Presence of growth hormone-releasing factor-like immunoreactivity in human cerebrospinal fluid.

Immunoreactive human growth hormone-releasing factor (I-hGRF) in human cerebrospinal fluid (CSF) was measured by radioimmunoassay using antiserum specific to the C-terminal portion of hGRF(1-44)NH2. Dilution curves of I-hGRF in the CSF were completely parallel to that of synthetic hGRF(1-44)NH2 standard. On Sephadex G-50 column chromatography a single peak of I-hGRF in the CSF was eluted at the position of synthetic hGRF(1-44)NH2. I-hGRF was present in the CSF of all control patients without any endocrine disease (mean +/- SE, 29.3 +/- 2.0 pg/ml) whereas I-hGRF in the CSF was not detectable (less than 5.8 pg/ml) in any of the patients with hypothalamic germinoma. In all patients with idiopathic GH deficiency, I-hGRF in the CSF was measurable but its concentration (15.1 +/- 1.0 pg/ml) was significantly (p less than 0.05) lower than that in the control subjects. No difference in I-hGRF levels of the CSF was observed between patients with acromegaly and control subjects. These findings demonstrate for the first time that I-hGRF is present in human CSF. Measurement of I-hGRF in the CSF may be useful for understanding the pathophysiology of hypothalamo-pituitary diseases.

LH and FSH in human cerebrospinal fluid.

LH and FSH of cerebrospinal fluid (CSF) and serum were radioimmunologically measured. Samples were obtained simultaneously from 116 subjects of the following groups: A. 22 patients with non-endocrine diseases, B. 18 patients with cranial diabetes insipidus (DI) of whom 4 with metastatic carcinomas, C. 5 patients with primary empty sella syndrome, D. one with hydatiform mole, and E. 70 patients with pituitary adenomas, i.e. growth hormone--or prolactin-secreting or "non-secreting" adenomas, of whom 38 patients with invasive and 32 with enclosed adenomas. LH and FSH are normal constituents of CSF and their CSF levels poorly correlates with the serum ones (LH r = 0.477 p less than 0.01). Enclosed adenomas with SSE showed low levels of LH in CSF. High CSF-gonadotropins concentrations (above 4.0 mIU/ml) with a low serum/CSF ratio (below 3) was frequently, but not constantly found in patients with invasive adenomas and are not indicative per se of this diagnosis. Some patients with brain metastasis from breast carcinoma and DI, or with non-tumoral diseases and DI showed similar high patterns of CSF gonadotropins though the serum levels were within normal range. This suggests that local vascular mechanisms, including the retrograde circulation of gonadotropins from the pituitary to the hypothalamus, influence the blood-brain barrier much more than the release of gonadotropins into the systemic blood circulation.

Somatomedin levels in cerebrospinal fluid from adults with pituitary disorders.

Somatomedin levels in cerebrospinal fluid (CSF) were determined in patients with acromegaly, pituitary deficiency, prolactinoma, and Cushing's disease by radioimmunoassay (RIA) for insulin-like growth factor 1 (IGF-1) and for IGF-2 as well as a radioreceptor assay (RRA) with adult human brain plasma membranes and IGF-2 as ligand. The mean value of RIA-IGF-2 (31 +/- 1.6 ng/ml) predominated over that of RIA-IGF-1 (5.8 +/- 0.3 ng/ml), but 10 times higher levels were found by RRA-IGF-2. Patients with acromegaly were not found to have higher values than those with GH deficiency even after corrections were made for possible leakage across the blood-CSF barrier. No correlations were found between CSF somatomedin levels determined by different techniques and immunoreactive IGF-1 or GH in the peripheral circulation except for a positive correlation between CSF RIA-IGF-2 and serum IGF-1 in patients with acromegaly. These findings suggest that somatomedins in CSF consist primarily of IGF-2-like peptides which are derived from production within the central nervous system or pituitary gland rather than from transport across the blood-CSF barrier.

[Corticotropin-releasing factor concentrations in cerebrospinal fluid and its diurnal rhythm in patients with Cushing's disease].

