Chronic Stimulation of Basal Prolactin (PRL) Secretion by Growth Hormone Releasing Hormone (GHRH) in Children with GH Neurosecretory Dysfunction J.Fragoso1, R. Barrio , S. Donnay2 and M. Hernandez3 1Servicio de Pediatria, Hospital Ramon y Cajal, Madrid 2 Departamento de Endocrinologia, Hospital Virgen de la Luz, Cuenca 3 Departamento de Pediatria, Hospital del Nino Jesus y Universidad Autonoma, Madrid, Spain
There is some controversy regarding the GHRH-effect on prolactin (PRL) secretion. Whereas most studies show that the acute administration of GHRH to short children, children with GH deficiency, and healthy adult men does not affect the PRL secretion, some authors have suggested that, specially at high dosages, GHRH can stimulate PRL secretion in healthy volunteers (Goldman, Molitch, Thorner, Vale, Rivier and Reichlin 1987) and in patients with active acromegaly (Losa, Schopohl, Konig, Mutter and Von Werder 1986). Few studies have dealt with chronic influence of GHRH on PRL secretion. In the present study we evaluated the changes of PRL responses to GHRH during GHRH treatment in children with growth hormone neurosecretory dysfunction (GHND). Methods All children who took part in the study were found to be capable of adequate growth hormone secretion using ornithine. Participation was limited to those whose heights were 2.3 SD below the mean for age, with no evidence of pubertal development. Eleven children with GHND received treatment with GHRH (1-29)NH2 (Serono) which was administered daily, subcutaneously in doses of 5 ug/Kg for 6 months. They were examined during 1, 3 and 6 months of GHRH therapy. Each patient had evaluation of PRL secretion by provocative GHRH stimulation (1.5 ug/Kg i. v.). Blood samples were collected at 0,15,30,45,60,90 and 120 minutes. PRL levels were measured by specific double antibody radioimmunoassay (RIA) directly in the plasma samples. Results are expressed as mean ± SEM. Significance of differences between means was evaluated by Student's t-test.
Horm. metabol. Res. 22 (1990) 53-54 © GeorgThiemeVerlagStuttgart • New York
Results The basal PRL concentrations before and after one month of therapy did not differ significantly. After three months of GHRH therapy, an immediate rise in plasma PRL levels was seen, sustained without change up to six months of GHRH therapy (Fig. l)(p 0.001). Discussion Patients with endogenous GHRH hypersecretion usually also have elevated PRL levels (Sampaolo, Faloia, Sarzani, Bartolacci, Schiavo, Butini and Morosini 1987). In our studies, GHRH given to GHND children as a single bolus injectin resulted in no significant changes of PRL levels in all periods studied. These results are in agreement with those of Van Vliet, Bosson, Robyn, Craen, Malvaux, VanderschuerenLodeweyckx and Wolter (1985), which have shown that GHRH bolus injection does not alter PRL levels in children with short stature. Nevertheless, other authors have suggested that, specially at high dosages, GHRH can stimulate PRL secretion in healthy volunteers (Sassolas et al. 1984; Losa et al. 1985) and children with short stature (Chatelain, Sassolas, Catbeh, Bio-Laporte, Ferry, Claustrat, David and Francois 1985). However, GHRH therapy is able to increase plasma PRL levels after three months of therapy and sustain it for at least six months of treatment. The reason for the increase of plasma PRL content after three months of GHRH therapy remains unclear. Immunohistochemical studies have suggested that GH and PRL are secreted both by different cells and by the same cells (Bassetti, Spada, Arosio, Brina and Giannattasio 1986). It has been described the presence of specific GHRH cell receptors in human prolactinoma cell cultures. Hoefflerand Frawley (1987) have shown that chronic (6-day) treatment of rat pituitary cells cultures with GHRH induced differential changes in the proportions of GH- or PRL-secreting cells, increasing the proportion of PRL secretors and pro-
Received: 11 July 1989
Accepted: 15 Oct. 1989 after revision
Downloaded by: University of Illinois. Copyrighted material.
