Abstract
Long-acting gonadotropin-releasing hormone (GnRH) analogs (GnRH-a) suppress gonadal steroid production and are used in precocious puberty, resulting in an arrest of pubertal development, a slower epiphyseal maturation, and a deceleration of growth, but an increased final height. However, the way that GnRH-a affect growth is not clear. GnRH-a treatment might not only affect gonadal steroid production but might also modulate the GH axis and thereby affect growth. We used a rat model to investigate the long-term effects of prepubertally started GnRH-a treatment (triptorelin) on growth, spontaneous GH secretion, hepatic GH receptors (GHR), and GH-binding protein (GHBP) and compared it with surgical gonadectomy. Triptorelin affected most parameters in the same direction as surgical gonadectomy but to a lesser extent. In females, growth was enhanced by triptorelin, baseline GH secretion was decreased, and hepatic GHR and GHBP were decreased. Apart from these effects on the GH axis, reduction of the direct inhibiting effect of estrogen on growth could be responsible for the triptorelin-induced growth. In males, triptorelin treatment enhanced body weight gain and slightly enhanced gain in length. GH peak amplitude was the only parameter of GH secretion affected and decreased, whereas GHR or GHBP were not affected. This stimulation of weight gain by long-term triptorelin treatment in male rats, which is opposite the effect of surgical gonadectomy, could indicate an interference of GnRH-a in the hormonal regulation of food intake and body weight control. We conclude that triptorelin treatment affected growth and the GH-GHR-GHBP axis in rats, more markedly in females than in males. However, triptorelin was not as effective as surgical gonadectomy.
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Abbreviations
- GnRH:
-
gonadotropin-releasing hormone
- GHR:
-
GH receptor
- GHBP:
-
GH binding protein
- GnRH-a:
-
GnRH analog
- BMI:
-
body mass index
- TIMP-1:
-
tissue inhibitor of metalloproteinase-1
References
Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E 1978 Hypophyseal response to continuous and intermittent delivery of hypothalamic gonadotropin releasing hormone. Science 202: 631–633
Furr B 1989 Pharmacology of the luteinizing hormone releasing hormone (LHRH) analogue, Zoladex. Horm Res 32( suppl 1): 86–92
Ward JA, Furr BJA, Valcaccia B, Curry B, Bardin CW, Gunsalus GL, Morris ID 1989 Prolonged suppression of rat testis function by a depot formulation of Zoladex, a GnRH agonist. J Androl 10: 478–486
Lerrant Y, Kottler M-L, Bergametti F, Moumni M, Blumberg-Tick J, Counis R 1995 Expression of gonadotropin-releasing hormone(GnRH) receptor gene is altered by GnRH agonist desensitization in a manner similar to that of gonadotropin B subunit genes in normal and castrated rat pituitary. Endocrinology 136: 2803–2808
Conn P, Staley D, Yasumoto T 1987 Homologous desensitization with gonadotropin releasin hormone also diminishes gonadotrope responsiveness to maitotoxin: a role for the GnRH receptor-regulated calcium channel in mediation of cellular desensitization. Mol Endocrinol 1: 154–159
Conn PM 1994 Gonadotropin-releasing hormone and its analogs. Annu Rev Med 45: 391–405
Redding TW, Schally AV, Tice TR, Meyers WE 1984 Long-acting delivery systems for peptides: inhibition of rat prostate tumors by controlled release of [D-Trp6]-luteinizing hormone-releasing hormone from injectable microcapsules. Proc Natl Acad Sci USA 81: 5845–5848
Oerter KE, Manasco P, Barnes KM, Jones J, Hill S, Cutler GBJ 1991 Adult height in precocious puberty after long-term treatment with deslorelin. J Clin Endocrinol Metab 73: 1235–1240