Since Vale et al isolated and sequenced a 41 amino acid peptide with corticotropin-releasing factor (CRF) activity from ovine hypothalami, intensive works have been done about its physiological activity and intracerebral distribution. However, little has been done yet about CRF metabolism in human cerebrospinal fluid (CSF). Using a specific ovine CRF radioimmunoassay (RIA), we measured the levels of CRF in CSF from 16 patients with Cushing's disease (group I), 8 patients with Acromegaly (group II), 5 patients with Prolactinoma (group III) and 10 patients without endocrine abnormalities (group IV). Moreover diurnal changes of CRF in CSF from 2 patients with Acromegaly and 2 patients with Cushing's disease were examined. Dilution curves of CRF in CSF were parallel to that of synthetic ovine CRF standard. The intraassay coefficient of variation was 9.2% and the interassay coefficient of variation 12.6%. The concentrations of CRF in CSF of groups I, II, III and IV were 38.83 +/- 9.02 pg/ml (mean +/- SD), 44.24 +/- 4.71, 47.62 +/- 8.05 and 49.45 +/- 12.86, respectively. Group I was significantly lower than group IV (p less than 0.05). On the other hand, group II or III was not significantly different from group IV. A diurnal rhythm of CRF in CSF was observed in 2 patients with Acromegaly. However, there was almost no change in the 2 patients with Cushing's disease. In considering rich amount of CRF in hypothalamus and CRF-positive fibers surrounding the third ventricle, CRF content in CSF seems to reflect mainly its metabolic activity in hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary hormone concentrations in cerebrospinal fluid in patients with prolactin and growth hormone-secreting tumors.

GH, PRL, LH, FSH and TSH were measured in serum and in cerebrospinal fluid (CSF) in 16 patients with chromophobe adenomas, in 8 with acromegaly and in 18 subjects with neurological diseases without endocrine troubles. Elevated mean GH and PRL levels in serum and in CSF were found in patients with chromophobe adenomas and with acromegaly. No constant correlation was observed between serum and CSF values. The highest hormonal levels in CSF were usually observed in adenomas with suprasellar extension, but this finding was inconstant. The determination of hormonal levels in CSF does not seem to supply any reliable information about the characteristics of pituitary tumors.

Polyamine levels in CSF from patients with pituitary tumors or nonneoplastic pituitary disease.

Cerebrospinal fluid polyamine determinations were performed in 21 patients harboring pituitary tumors and six patients with nonneoplastic pituitary disease. Although CSF putrescine levels were significantly elevated in some patients harboring tumors, other patients showed no elevation. Polyamine levels did not correlate with tumor size, as assessed by the presence or absence of suprasellar extension. Data on patients harboring nonneoplastic pituitary disease were variable. Compared with other findings from this laboratory on the use of polyamine levels for the diagnosis and management of other brain tumors, these findings suggest that CSF polyamine levels will not have a significant diagnostic role in the treatment of patients suspected to have pituitary disease.

Immunoreactive beta-endorphin and adrenocorticotropin in human cerebrospinal fluid.

To elucidate the significance of beta-endorphin in human cerebrospinal fluid (CSF), CSF levels of beta-endorphin-like immunoreactivity (beta-EP-LI) in various diseases were determined by a specific radioimmunoassay and compared with simultaneously determined ACTH-like immunoreactivity (ACTH-LI) levels in CSF. CSF beta-EP-LI and ACTH-LI in the control group, consisting of 5 normal subjects and 19 patients with nonendocrine diseases, were 22.2+/-1.3 and 14.6+/-0.4 fmol/ml, respectively. CSF levels of these peptides in patients with schizophrenia (n = 19) and acromegaly (n = 10) were not significantly different from those in the control group. Patients with Cushing's disease (n = 7) had significantly lower CSF beta-EP-LI and ACTH-LI levels than those in the control group. Four of them showed a parallel increase in CSF beta-EP-LI and CSF ACTH-LI levels after the complete removal of pituitary microadenomas (P < 0.05). Gel chromatography of CSF beta-EP-LI from a normal volunteer, a control patient, and one patient each with catatonia, Nelson's syndrome, Cushing's syndrome (adrenal adenoma), and acromegaly gave similar patterns consisting of three peaks with the elution positions comparable to those of authentic beta-endorphin, beta-lipotropin, and possibly their precursor molecule. Gel chromatographic patterns of CSF beta-EP-LI and ACTH-LI were compared in a normal volunteer. The first peaks of beta-EP-LI and ACTH-LI eluted at the same position and the second peak of ACTH-LI coincided with the elution position of authentic ACTH.CSF beta-EP-LI and ACTH-LI levels determined every 5 min over a period of 80 min in three normal volunteers did not show moment-to-moment variability.A significant correlation (r = 0.75, P < 0.001) was seen between CSF beta-EP-LI and ACTH-LI levels in normal subjects and patients studied (n = 73). This suggests that beta-endorphin and ACTH in human CSF share the common regulatory mechanism in normal and pathologic conditions.

