Rapid antidepressant activity of destyr gamma endorphin: correlation with urinary melatonin.
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Biomedical subjects
Publications and source records attributed to B Claustrat.
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In this study the daily variations of plasma sex hormone-binding globulin (SHBG) binding capacity were measured together with plasma testosterone and luteinizing hormone (LH) concentrations in 7 healthy rested adult males. Plasma SHBG-binding capacity demonstrated a significant circadian rhythm (acrophase = 2.06 p.m.; mesor = 0.35 +/- 0.6 ng testosterone bound/100 ml; amplitude = 17% of the mesor). Plasma testosterone also showed a circadian rhythm (acrophase = 7.02 a.m.; mesor = 4.38 +/- 0.67 ng/ml; amplitude = 18% of the mesor). The free testosterone index (or the ratio between plasma testosterone and SHBG-binding capacity) was not correlated with plasma LH levels. In our hands this last parameter did not vary according to a circadian pattern. These data are discussed in terms of a feedback mechanism controlling the pituitary-testis axis regulation.
Four normal subjects and 54 growth hormone (GH)-deficient patients including 43 children with growth failure were given an intravenous bolus of growth hormone-releasing factor (GHRF). Plasma prolactin (Prl) and GH after GHRF were studied. Basal plasma Prl was either normal or elevated and could not predict the GH response to GHRF. A correlation was found, within the group with basal hyperprolactinemia, between basal Prl and the net Prl increase after GHRF. No correlation was found between the net GH and the net Prl increase after GHRF. Plasma Prl was significantly, although weakly, increased after GHRF in the normal subjects.
The plasma levels of proteins bound to steroids come under the influence of the levels of estrogens. This is why we have studied the changes in plasma SHBG in sterile women who were being treated by gonadotropins (HMG-HCG). The plasma level of SHBG was worked out using Laurell's electroimmunoassay technique with an autoradiographic display using estradiol labeled with I.125. It only takes 48 hours contact with radio films. Out of 12 patients 9 responded to the treatment as demonstrated by the plasma levels of estradiol (E2) and progesterone (P). We have found that in these women there was a rise in plasma SHBG which was significant from the 7th day of the treatment onwards (3.7 +/- 1.7 mg/l as against 5.9 +/- 2.6 mg/l, p less than 0.01) and this reached nearly twice the base level when E2 reached its maximum level (6.4 +/- 2.7 mg/l). When treatment was stopped the plasma level of SHBG dropped to that of the follicular phase, but it was out of step with the plasma E2 levels. The index of free E2 as compared with E2/TEBG showed a close superimposition when compared with the levels of E2 obtained using a radioimmunological method. This fact reinforces the value of plasma E2 as the way of monitoring the effect of induction of ovulation. Our overall conclusion is that a marked and rapid change in the level of plasma E2 directly influences the level of plasma SHBG. The consequences for treatment are that it is important to respect as far as possible the physiological conditions that are present when induction of ovulation is undertaken.
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This report describes the histologic, immunocytochemical, and ultrastructural study of a multihormonal carcinoid tumor of the pancreas, secreting a growth hormone releasing factor (GRF) which provoked acromegaly. The patient presented a nonfamilial multiple endocrine neoplasia, type 1. The absence of radiologic signs of a pituitary adenoma in conjunction with elevated plasma levels of pancreatic polypeptide, glucagon, somatostatin, as well as growth hormone (GH), led to the discovery of the tumor. Its surgical excision produced a rapid disappearance of most of the clinical and biologic disorders. No immunoreactive GH was found in the tumor using radioimmunoassay and immunocytochemistry. In contrast, three peptides with GH-releasing activity were extracted and characterized. Immunocytochemistry showed that the GRF-reactive cells, together with rare somatostatin-storing cells, made up areas which demonstrated a medullary pattern of growth with extracellular amyloid deposits. Under electron microscopic examination, actively secreting cells were observed which carried endocrine granules of 100 to 150 nm in diameter. The other regions of the tumor presented a different type of growth and were composed of pancreatic polypeptide-, glucagon-, or somatostatin-reacting cells. Cells immunostained with antisera raised against beta-endorphin were also noted. These data suggest that GRF may be a new biologic marker for pancreatic endocrine tumors.
The dexamethasone suppression test (DST) was administered after baseline cortisol measurements in 20 patients (10 males, 10 females) who met DSM-III criteria for obsessive-compulsive disorder (OCD). Six patients (30%) showed an abnormal escape from dexamethasone suppression. DST suppressors vs. DST nonsuppressors showed no differences on age, rate of secondary depressive disorders, or scores on the Hamilton Rating Scale for Depression, the Minnesota Multiphasic Personality Inventory D scale, or OCD rating scales. Surprisingly, there was a trend for suppressors to have a stronger family history of depressive disorders, and for nonsuppressors to include an excess of male subjects. Moreover, there was a significant correlation between levels of cortisol before and after DST. In five of six nonsuppressors, both depressive symptoms and obsessive-compulsive behaviors showed a diminution in response to antidepressant therapy combined, in one case, with intensive behavior therapy. The relationships between OCD and endogenous depression, as well as the specificity of the DST, are discussed.
