The aim of this study was to assess the ontogenetic changes in vitro in both the responsiveness of anterior pituitary tissue to growth hormone-releasing hormone (GHRH) and the critical role of GHRH in the long-term regulation of pulsatile GH secretion during perinatal porcine life. A superfusion system was used to apply three consecutive 10-min pulses of GHRH (the first of 1 nM and the other two of 10 nM) for 3 consecutive days in pituitary glands isolated from fetal (95- and 110-day) and neonatal (12-day) male pigs. In fetuses, total GHRH-induced GH release decreased progressively over the 3 days. However, in neonates, GH did not decrease until day 3, but remained higher than in fetuses. When each GH pulse was assessed individually, fetuses showed a similar pattern. GH secretion induced by the first GHRH pulse on days 1 and 2 was lower than that induced by the second and third pulses. By day 3, GH release lowered dramatically after all pulses. In contrast, in neonates no differences were observed among the GH levels induced by the three GHRH pulses at any day, although day 3 showed lower GH rates. In conclusion, during perinatal development, a desensitizing effect to long-term repetitive GHRH pulses was observed in both fetuses and neonates, but this effect was delayed in neonates. Thus, the capacity of somatotrope cells to maintain GH response to GHRH seems to be developmentally regulated during perinatal stages. Furthermore, the frequency of GHRH pulses, rather than the concentrations, might be a key factor to elicit desensitization.

1.
Gahete MD, Durán-Prado M, Luque RM, Martíınez-Fuentes AJ, Quintero A, Gutiérrez-Pascual E, Córdoba-Chacón J, Malagón MM, Gracia-Navarro F, Castaño JP: Understanding the multifactorial control of growth hormone release by somatotropes. Ann NY Acad Sci 2009;1163:137–153.
2.
Nogami H, Hisano S: Functional maturation of growth hormone cells in the anterior pituitary gland of the fetus. Growth Horm IGF Res 2008;18:379–388.
3.
Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB: Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 1982;218:585–587.
4.
Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R: Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973,179:77–79.
5.
Silverman BL, Bettendorf M, Kaplan SL, Grumbach MM, Miller WL: Regulation of growth hormone (GH) secretion by GH-releasing factor, somatostatin, and insulin-like growth factor I in ovine fetal and neonatal pituitiary cells in vitro. Endocrinology 1989;124:84–89.
6.
Torronteras R, Gracia-Navarro F, Elsaesser F: Control of growth hormone secretion from porcine fetal and neonatal pituitary tissue in vitro by growth hormone-releasing hormone, somatostatin, and insulin-like growth factor. Neuroendocrinology, 1997;65:117–128.
7.
Shibasaki T, Yamauchi N, Hotta M, Masuda A, Iñaki T, Demura H, Ling N, Shizume K: In vitro release of growth hormone-releasing factor from rat hypothalamus: effect of insulin-like growth factor I. Regul Pept 1986;15:47–52.
8.
Klindt J, Stone RT: Porcine growth hormone and prolactin: concentrations in the fetus and secretory patterns in the growing pig. Growth 1984;48:1–15.
9.
Ceda GP, Valenti G, Butturini U, Hoffman AR: Diminished pituitary responsiveness to growth hormone-releasing factor in aging male rats. Endocrinology 1986;11:2109–2114.
10.
Collins BJ, Szabo M, Cuttler L: Differential desensitization response of the neonatal and adult rat somatotroph to growth hormone-releasing hormone and phorbol ester. Mol Cell Endocrinol 1996;117:75–81.
11.
Foltzer-Jourdainne C, Harvey S, Mialhe P: In vitro control of growth hormone secretion by synthetic releasing factors in young and adult ducks (Anas platyrhynchos). J Endocrinol 1988;119:421–429.
12.
Farmer C, Pommier SA, Brazeau P: Validation of a culture system for porcine pituitary cells: effects of growth hormone-releasing factor and/or somatostatin on growth hormone secretion. J Anim Sci 1993;71:923–929.
13.
Leppäluoto J, Laisi U, Lybeck H, Partanen J, Ranta T, Virkkunen P: Pulsatile secretion of ACTH, GH, LH and TSH in man. Acta Physiol Scand 1975;95:470–476.
14.
Drisko JE, Faidley TD, Chang CH, Zhang D, Nicolich S, Hora DF, McNamara L, Rickes E, Abribat T, Smith RG, Hickey GJ: Hypophyseal-portal concentrations of growth hormone-releasing factor and somatostatin in conscious pigs: relationship to production of spontaneous growth hormone pulses. Proc Soc Exp Biol Med 1998;217:188–196.