Oostdijk W, Rikken B, Schreuder S, Otten B, Odink R, Rouwe C, Jansen M, Gerver WJ, Waelkens J, Drop S 1996 Final height in central precocious puberty after long-term treatment with a slow-release GnRH-agonist. Arch Dis Childhood 75: 292–297
Job JC, Toublanc JE, Landier F 1994 Growth of short normal children in puberty treated for 3 years with growth hormone alone or in association with gonadotropin-releasing hormone agonist. Horm Res 41: 177–184
Saggese G, Cesaretti G, Barsanti S, Rossi A 1995 Combination treatment with growth hormone and gonadotropin-releasing hormone analogs in short normal girls. J Pediatr 126: 468–473
Balducci R, Toscano V, Mangiantini A, Municchi G, Vaccaro F, Picone S, Di Rito A, Boscherinin B 1995 Adult height in short normal adolescent girls treated with gonadotropin-releasing hormone analog and growth hormone. J Clin Endocrinol Metab 80: 3596–3600
Lindner D, Job JC, Chaussain JL 1993 Failure to improve height prediction in short-stature pubertal adolescents by inhibiting puberty with luteinizing hormone-releasing hormone analogues. Eur J Pediatr 152: 393–396
Dimartino-Nardi J, Wu R, Fishman K, Saenger P 1991 The effect of long-acting analog of luteinizing hormone-releasing hormone on growth hormone secretory dynamics in children with precocious puberty. J Clin Endocrinol Metab 73: 902–906
DiMartino NJ, Wu R, Varner R, Wong WL, Saenger P 1994 The effect of luteinizing hormone-releasing hormone analog for central precocious puberty on growth hormone (GH) and GH-binding protein. J Clin Endocrinol Metab 78: 664–668
Kamp GA, Manasco PK, Barnes KM, Jones J, Rose SR, Hill SC, Cutler GJ 1991 Low growth hormone levels are related to increased body mass index and do not reflect impaired growth in luteinizing hormone-releasing hormone agonist-treated children with precocious puberty. J Clin Endocrinol Metab 72: 301–307
Sklar C, Rothenberg S, Blumberg D, Oberfield SE, Levine LS, David R 1991 Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I and prolactin secretion. J Clin Endocrinol Metab 73: 734–738
Oliveira SB, Donnadieu M, Chaussain JL 1993 Changes in growth hormone-binding protein in girls with central precocious puberty treated with a depot preparation of luteinizing hormone-releasing hormone analogue. Horm Res 39: 42–46
Tannenbaum GS, Martin JB 1976 Evidence for an endogenous ultradian rhythm governing growth hormone secretion in the rat. Endocrinology 98: 562–570
Clark RG, Chambers G, Lewin J, Robinson ICAF 1986 Automated repetitive microsampling of blood: growth hormone secretion in conscious male rats. J Endocrinol 111: 27–35
Clark RG, Carlsson L, Robinson I 1987 Growth hormone secretory profiles in conscious female rats. J Endocrinol 114: 399–407
Maes M, de Hertogh R, Watrin-Granger P, Ketelslegers JM 1983 Ontogeny of liver somatotropic and lactogenic binding sites in male and female rats. Endocrinology 113: 1325–1332
Massa G, Mulumba N, Ketelslegers J-M, Maes M 1990 Initial characterization and sexual dimorphism of serum growth hormone-releasing binding protein in adult rats. Endocrinology 126: 1976–1980
Jansson JO, Eden S, Isaksson OGP 1985 Sexual dimorphism in the control of growth hormone secretion. Endocr Rev 6: 128–150
Carmignac DF, Gabrielsson BM, Robinson ICAF 1993 Growth hormone binding protein (GHBP) in the rat: effects of gonadal steroids. Endocrinology 133: 2445–2452
Hughes P, Tanner J 1970 A longitudinal study of the growth of the blackhooded rat: methods of measurement and rates of growth for skull, limbs, pelvis, nos-rump and tail lengths. J Anat 106: 349–370
Gevers EF, Wit JM, Robinson ICAF 1995 Effect of gonadectomy on growth and GH responsiveness in dwarf rats. J Endocrinol 145: 69–79
Merriam GR, Wachter KW 1982 Algorithms for the study of episodic hormone secretion. Am J Physiol 243:E310–E318
