Abstract. In this study we have identified and characterized several vasopressin-like peptides in the plasma of a patient with the syndrome of inappropriate antidiuretic hormone secretion and oat cell carcinoma of the lung. Immunoreactive plasma vasopressin was measured after gel filtration (Sephadex G-25) or C-18 cartridge extraction using two different region-specific antisera: AS1 and AS2. Antiserum AS1 is more specifically directed towards the antigenic site of the hexapeptidic ring of arginine-vasopressin (AVP), whereas AS2 is more specifically directed towards the C-terminal region of AVP. Unexpectedly, the Sephadex G-25 gel filtration elution profile of the immunoreactive vasopressin was very heterogeneous, indicating the presence of several molecular species. After extraction of total AVP and AVP-like peptides of this plasma, an unusual AS1/AS2 ratio of immunoreactivity was observed, suggesting the presence of vasopressin-like peptides which differ from AVP in the C-terminus.
Simon Smitz, Jean-Jacques Legros, Paul Franchimont and Marc le Maire
Dario Giugliano, Domenico Cozzolino, Roberto Torella, Pierre J Lefebvre, Paul Franchimont and Felice D'Onofrio
The responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human β-endorphin (0.5 mg/h) were studied in 10 formerly obese subjects who had lost 35 kg by dieting (body mass index <25) and compared with those of 10 normal-weight control (body mass index <25) and 10 obese (body mass index >30) subjects. The fasting plasma concentrations of β-endorphin were significantly higher in both the obese and the post-obese group than in the control group. In both obese and post-obese subjects, the infusion of β-endorphin caused significant increases in peripheral plasma glucose, insulin, C-peptide and glucagon concentrations. In the control group, matched for age, sex and weight with the formerly obese group, there was no appreciable change in plasma insulin and C-peptide concentrations during the infusion of β-endorphin, but the rise in plasma glucose was more sustained. Thus, 1. the increased plasma β-endorphin concentrations found in human obesity are not corrected by normalization of body weight; and 2. formerly obese, normal-weight subjects behave as obese subjects in their metabolic and hormonal responses to β-endorphin infusion. The alteration of the opioid system in human obesity may play some role in the predisposition to weight gain.
Paul Franchimont, Didier Urbain-Choffray, Pierre Lambelin, Marie-Anne Fontaine, Gerard Frangin and Jean-Yves Reginster
Abstract. This study sought to determine whether GH response to synthetic GHRH was impaired in 13 postmenopausal (55-71 years) as compared with that in 8 eugonadal women and whether IGF-I and bone metabolism were consequently depressed. Thereafter, the effects of daily iv injections of 80 μg GHRH-44 for 8 days were studied in the same postmenopausal group. In addition to significantly higher basal IGF-I and osteocalcin levels (P< 0.005) in eugonadal as compared with the postmenopausal women, the administration of one GHRH-44 injection resulted in significantly higher 120-min postinjection GH maximum peak and cumulative responses in the former group as well (P< 0.005). Highly significant correlations were observed between 17β-estradiol plasma levels and either GH maximum peak or cumulative responses to GHRH-44 when both groups were pooled together, but not when considered independently. In postmenopausal women, a correlation was found between both age and duration of menopause and GH responses. Repeated GHRH-44 injections in postmenopausal women induced a significant increase in GH response (P< 0.001) as well as in IGF-I levels from day 4 to 8. No phospho-calcium parameters were modified except for a significant rise in osteocalcin from day 2 to 8. These data indicate an age-related loss of sensitivity of somatotrope cells to GHRH-44 in postmenopausal women, partly corrected by repeated daily GHRH-44 injections. As a consequence of the GHRH-induced increase in GH secretion, IGF-I was also enhanced and may be responsible for a stimulatory effect on bone formation, as shown by the osteocalcin increase, uncoupled from bone resorption.