The temporal organization of plasma melatonin, cortisol, growth hormone (GH) and prolactin secretion was examined in healthy rested controls and in patients suffering from episodic cluster headache. Eleven patients with typical cluster headache (10 men, 1 female) and 8 male controls were studied over a 24-h period: blood was collected at 2-h intervals during the day and at 1-h intervals at night. Plasma melatonin, cortisol, GH and prolactin levels were determined by radioimmunoassay. Most of the cluster headache patients showed a decrease in nocturnal melatonin secretion and the melatonin rhythm was even completely abolished in one patient. Chronobiological analysis of the cluster headache patients' 24-h plasma melatonin profile showed a significant decrease in amplitude and mesor: these were 58.7 pg/ml and 34.4 pg/ml respectively in control subjects, versus 18.7 pg/ml and 17.6 pg/ml for the patients. In addition, patients showed a significant phase-advance in their melatonin rhythm. For cortisol, the rhythm appeared slightly blunted in the cluster headache group and was significantly phase-advanced. The plasma prolactin profile showed no significant alteration, but for plasma GH the nocturnal peak was advanced in some patients; in the absence of sleep recording, however, no conclusion could be drawn. Results from this study suggest a neuroendocrine dysregulation in cluster headache in the endogenous clock which controls the pineal rhythmicity.
A beta-endorphin (beta END)-containing pituitary adenoma was demonstrated by immunocytochemical, biochemical, and ultrastructural methods in a 43-yr-old man who had impotence, slight testicular atrophy, and an enlarged sella turcica (grade II0), but no manifestations of Cushing's disease. Preoperative hormone data revealed hyperprolactinemia (97 ng/ml), low plasma cortisol levels without circadian rhythm, undetectable plasma ACTH, and normal plasma FSH and LH levels, with an impaired response to LRH. After hypophysectomy, these hormone levels normalized and responded normally to dynamic tests. Immunocytochemically, 30% of the tumor cells reacted only with beta END antiserum. beta END immunoreactivity was the only component revealed by RIA and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A characteristic ultrastructural aspect is also described. These findings demonstrate dissociation in the secretion of the proopiomelanocortin-derived peptides and suggest a relationship between hyperprolactinemia and tumor secretion of beta END.
Synthetic human pancreatic tumor GH-releasing hormone (hpGRH 1-44-NH2) was given by iv bolus injection to 10 normal men at doses of 75, 150, 300, and 600 micrograms. At all doses the plasma GH responses were similar in an individual subject. Among subjects, however, the responses were significantly different, with peak GH concentrations ranging between 9.0 micrograms/liter and 54.9 micrograms/liter. The GH released in response to GRH was bioactive in the Nb2 lymphoma cell multiplication assay. The circulating GH 30 and 60 min after GRH was detected in 3 molecular forms corresponding to little, big, and big-big GH. These forms averaged 50%, 30%, and 20% of the total immunoreactive GH, respectively. The mean rise of plasma somatomedin-C, from 1.86 U/ml to 2.21 U/ml 24 h after GRH, was not statistically significant. A small but statistically significant GRH dose-dependent rise in plasma PRL (mean PRL concentrations 10 min after 600 micrograms GRH, 11.13 micrograms/liter occurred consistently after GRH injection. The evidence that the GH released by GRH is bioactive supports the potential use of GRH for therapeutic applications.
The temporal organization of plasma melatonin and cortisol secretion was examined in healthy rested controls and in depressed patients: 11 patients suffering from a primary affective disorder (10 female, 1 male) and 8 male controls were studied over a 24-hr period; blood was collected at 2-hr intervals during the day at 1-hr intervals at night. Plasma melatonin and cortisol levels were determined by radioimmunoassay. In addition, melatonin was determined in plasma sampled at 3 AM in older male controls (n = 8) and in females (n = 10) at ovulation. The controls showed low or undetectable (less than 5 pg/ml) diurnal plasma melatonin levels and a very marked nocturnal rhythm (acrophase: 2.27 AM, mesor: 34.4 pg/ml, amplitude: 58.7 pg/ml). For the three control groups, no significant difference was observed in the nocturnal melatonin peak at 3 AM. The depressed patients also showed a significant melatonin rhythm but with lower amplitude (14.5 pg/ml) and mesor (19.1 pg/ml). The latter rhythm was not significantly phase-advanced with respect to the controls (acrophase at 1.18 and 2.34 AM, respectively). In 9 of the 11 patients, nocturnal melatonin secretion was less marked and frequently associated with hypercortisolemia. An additional episodic melatonin secretion was observed in the late afternoon in only two patients. In depressed patients, there was an increase in the mean cortisol secretion level (mesor at 13.6 micrograms/100 ml against 9.1 micrograms/100 ml in the controls), but the amplitude and the acrophase were not significantly modified. These data are discussed in terms of both the hypothalamus-pituitary-adrenal-epiphysis and aminergic abnormalities.