Maiter D, Underwood LE, Maes M, Ketelslegers JM 1988 Acute down-regulation of the somatogenic receptors in rat liver by a single injection of growth hormone. Endocrinology 122: 1291–1296
Lowry O, Rosebrough N, Farr A, Randall R 1951 Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275
Gevers EF, Wit JM, Robinson ICAF 1996 Growth, growth hormone (GH)-binding protein and GH receptors are differentially regulated in the rat by peak and trough components of the GH secretory pattern. Endocrinology 137: 1013–1018
Massa GG, Bouillon R, Vanderschueren-Lodewyckx M 1992 Serum growth hormone binding protein and insulin-like growth factor I levels in Turner syndrome before and during treatment with recombinant human growth hormone and ethinylestradiol. J Clin Endocrinol Metab 75: 1298–1302
Postel VM, Tar A, Hocquette JF, Clot JP, Fontoura M, Brauner R, Rappaport R 1991 Human plasma growth hormone (GH)-binding proteins are regulated by GH and testosterone. J Clin Endocrinol Metab 73: 197–202
Clark RG, Carlsson L, Robinson ICAF 1987 Growth hormone secretory profiles in conscious female rats. J Endocrinol 114: 399–407
Jansson JO, Eden S, Isaksson O 1983 Sites of action of testosterone and estradiol on longitudinal bone growth. Am J Physiol 243:E135–E140
Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331: 1056–1061
Juul A, Scheike T, Nielsen CT, Krabbe S, Muller J, Skakkebaek NE 1995 Serum insulin-like growth factor I (IGF-I) and IGF-I binding protein 3 levels are increased in central precocious puberty: effects of two different treatment regimens with gonadotropin-releasing hormone agonists, without or in combination with an antiandrogen (cyproterone acetate). J Clin Endocrinol Metab 80: 3059–3067
Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL, Clifton DK, Steiner RA 1996 Leptin is a metabolic signal to the reproductive system. Endocrinology 137: 3144–3147
Painson J, Thorner M, Krieg R, Tannenbaum GS 1992 Short term adult exposure to estradiol feminizes the male pattern of spontaneous and growth hormone-releasing factor-stimulated growth hormone secretion in the rat. Endocrinology 130: 511–519
Ohlsson L, Isaksson O, Jansson JO 1987 Endogenous testosterone enhances growth hormone (GH)-releasing factor induced GH secretion in vitro. J Endocrinol 113: 249–253
Chowen JA, Argente J, GonzalezParra S, GarciaSegura LM 1993 Differential effects of the neonatal and adult sex steroid environments on the organization and activation of hypothalamic growth hormone-releasing hormone and somatostatin neurons. Endocrinology 133: 2792–2802
Werner H, Koch Y, Baldino F, Gozes I 1988 Steroid regulation of somatostatin mRNA in the rat hypothalamus. J Biol Chem 263: 7666–7671
Reichlin S 1992 In: Wilson JD, Foster DW (eds) Williams Textbook of Endocrinology, Saunders, Philadelphia, pp 178
Baumbach WR, Horner DL, Logan JS 1989 The growth hormone-binding protein in rat serum is an alternatively spliced form of the rat growth hormone receptor. Genes Dev 3: 1199–1205
Clark RG, Mortensen DL, Carlsson LMS, Spencer SA, McKay P, Mulkerrin M, Morre J, Cunningham BC 1996 Recombinant human growth hormone(GH)-binding protein enhances the growth promoting activity of human GH in the rat. Endocrinology 137: 4308–4315
Lim L, Spencer SA, McKay P, Waters MJ 1990 Regulation of growth hormone (GH) bioactivity by a recombinant human GH-binding protein. Endocrinology 127: 1287–1291
Sotiropoulos A, Goujon L, Simonin G, Kelly PA, Postel-Vinay MC, Finidori J 1993 Evidence for generation of the growth hormone-binding protein through proteolysis of the growth hormone receptor membrane receptor. Endocrinology 132: 1863–1865