15.
Tannenbaum GS, Ling N: The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology 1984;115:1952–1957.
16.
Davis SL, Ohlson DL, Klindt J, Anfinson MS: Episodic growth hormone secretory patterns in sheep: relationship to gonadal steroid hormones. Am J Physiol 1977;233:519–523.
17.
Suttie JM, Fennessy PF, Corson ID, Laas FJ, Crosbie SF, Butler JH, Gluckman PD: Pulsatile growth hormone, insulin-like growth factors and antler development in red deer (Cervus elaphus scoticus) stags. J Endocrinol 1989;121:351–360.
18.
Wheaton JE, Al-Raheem SN, Massri YG, Marcek JM: Twenty-four hour growth hormone profiles in Angus steers. J Anim Sci 1986;62:1267–1272.
19.
Plotsky PM, Vale W: Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science 1985;230:461–463.
20.
Bertherat J, Bluet-Pajot MT, Epelbaum J: Neuroendocrine regulation of growth hormone. Eur J Endocrinol 1995;132:12–24.
21.
McMahon CD, Radcliff RP, Lookingland KJ, Tucker HA: Neuroregulation of growth hormone secretion in domestic animals. Domest Anim Endocrinol 2001;20:65–87.
22.
Hassan HA, Merkel RA: Perifusion model system to culture bovine hypothalamic slices in series with dispersed anterior pituitary cells. In vitro Cell Dev Biol 1994;30:435–442.
23.
Klindt J, Ford JJ, Berardinelli JG, Anderson LL: Growth hormone secretion after hypophysial stalk transection in pigs. Proc Soc Exp Biol Med 1983;172:508–513.
24.
Torronteras R, Gracia-Navarro F, Elsaesser F: Different effects of somatostatin on in vitro growth hormone release in two porcine breeds with different growth rates. J Neuroendocrinol 1996;8:891–900.
25.
Soya H, Suzuki M: Somatostatin rapidly restores rat growth hormone (GH) release response attenuated by prior exposure to human GH-releasing factor in vitro. Endocrinology 1988;122:2492–2498.
26.
Sugihara H, Minami S, Wakabayashi I: Post-somatostatin rebound secretion of growth hormone is dependent on growth hormone-releasing factor in unrestrained female rats. J Endocrinol 1989;122:583–591.
27.
Bauer M, Parvizi N: Pulsatile and diurnal secretion of GH and IGF-I in the chronically catheterized pig fetus. J Endocrinol 1996;149:125–133.
28.
Elsaesser F, Granz S, Torronteras R: Ontogeny and control of growth hormona gene expresión and secretion in the fetal pig. Reprod Dom Anim 1995;30:163–169.
29.
Farmer C, Randall G, Brazeau P: In vitro growth hormone (GH) response to GH-releasing factor (GRF) or somatostatin (SRIF) in foetal pigs. J Dev Physiol 1992;17:93–98.
30.
Kraicer J, Sheppard MS, Luke J, Lussier B, Moor BC, Cowan JW: Effect of withdrawal of somatostatin and growth hormone (GH)-releasing factor on GH release in vitro. Endocrinology 1988;122:1810–1815.
31.
Serpek B, Elsaesser F, Meyer HH: Development of an enzyme immunoassay for the determination of porcine growth hormone in plasma. Anal Chim Acta 1993;275:183–187.
32.
Horváth JE, Groot K, Schally AV: Growth hormone-releasing hormone stimulates cAMP release in superfused rat pituitary cells. Proc Natl Acad Sci USA 1995;92:1856–1860.
33.
Critchlow V, Dyke A, Kaler LW: Release of growth hormone, prolactin, and somatostatin during perifusion of anterior pituitary and preoptic-medial basal hypothalamus form male and female rats. Brain Res 1986;398:347–353.
34.
Dacheux F: Functional differentiation of the anterior pituitary cells in the fetal pig. An ultrastructural immunocytochemical study. Cell Tissue Res 1984;235:623–633.
35.
Rettmer I, Parvizi N: Ontogeny of the regulation of GH secretion: effects of GRF, SRIF and morphine. Exp Clin Endocrinol Diabet 1996;104:68–76.
36.
Clark RG, Robinson IC: Growth hormone responses to multiple injections of a fragment of human growth hormone-releasing factor in conscious male and female rats. J Endocrinol 1985;106:281–286.
37.