CSF and plasma somatostatin levels in acromegaly.

Cerebrospinal fluid (CSF) and plasma levels of somatostatin have been measured in patients with active acromegaly and the results compared to those obtained in patients with non-endocrine diseases. Plasma levels have also been studied in acromegalics given oral glucose. The mean CSF somatostatin level in twenty patients without endocrine disease was 76 pg/ml (range 46-112) which did not differ significantly from that found in eight acromegalics (mean 87 pg/ml, range 48-160). Plasma somatostatin in twenty-two acromegalic patients on no medical treatment was 43 pg/ml (range 9-113), not significantly different from values in a normal control population. There were no differences in the somatostatin levels of non-diabetic acromegalics. After oral glucose, there was a rise in circulating somatostatin in eleven out of twelve acromegalic patients, and this rise did not differ from that seen in normal subjects. It is probable that altered somatostatin secretion is neither the cause nor the result of acromegaly; however it is possible that local changes in somatostatin concentration which are not reflected in peripheral plasma or CSF levels may occur near the site of its production.

High level of human growth hormone (HGH) in cerebrospinal fluid patients with pituitary tumors.

Six patients with suprasellar extension of pituitary HGH-secreting tumors showed the cerebrospinal fluid (CSF) content in human growth hormone (HGH) to be very high, i.e. 164.3 +/- muU/ml (mean +/- SEM) (range 8.4--413.8 muU/ml) as compared to ten patients with uncomplicated acromegaly whose values were 50-fold lower, i.e. 3.4 +/- 0.5 muU/ml (range 0.6--7.0 muU/ml), and nine patients with suprasellar extension of other pituitary tumors, showing also low levels of HGH in the CSF, i.e. 2.9 +/- 0.8 muU/ml (range 0.6--7.2 muU/ml). A control group of 29 normal patients without pituitary or brain diseases showed extremely low values of HGH in the CSF (1.9 +/- 0.2 muU/ml), one third being below the sensitivity limit of the assay method. Another control group of 70 patients with hypothalamic diabetes insipidus (n = 18), brain traumatisms (n = 10), brain surgery (n = 20), as well as various brain diseases (n = 22), also showed low HGH levels in the CSF, like the normal control group. It is shown that a high level of HGH in the CSF has a potential usefulness in the diagnosis of suprasellar extension of the pituitary mass in acromegaly.

Distribution of growth hormone and thyroid-stimulating hormone in cerebrospinal fluid and pathological compartments of the central nervous system.