Introduction
Horm. metabol. Res. 22 (1990)
J. Fragoso, R. Barrio, S. DonnayandM.
Hernandez
during a commensurate decrease in the G H population. This could be due to changes in the lactotrope cells or modifications in G H R H receptors. Our results demonstrate that G H R H , that do not normally affect the acute release of PRL, can exert a chronic influence (directly or indirectly) on PRL plasma concentration. Studies aimed at addressing which mechanism was operative in the present investigation are currently underway in our laboratory. References Bassetti, M., A. Spada, M. Arosio, M. Brina, G. Giannattasio:i. Clin. Endocrinol. Metab. 62:1093-1100 (1986) Chatelain, P. G., G. Sassolas, N. Catbeh, S. Bio-Laporte, S. Ferry, B. Claustrat, M. David, R. Francois .Hormone Res. 22:46-51 (1985) Goldman, J. A., M. E. Molitch, M. 0. Thorner, W. Vale, J. Rivier, S. Reichlin:}. Endocrinol. Invest. 10:397-406 (1987) Hoeffler, J. P., L. S. Frawley: Endocrinology 120:791-795 (1987) Losa, M., J. Schopohl, O. A. Midler, K. von Werder: Acta Endocrinol. 109:467-473(1985) Sampaolo, G., E. Faloia, R. Sarzani, V. Bartolacci, P. Schiavo, L. Butini, P. Morosini: Recenti Prog. Med. 78:115-118 (1987) Sassolas, G„ P. Chatelain, R. Cohen, J. P. Boissel, S. Laporte, B. Galleyrand, B. Claustrat, A. Elm-Charfi, J. A. Chayvialle, H. Cohen, S. Ferry, E. Underwood:}. Clin. Endocrinol. Metab. 59: 705-709 (1984) Van Vliet, G., D. Bosson, C. Robyn, M. Craen, P. Malvaux, M. Vanderschueren-Lodeweyckx, R. Wolter:Horm.Res.22:32-45(1985)
Requests for reprints should be addressed to:
Fig. 1 Plasma prolactin (PRL) response to growth hormone releasing hormone (GHRH)-(1-29)-NH2 in children with GH neurosecretory dysfunction before (A) and after 1 (B), 3 (C) and 6 (D) months of GHRH therapy.
M. Hernandez Departamento de Pediatria Hospital del Nino Jesus Avda. Menendez Pelayo 65 28009 Madrid (Spain)
Downloaded by: University of Illinois. Copyrighted material.
54
There is some controversy regarding the GHRH-effect on prolactin (PRL) secretion. Whereas most studies show that the acute administration of GHRH to short children, children with GH deficiency, and healthy adult men does not affect the PRL secretion, some authors have suggested that, specially at high dosages, GHRH can stimulate PRL secretion in healthy volunteers (Goldman, Molitch, Thorner, Vale, Rivier and Reichlin 1987) and in patients with active acromegaly (Losa, Schopohl, Konig, Mutter and Von Werder 1986). Few studies have dealt with chronic influence of GHRH on PRL secretion. In the present study we evaluated the changes of PRL responses to GHRH during GHRH treatment in children with growth hormone neurosecretory dysfunction (GHND). Methods All children who took part in the study were found to be capable of adequate growth hormone secretion using ornithine. Participation was limited to those whose heights were 2.3 SD below the mean for age, with no evidence of pubertal development. Eleven children with GHND received treatment with GHRH (1-29)NH2 (Serono) which was administered daily, subcutaneously in doses of 5 ug/Kg for 6 months. They were examined during 1, 3 and 6 months of GHRH therapy. Each patient had evaluation of PRL secretion by provocative GHRH stimulation (1.5 ug/Kg i. v.). Blood samples were collected at 0,15,30,45,60,90 and 120 minutes. PRL levels were measured by specific double antibody radioimmunoassay (RIA) directly in the plasma samples. Results are expressed as mean ± SEM. Significance of differences between means was evaluated by Student's t-test.