Dubreuil P, Pelletier G, Petitclerc D, Lapierre H, Gaudreau P, Brazeau P: Effects of active immunization against somatostatin on serum growth hormone concentration in growing pigs: influence of fasting and repetitive somatocrinin injections. Endocrinology 1989;125:1378–1384.
38.
Kovács M, Fáncsik A, Mezö I, Teplán I, Flerko B: Effects of continuous and repetitive administration of a potent analog of GH-RH(1–30)NH2 on the GH release in rats. Neuroendocrinology 1994;59:371–379.
39.
Shibasaki T, Hotta M, Yamauchi N, Masuda A, Imaki T, Demura H, Ling N, Shizume K: Desensitization of rat pituitary somatotrophs to growth hormone-releasing factor occurs in vitro. Endocrinol Jpn 1987;34:799–807.
40.
Blumenfeld Z, Tapaneinen P, Kaplan SL, Grumbach MM, Jaffe RB: Partial loss of responsiveness of human fetal pituitary cells to hGHRH after chronic exposure. Acta Endocrinol (Copenh) 1989;121:721–726.
41.
Bilezikjian LM, Seifert H, Vale WW: Desensitization to growth hormone-releasing factor (GRF) is associated with down-regulation of GRF-binding sites. Endocrinology 1986;118:2045–2052.
42.
Girard N, Boulanger L, Denis S, Gaudreau P: Differential in vivo regulation of the pituitary growth hormone-releasing hormone (GHRH) receptor by GHRH in young and aged rats. Endocrinology 1999;140:2836–2842.
43.
Aleppo G, Moskal II SF, De Grandis PA, Kineman RD, Frohman LA: Homologous down-regulation of growth hormone-releasing hormone receptor messenger ribonucleic acid levels. Endocrinology 1997;138:1058–1065.
44.
Giustina A, Veldhuis JD: Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998;19:717–797.
45.
Ramírez JL, Castaño JP, Torronteras R, Martínez-Fuentes AJ, Frawley LS, García-Navarro S, Gracia-Navarro F: Growth hormona (GH)-releasing factor differentially activates cyclic adenosine 3′,5′-monophosphate- and inositol phosphate-dependent pathways to stimulate GH release in two porcine somatotrope subpopulations. Endocrinology 1999;140:1752–1759.
46.
Kineman RD, Kamegai J, Frohman LA: Growth hormone (GH)-releasing hormone (GHRH) and the GH secretagogue (GHS), L692,585, differentially modulate rat pituitary GHS receptor and GHRH receptor messenger ribonucleic acid levels. Endocrinology 1999:140:3581–3586.
47.
Luque RM, Kineman RD, Park S, Peng X-D, Gracia-Navarro F, Castaño JP, Malagón MM: Homologous and heterologous regulation of pituitary receptors for Ghrelin and growth hormone-releasing hormone. Endocrinology 2004;145:3182–3189.
48.
Cuttler L, Collins BJ, Szabo M: Ontogeny of the GH response to phorbol ester and phospholipase C in rat pituitary cells. J Endocrinol 1995;145:307–314.
49.
Miller TL, Godfrey PA, Dealmeida VI, Mayo KE: The rat growth hormone-releasing hormone receptor gene: structure, regulation, and generation of receptor isoforms with different signalling properties. Endocrinology 1999;140:4152–4165.
50.
Hassan HA: Biological activities of two porcine growth hormone-releasing hormone receptor isoforms. Arch Biochem Biophys 2001;387:20–26.
51.
Parenti M, Dall’ara A, Rusconi L, Cocchi D, Muller EE: Different regulation of growth hormone-releasing factor-sensitive adenylate cyclase in the anterior pituitary of young and aged rats. Endocrinology 1987;121:1649–1653.
52.
Anderson LL, Jeftinija S, Scanes CG: Growth hormone secretion: molecular and cellular mechanisms and in vivo approaches. Exp Biol Med 2004;229:291–302.
53.
Muller EE, Locatelli V, Cocchi D: Neuroendocrine control of growth hormone secretion. Physiol Rev 1999;79:511–607.
54.
Clayton RN, Bailey LC: Somatostatin partially reverses desensitization of somatotrophs induced by growth hormone-releasing factor. J Endocrinol 1987;112:69–76.
55.
Sato M, Takahara J, Fujioka Y, Niimi M, Irino S: Physiological role of growth hormona (GH)-releasing factor and somatostatin in the dynamics of GH secretion in adult male rat. Endocrinology 1988;123:1928–1933.
56.
Rittmaster RS, Loriaux DL, Merriam GR: Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization independent of GH pool depletion. Neuroendocrinology 1987;45:118–122.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.