Paul Franchimont, Sabine M. Almer, Chantal-J. Charlet-Renard, Christine L. Daubresse and Peter P. Kicovic
The effect of a new GnRH antagonist (ORG 30850 ANT) on FSH, LH, and PRL secretion was studied using male rat pituitary cells in monolayer cell culture. In the absence of GnRH, ORG 30850 ANT did not alter spontaneous FSH and LH secretion into culture medium or the cell content of these hormones. In the presence of GnRH (10−8 mol/l), ORG 30850 ANT significantly and dose-dependently inhibited FSH and LH secretion into culture medium while increasing their cell content. Conversely, in the presence of a single dose of ORG 30850 ANT, FSH and LH secretion rose significantly when subjected to increasing amounts of GnRH, whereas the hormonal cell content diminished. Furthermore, inhibition of GnRH-induced FSH and LH release by ORG 30850 ANT was not changed by pre-incubation with the GnRH antagonist regardless of the pre-incubation time. The inhibitory effect of the GnRH antagonist was observed early, with its peak occurring within 6 h of culture. These short-term studies indicate that ORG 30850 ANT specifically inhibits GnRH-induced gonadotropin release into culture medium, exerts no effect on the rate of gonadotropin production in the presence or absence of GnRH, competitively and reversibly inhibits the binding of natural GnRH to its receptors, and does not lead to any modifications in PRL secretion.
Giuseppe Paolisso, Dario Giugliano, André J. Scheen, Paul Franchimont, Felice D'Onofrio and Pierre J. Lefèbvre
Abstract. The present study aimed at evaluating the effect of human β-endorphin on pancreatic hormone levels and on glucose metabolism in normal subjects. Infusion of 143 nmol/h β-endorphin in 7 subjects caused a significant rise in plasma glucose concentrations (+ 1.7 ± 0.3 mmol/l) which was preceded by a significant increase in peripheral plasma glucagon levels (+ 44 ± 13 ng/1). No changes occurred in the plasma concentrations of insulin and catecholamines (adrenaline and noradrenaline). The influence of β-endorphin per se on glucose homeostasis was studied in 7 other subjects using the euglycaemic clamp technique in which the endocrine pancreatic function was fixed at its basal level with somatostatin together with replacement of basal insulin and glucagon by the exogenous infusion of these hormones. In this new metabolic conditions, β-endorphin failed to have significant influences on the various parameters of tracer-estimated glucose metabolism (production, utilization, and clearance) and on the plasma levels of the gluconeogenic precursors (glycerol and alanine). Moreover, the levels of pancreatic and counterregulatory hormones (cortisol and catecholamines) were not different between β-endorphin and control studies. We conclude that the naturally occurring opioid peptide β-endorphin produced an hyperglycaemic effect in man which appears to be mediated by glucagon. The opioid seems to have no direct effect on glucose metabolism. These results suggest that the metabolic effects of β-endorphin in normal man are secondary to its impact on pancreatic hormone secretion and not a consequence of a direct modulation of glucose metabolism.
H David McIntyre, Daniel J Maréchal, Ginette P Déby, Anne G Mathieu, M-T Hézée-Hagelstein and Paul P Franchimont
Immunoreactive SRIH was detected in the rat ovary (15.6 pg/mg wet weight, 520 pg/mg protein) and was localized to the granulosa cells (168±6 pg/106 cells). Serial dilution studies showed parallelism of the inhibition curve for synthetic SRIH-14 and those of extracts of whole ovary and media conditioned by granulosa cells. The quantity of immunoreactive SRIH released into granulosa cell conditioned media decreased with time, while the intracellular content remained relatively constant. Gel chromatography showed peaks of immunoreactivity co-eluting with SRIH-14 (38%), SRIH-28 (31%) and a high molecular weight component. The addition of synthetic SRIH-14 stimulated meiotic maturation in cumulus-enclosed rat oocytes, with dose dependency being observed at SRIH-14 concentrations between 1 and 1000 pmol/l. No evidence of pre-pro-SRIH gene expression could be demonstrated in either rat ovary or testis using both Northern analysis and reverse transcriptase/polymerase chain reaction amplification of polyadenylated RNA. SRIH may be produced in the ovary during a specific stage of ontogeny or by an alternative gene. It is also possible that SRIH is actively taken up and stored by granulosa cells without being produced locally.