Horm. metabol. Res. 22 (1990) 53-54 © GeorgThiemeVerlagStuttgart • New York
Results The basal PRL concentrations before and after one month of therapy did not differ significantly. After three months of GHRH therapy, an immediate rise in plasma PRL levels was seen, sustained without change up to six months of GHRH therapy (Fig. l)(p 0.001). Discussion Patients with endogenous GHRH hypersecretion usually also have elevated PRL levels (Sampaolo, Faloia, Sarzani, Bartolacci, Schiavo, Butini and Morosini 1987). In our studies, GHRH given to GHND children as a single bolus injectin resulted in no significant changes of PRL levels in all periods studied. These results are in agreement with those of Van Vliet, Bosson, Robyn, Craen, Malvaux, VanderschuerenLodeweyckx and Wolter (1985), which have shown that GHRH bolus injection does not alter PRL levels in children with short stature. Nevertheless, other authors have suggested that, specially at high dosages, GHRH can stimulate PRL secretion in healthy volunteers (Sassolas et al. 1984; Losa et al. 1985) and children with short stature (Chatelain, Sassolas, Catbeh, Bio-Laporte, Ferry, Claustrat, David and Francois 1985). However, GHRH therapy is able to increase plasma PRL levels after three months of therapy and sustain it for at least six months of treatment. The reason for the increase of plasma PRL content after three months of GHRH therapy remains unclear. Immunohistochemical studies have suggested that GH and PRL are secreted both by different cells and by the same cells (Bassetti, Spada, Arosio, Brina and Giannattasio 1986). It has been described the presence of specific GHRH cell receptors in human prolactinoma cell cultures. Hoefflerand Frawley (1987) have shown that chronic (6-day) treatment of rat pituitary cells cultures with GHRH induced differential changes in the proportions of GH- or PRL-secreting cells, increasing the proportion of PRL secretors and pro-
Received: 11 July 1989
Accepted: 15 Oct. 1989 after revision
Downloaded by: University of Illinois. Copyrighted material.
Introduction
Horm. metabol. Res. 22 (1990)
J. Fragoso, R. Barrio, S. DonnayandM.
Hernandez
during a commensurate decrease in the G H population. This could be due to changes in the lactotrope cells or modifications in G H R H receptors. Our results demonstrate that G H R H , that do not normally affect the acute release of PRL, can exert a chronic influence (directly or indirectly) on PRL plasma concentration. Studies aimed at addressing which mechanism was operative in the present investigation are currently underway in our laboratory. References Bassetti, M., A. Spada, M. Arosio, M. Brina, G. Giannattasio:i. Clin. Endocrinol. Metab. 62:1093-1100 (1986) Chatelain, P. G., G. Sassolas, N. Catbeh, S. Bio-Laporte, S. Ferry, B. Claustrat, M. David, R. Francois .Hormone Res. 22:46-51 (1985) Goldman, J. A., M. E. Molitch, M. 0. Thorner, W. Vale, J. Rivier, S. Reichlin:}. Endocrinol. Invest. 10:397-406 (1987) Hoeffler, J. P., L. S. Frawley: Endocrinology 120:791-795 (1987) Losa, M., J. Schopohl, O. A. Midler, K. von Werder: Acta Endocrinol. 109:467-473(1985) Sampaolo, G., E. Faloia, R. Sarzani, V. Bartolacci, P. Schiavo, L. Butini, P. Morosini: Recenti Prog. Med. 78:115-118 (1987) Sassolas, G„ P. Chatelain, R. Cohen, J. P. Boissel, S. Laporte, B. Galleyrand, B. Claustrat, A. Elm-Charfi, J. A. Chayvialle, H. Cohen, S. Ferry, E. Underwood:}. Clin. Endocrinol. Metab. 59: 705-709 (1984) Van Vliet, G., D. Bosson, C. Robyn, M. Craen, P. Malvaux, M. Vanderschueren-Lodeweyckx, R. Wolter:Horm.Res.22:32-45(1985)
Requests for reprints should be addressed to:
Fig. 1 Plasma prolactin (PRL) response to growth hormone releasing hormone (GHRH)-(1-29)-NH2 in children with GH neurosecretory dysfunction before (A) and after 1 (B), 3 (C) and 6 (D) months of GHRH therapy.
M. Hernandez Departamento de Pediatria Hospital del Nino Jesus Avda. Menendez Pelayo 65 28009 Madrid (Spain)
Downloaded by: University of Illinois. Copyrighted material.
54