Weissberger AJ, Ho KK, Lazarus L 1991 Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 72: 374–381
Maiter D, Lause P, Adam E, Mulumba N, Robinson ICAF 1996 Long-term effects of gonadal hormones on liver IGF-I and GH receptor(GHR)/GH binding protein (GHBP) gene expression in the rat. Proceedings of the 10th International Conference of Endocrinology, San Francisco, Abstract P2-344
Cook J, Doty K, Conn P, Hansen J 1992 Assessment of depot leuprolide acetate dose-adequacy for central precocious puberty. J Clin Endocrinol Metab 74: 1206–1209
Filicori M, Flamigni C, Cognigni G, Dellai P, Arnone R, Falbo A, Capelli M 1993 Comparison of the suppressive capacity of different depot gonadotropin-releasing hormone analogs in women. J Clin Endocrinol Metab 77: 130–133
Orth JM, Gunsalus G, Lamperti AA 1988 Evidence from Sertoli cell-depleted rats indicates that spermatic number in adults depends on numbers of Sertoli cells produced during perinatal development. Endocrinology 122: 787–794
Garnelo P, Pinilla L, Gaytan F, Aguilar E 1992 Pituitary-testis function in rats treated neonatally with a gonadotrophin-releasing hormone agonist: short- and long-term effects. J Endocrinol 134: 269–277
Kolho K-L, Huhtaniemi I 1989 Suppression of pituitary-testis function in rats treated neonatally with a gonadotrophin-releasing hormone agonist and antagonist: acute and long-term effects. J Endocrinol 123: 83–91
Struthers RS, Gaddy KD, Vale WW 1992 Activin inhibits binding of transcription factor Pit-1 to the growth hormone promoter. Proc Natl Acad Sci USA 89: 11451–11455
Boujrad N, Ogwuegbu O, Garnier M, Lee CH, Martin BM, Papadopoulos V 1995 Identification of a stimulator of steroid hormone synthesis isolated from testis. Science 268: 1609–1612
Santen RJ, Demers LM, Max DT, Smith J, Stein BS, Glode LM 1984 Long term effects of a gonadotropin-releasing hormone superagonist analog in men with prostatic carcinoma. J Clin Endocrinol Metab 58: 397–400
Marchetti B, Gallo F, Farinella Z, Romeo C, Morale MC 1996 Luteinizing hormone-releasing hormone receptors in the neuroendocrine-immune network. Annals New York Academy of Sciences 784: 209–236
Stojilkovic SS, Catt KJ 1995 Expression and signal transduction pathways of gonadotropin-releasing hormone receptors. Recent Prog Horm Res 50: 161–205
Pfaff DW, Schwanzel-Fukuda M, Parhar IS, Lauber AH, McCarthy MM, Kow L-M 1994 GnRH neurons and other cellular and molecular mechanisms for simple mammalian reproductive behaviors. Recent Prog Horm Res 49: 1–25
Acknowledgements
The authors thank Anita Mynett for help with some of the experiments, Danielle Carmignac for measuring GHBP, and Organon(The Netherlands) for measuring estrogen levels. We thank Ferring (Malmö, Sweden) for the generous supply of Decapeptyl-CR. We also thank NIDDK for the supply of GH-RIA reagents and Dr. William Baumbach (American Cyanamid Co., Princeton, NJ), Dr. Lena Carlsson and Dr. Ross Clark (Genentech, South San Francisco, CA) for GHBP-RIA reagents. We are grateful to Lyset Rekers for statistical help and to Dr. Wilma Oostdijk for critical advice on preparing the manuscript.
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Supported in part by a grant from the Ter Meulen Fund (Royal Netherlands Academy for Arts and Sciences).
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Gevers, E., Wit, JM. & Robinson, I. Effects of Long-Term Gonadotropin-Releasing Hormone Analog Treatment on Growth, Growth Hormone (GH) Secretion, GH Receptors, and GH-Binding Protein in the Rat. Pediatr Res 43, 111–120 (1998). https://doi.org/10.1203/00006450-199801000-00017
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DOI: https://doi.org/10.1203/00006450-199801000-00017
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