Abstract
Central precocious puberty is commonly treated by gonadotropin releasing hormone (GnRH) agonists. To compare modes of action and effectiveness of GnRH analogues and assess treatment combinations of agonistic (triptorelin) and antagonistic (cetrorelix acetate) GnRH analogues with established treatment, we used prepubertal 31-d-old ovariectomized female rats. Strongest inhibition of LH and FSH occurred after 2-d treatment with antagonist alone (LH 0.08 ± 0.02 versus 3.2 ± 0.56 ng/mL in controls; FSH 10.8 ± 2.8 versus 44.2 ± 5.0 ng/mL in controls, p < 0.001). Combined agonist/antagonist was second most effective of the treatments (after 5 d treatment, LH 0.52 ± 0.15 versus 4.9 ± 1.1 ng/mL in controls; p < 0.01). Pituitary gonadotropin subunit LHβ mRNA levels were inhibited in all groups except controls, but pituitary GnRH receptor mRNA was stimulated by agonist yet unaffected by combined analogues. Explanted ovaries were incubated with either analogue, both 10−6 M. After 4 h, GnRH receptor mRNA levels were significantly reduced by antagonist but not agonist. To verify puberty-inhibiting effects of GnRH analogues, we used 26-d-old female rats with androgen-induced precocious puberty after injecting subcutaneously single 300 μg danazol on postnatal d 5. Single application of cetrorelix depot (cetrorelix embonate) reduced serum estradiol levels and pituitary LHβ expression; GnRH receptor mRNA levels were down-regulated in the pituitary and ovary (p < 0.05). In androgen-induced precocious puberty model, single injection of antagonist effectively arrests premature hormonal activation and down-regulates pituitary and ovarian GnRH receptors. We conclude that GnRH analogue combination and especially antagonist alone treatment most directly suppress gonadotropin levels. This implies that early treatment gonadotropin flare-up associated with agonist treatment is avoidable.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- GnRH:
-
gonadotropin-releasing hormone
- LHβ:
-
LH subunit β
- POA:
-
preoptic area
- MBH:
-
mediobasal hypothalamus
- ER:
-
estrogen receptor
- Co:
-
controls
References
Urbanski HF, Ojeda SR 1990 A role for N-methyl- d -aspartate (NMDA) receptors in the control of LH secretion and initiation of female puberty. Endocrinology 126: 1774–1776
Moguilevsky JA, Carbone S, Szwarcfarb B, Rondina D 1991 Sexual maturation modifies the GABAergic control of gonadotrophin secretion in female rats. Brain Res 563: 12–16
Bourguignon JP, Gérard A, Alvarez Gonzalez ML, Franchimont P 1992 Neuroendocrine mechanisms of onset of puberty. J Clin Invest 90: 1736–1744
Rage F, Hill DF, Sena-Esteves M, Breakefield XO, Coffey RJ, Costa ME, McCann SM, Ojeda SR 1997 Targeting transforming growth factor alpha expression to discrete loci of the neuroendocrine brain induces female sexual precocity. Proc Natl Acad Sci U S A 94: 2735–2740
Aubert ML, Pierroz DD, Gruaz NM, d‘Alleves V, Vuagnat BA, Pralong FP, Blum WF, Sizonenko PC 1998 Metabolic control of sexual function and growth: role of neuropeptide Y and leptin. Mol Cell Endocrinol 140: 107–113
Lebrethon MC, Vandersmissen E, Gerard A, Parent AS, Junien JL, Bourguignon JP 2000 In vitro stimulation of the prepubertal rat gonadotropin-releasing hormone pulse generator by leptin and neuropeptide Y through distinct mechanisms. Endocrinology 141: 1464–1469
Crowley WF, Comite F, Vale W, Rivier J, Loriaux DL, Cutler GB 1981 Therapeutic use of pituitary desensitization with a long-acting LHRH agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab 52: 370–372
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 U S A 81: 5845–5848
Plosker GL, Brogden RN 1994 Leuprorelin—a review of its pharmacology and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders. Drugs 48: 930–967
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 Child 75: 292–297
Heger S, Partsch CJ, Sippell WG 1999 Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab 84: 4583–4590
Partsch CJ, Heger S, Sippell WG 2002 Management and outcome of central precocious puberty. Clin Endocrinol Oxf 56: 129–148
Beckers T, Marheineke K, Reiländer H, Hilgard P 1995 Selection and characterization of mammalian cell lines with stable over-expression of human pituitary receptors for gonadoliberin. Eur J Biochem 231: 535–543
Roth C, Leonhardt S, Seidel C, Luft H, Wuttke W, Jarry H 2000 Comparative analysis of different puberty inhibiting mechanisms of two GnRH agonists and the GnRH antagonist cetrorelix using a female rat model. Pediatr Res 48: 468–474