Human growth hormone (HGH) radio-immunoassay (RIA) was adapted for an accurate measurement of immunoreactive HGH concentrations in the CSF in different cases of hypothalamic-somatotropin dysfunctions. In control subjects (n = 43) mean HGH levels were 0.35 +/- 0.03 ng/ml in CSF and 1.95 +/- 0.2 ng/ml in plasma with a CSF/plasma ratio of 17%. The thyroid-stimulating hormone (TSH) RIA gave in controls mean basal levels of 2.65 +/- 0.2 muU/ml in CSF and 5.95 +/- 0.3 muU/ml in plasma with a CSF/plasma ratio of 44%. HGH and TSH concentrations in CSF and plasma show a very good correlation; but the regression curves for both hormones are distinctly different and appear specific for each polypeptide hormone. Hypothalamic-somatotropin hyperreactivity was reported in diabetic retinopathy (DR). CSF and plasma HGH concentrations in a group of diabetic patients with progressing retinopathy (n = 27) were not different from those in normal subjects (respectively 0.35 +/- 0.05 in CSF and 2.10 +/- 0.25 ng/ml in plasma with a CSF/plasma ratio of 16%). The HGH regression curve obtained in diabetics is similar to that of controls. These data do not substantiate the hypothesis of an HGH hyperreactivity in diabetic retinopathy. In somatotropin hypersecretion (acromegaly) without adenoma suprasellar extension, higher HGH concentrations recorded in CSF than in plasma cannot be attributed to an anatomical break-down of the CSF blood-brain barrier and suggest an active transport process of pituitary hormones to the CNS. HGH and TSH concentrations were measured in the cystic fluid of CNS tumors. In 1 case of a cystic dysembryoma, the HGH and TSH of CF were considerably increased. In gliomas (n = 8) the HGH and TSH cystic fluid concentrations were more elevated (respectively 0.72 +/- 0.2 ng/ml and 3.6 +/- 0.7 muU/ml) than in the CSF of controls.

Cerebrospinal fluid prolactin: a reflection of abnormal prolactin secretion in patients with pituitary tumors.

Cerebrospinal fluid prolactin levels were determined in 33 patients with pituitary disease, 3 pregnant women at term and 30 control subjects. Prolactin which was immunologically similar to the human prolactin standard was detected by radioimmunoassay in the CSF of most of these subjects. Elevated serum and CSF PRL concentrations were found in three pregnant subjects and in twelve patients with putuitary tumors. Ten patients with pituitary tumors had serum PRL concentrations greater than their corresponding CSF PRL levels. A significant correlation was noted between the elevated serum and CSF prolactin levels in the twelve hyperprolactinemic patients which suggested that the CSF prolactin concentration was influenced by the serum PRL level. Two patients with pituitary tumor however, had CSF prolactin concentrations higher than their serum levels, which suggested that direct secretion of prolactin from the tumor to the CSF can also occur. Three patients with chromophobe adenomas had normal serum PRL concentrations and elevated CSF prolactin levels which differentiated them from fifteen patients with the primary empty sella syndrome who had normal serum and CSF prolactin levels. The finding of normal CSF prolactin levels in the primary empty sella patients argues against the postulate that the diaphragma sellae significantly influences CSF pituitary peptide concentrations.

Suprasellar extension of tumor associated with increased cerebrospinal fluid activity of growth hormone.

The diagnosis of hormonally active acromegaly has been aided by the radioimmunoassay for human growth hormone (hGH). We report a case in which baseline plasma hGH levels were elevated minimally and partial suppression during the glucose tolerance test occurred. Subsequent hGH assay of the cerebrospinal fluid, however, confirmed active acromegaly and correctly predicted suprasellar extension of the tumor.

Somatomedin activity in cerebrospinal fluid.

Somatomedin activity has been demonstrated in the cerebrospinal fluid (CSF) of 12 normal subjects and one patient with acromegaly. In all cases the concentration was lower in the CSF than in the corresponding serum, and a significant correlation was demonstrated between the somatomedin activity in the two body fluids (p smaller than 0.01).

Radioimmunoassay of human growth hormone: technique and application to plasma, cerebrospinal fluid, and pituitary extracts.

A radioimmunoassay for human growth hormone using activated charcoal is described and its precision, accuracy, and sensitivity are defined. Results are presented for growth hormone measurements in plasma obtained during hypoglycaemia induced with insulin in patients of short stature and during glucose tolerance tests in patients with acromegaly. The method was used to measure growth hormone concentrations in cerebrospinal fluid and in extracts of pituitary tumours. No growth hormone was detected in the cerebrospinal fluid of patients without acromegaly. In patients with acromegaly, the concentration of growth hormone in cerebrospinal fluid was measurable and was considerably elevated in one patient with extrasellar extension of a pituitary tumour. Extracts of chromophobe pituitary tumours contained very small concentrations of growth hormone. In extracts of pituitary tumours removed from acromegalic patients, concentrations fell either below or within the normal range.