2 h after hCRH administration in the rating scales applied ('Befindlichkeits-Skala', 'Eigenschaftswörterliste', 'Kurzskala Stimmung-Aktivierung', Self-Rating Depression Scale, Hamilton Rating Scale for Depression). Based on our preliminary data, a psychotropic effect and at least a mediating function of hCRH regarding pathophysiology and etiopathogenesis of endogenous depressions must be assumed.

A double-blind study was conducted involving 45 "therapy-resistant" endogenous depressive inpatients who were treated with Doxepin intravenously or orally. After a period of 3 weeks there was no significant difference in the clinical ratings (HRSD, SDS). In the parenteral treatment group, however there was a statistically significant quicker onset of action (day 3). Compared to oral application higher Doxepin plasma concentrations during day 1 to 6 could be obtained by drip-infusion in spite of lower dosage.