Among 30 agoraphobic subjects with panic attacks, 6 presented an abnormal dexamethasone suppression test. In non suppressor patients there was a statistical trend towards an excess of major depressive disorders, and of depression in first degree relatives. It suggests that agoraphobia with panic attacks might be a heterogeneous entity. Some agoraphobias with panic attacks might be more related to endogenous depression than to anxiety states.
A young man with hypogonadotropic hypogonadism treated with hCG had resistance to this therapy and was found to have antibodies to hCG. We subsequently sought, using a sensitive radioimmunological method, anti-hCG antibodies in plasma from eight other hCG-treated children shown to have isolated hypogonadotropic hypogonadism. Antibodies to hCG were found in four of the nine. These antibodies were associated with the immunoglobulin fraction of plasma. In one patient antibodies were detected for 5 yr after therapy was discontinued. The titer and affinity constants of these antibodies were notably influenced by the therapeutic regimen used: the titer was significantly decreased and the affinity constant was lowered after reinstitution of therapy with larger hCG doses. In one patient the presence of anti-hCG antibody was associated with the failure to respond to hCG therapy.
Somatocrinin (hp-GRF-44), a growth hormone releasing factor, stimulates acute pituitary response in a 11 years and 4 months old boy, with growth hormone deficiency. The capability of the anterior pituitary to secrete growth hormone in response to an IV injection of somatocrinin (120 micrograms 4 micrograms/kg) was documented, therefore proving the hypothalamic origin of the deficit which had been suspected because of association of diabetes insipidus and hyperprolactinemia.
In exceptional cases, acromegaly develops as the clinical expression of an ectopic secretion of Growth Hormone (GH) or Growth Hormone-Releasing Factor (GRF), tumorous in origin. In the present report, we describe an instance of acromegaly caused by the secretion of GRF from a voluminous pancreatic tumor. The resection of this tumor resulted in a temporary disappearance of the biological and clinical symptoms of acromegaly, which then reappeared in conjunction with a rise in plasma GRF. From this pancreatic tumor, substances displaying a potent GRF activity were isolated and characterized. Amino acid analyses revealed that they were related to 3 peptides containing respectively 44, 40 and 37 aminoacids. The largest (hp GRF (1-44)-NH2) referred as hp GRF or somatocrinin is considered to be the primary molecule. The pancreatic tumor was multisecreting as proved by high plasma levels of somatostatin, pancreatic polypeptide and glucagon, normalized after the tumor removal, taken together with the immunocytochemical demonstration of the presence of these peptides in the tissue and with the isolation of somatostatin. In contrast hypercalcemia associated with an elevated plasma level of IR-PTH was unmodified by tumor removal. Diagnosis of acromegaly as ectopic endocrine syndrome will probably be facilitated by plasma GRF radioimmunoassay, as a result of production of anti synthetic GRF antibodies.
Castrated Quails were perfused for 24 h with estradiol-17 beta (E2: 2 ng/mn) through either the jugular vein or the portal vein. The parameters compared included: plasma E2 levels, changes in oviduct weight, DNA and soluble protein content, estrophilin concentration in nuclear preparations of oviducts and progestophilin concentration in the cytosol of oviducts. The cumulative results suggest that: (1) E2 affects the proliferation of cells by an indirect pathway that involve a message generated in the liver. (2) The control of the synthesis of cell-type specific protein required the direct action of E2 at the level of the oviduct cells.
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Microdissected samples of juvenile cat brain tissue were assayed for melatonin content using a double antibody radioimmunoassay. Immunoreactive melatonin was consistently detected, albeit in variable amounts, in pineal, habenula, the region of the nucleus gracilis, gigantocellular reticular formation of the pons and medulla oblongata. Among the negative areas were raphe nuclei, substantia nigra and locus caeruleus. These findings suggest that melatonin may play a role in some structures of the central nervous system outside the pineal-hypothalamo-pituitary axis. This immunoreactive melatonin could reflect a local synthesis, or a tissular uptake of melatonin from blood or cerebrospinal fluid.