Friend KE, Ang LW, Shupnik MA 1995 Estrogen regulates the expression of several different estrogen receptor mRNA isoforms in rat pituitary. Proc Natl Acad Sci U S A 92: 4367–4371
Gustafsson JA 1999 Estrogen receptor beta—a new dimension in estrogen mechanism of action. J Endocrinol 163: 379–383
Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA 1997 Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 138: 863–870
Schreihofer DA, Stoler MH, Shupnik MA 2000 Differential expression and regulation of estrogen receptors (ERs) in rat pituitary and cell lines: estrogen decreases ERalpha protein and estrogen responsiveness. Endocrinology 141: 2174–2184
Roth C, Schricker M, Lakomek M, Strege A, Heiden I, Luft H, Munzel U, Wuttke W, Jarry H 2001 Autoregulation of the GnRH system during puberty: effects of antagonistic versus agonistic GnRH analogues in a female rat model. J Endocrinol 169: 361–371
Morishita H, Takemoto M, Kondo H, Higuchi K, Aono T 1993 Induction of true precocious puberty by neonatal treatment with danazol in female rats. Neurosci Lett 157: 33–36
Roth C, Leonhardt S, Theiling K, Lakomek M, Jarry H, Wuttke W 1998 Ontogeny of the GnRH-, glutaminase- and glutamate decarboxylase-gene expression in the hypothalamus of female rats. Brain Res Dev Brain Res 110: 105–114
Sakamoto S, Tajima M, Sawaki K, Suzuki S, Kudo H, Sassa S, Kuwa K, Sugiura Y, Kasahara N, Nagasawa H 1993 Effects of luteinizing hormone-releasing hormone analogue on DNA synthesis in rat prostate and uterus. In Vivo 7: 13–16
Haisenleder DJ, Cox ME, Parsons SJ, Marshall JC 1998 Gonadotropin-releasing hormone pulses are required to maintain activation of mitogen-activated protein kinase: role in stimulation of gonadotrope gene expression. Endocrinology 139: 3104–3111
Loumaye E, Naor Z, Catt KJ 1982 Binding affinity and biological activity of gonadotropin releasing hormone agonists in isolated pituitary cells. Endocrinology 111: 730–736
Tsutsumi M, Laws SC, Rodic V, Sealfon SC 1995 Translational regulation of the gonadotropin-releasing hormone receptor in alphaT3–1 cells. Endocrinology 136: 1128–1136
Norwitz ER, Jeong KH, Chin WW 1999 Molecular mechanisms of gonadotropin-releasing hormone receptor gene regulation. J Soc Gynecol Investig 6: 169–178
Nett TM, Turzillo AM, Baratta M, Rispoli LA 2002 Pituitary effects of steroid hormones on secretion of follicle-stimulating hormone and luteinizing hormone. Domest Anim Endocrinol 23: 33–42
Kang SK, Choi KC, Cheng KW, Nathwani PS, Auersperg N, Leung PC 2000 Role of gonadotropin-releasing hormone as an autocrine growth factor in human ovarian surface epithelium. Endocrinology 141: 72–80
Behre HM, Kliesch S, Pühse G, Reissmann T, Nieschlag E 1997 High loading and low maintenance doses of a gonadotropin-releasing hormone antagonist effectively suppress serum luteinizing hormone, follicle-stimulating hormone, and testosterone in normal men. J Clin Endocrinol Metab 82: 1403–1408
Broqua P, Riviere PJ, Conn PM, Rivier JE, Aubert ML, Junien JL 2002 Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix. J Pharmacol Exp Ther 301: 95–102
Ashton WT, Sisco RM, Kieczykowski GR, Yang YT, Yudkovitz JB, Cui J, Mount GR, Ren RN, Wu TJ, Shen X, Lyons KA, Mao AH, Carlin JR, Karanam BV, Vincent SH, Cheng K, Goulet MT 2001 Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity. Bioorg Med Chem Lett 11: 2597–2602
Millar RP, Zhu YF, Chen C, Struthers RS 2000 Progress towards the development of non-peptide orally-active gonadotropin-releasing hormone (GnRH) antagonists: therapeutic implications. Br Med Bull 56: 761–772
Acknowledgements
The authors thank Dr. Reissmann, Asta Medica, who kindly provided the drug cetrorelix acetate and long-acting cetrorelix embonate to us as a gift. The authors also thank M. Neff-Heinrich for linguistic help in editing the manuscript and M. Metten for her assistance in the laboratory.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) Grant RO 2220/2-1.
Rights and permissions
About this article
Cite this article
Roth, C., Hegemann, F., Hildebrandt, J. et al. Pituitary and Gonadal Effects of GnRH (Gonadotropin Releasing Hormone) Analogues in Two Peripubertal Female Rat Models. Pediatr Res 55, 126–133 (2004). https://doi.org/10.1203/01.PDR.0000100463.84334.3F
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000100463.84334.3F
This article is cited by
-
Neuromodulatory effect of GnRH from coeliac ganglion on luteal regression in the late pregnant rat
Cell and Tissue Research (2021)
