PDF herunterladen
Semin Reprod Med 2007; 25(5): 326-336
DOI: 10.1055/s-2007-984738
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Regulation of Gonadotropin-Releasing Hormone in Nonhypothalamic Tissues

Helen H. Kim1 , Keeley L. Mui1 , Amisra A. Nikrodhanond1 , Niña Carmela R. Tamayo1
  • 1In Vitro Fertilization Program, Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
20. August 2007 (online)

    Lizenzen und Reprints

ABSTRACT

It is well established that hypothalamic gonadotropin-releasing hormone (GnRH) controls reproductive function by stimulating the production of gonadotropins from the pituitary. GNRH gene and its receptor (GnRHR) have also been detected outside the hypothalamus, and a growing body of literature supports an extrapituitary role for GnRH action. The exact function of GnRH in these tissues is not known, but GnRH expression has been described in reproductive tissues, including the ovary, placenta, breast, testes, and prostate. This article provides an overview of the regulation of GnRH gene expression in nonhypothalamic reproductive tissues. After GnRH gene structure is reviewed, the physiologic role of GnRH and regulation of its expression in several reproductive tissues are examined. When possible, transcriptional regulation is discussed, but due to low levels of expression, transcriptional regulation of GnRH in extrahypothalamic tissues has been extremely difficult to study. Consequently, the factors that mediate GnRH gene expression in these tissues are only beginning to be identified.

KEYWORDS

Gonadotropin-releasing hormone (GnRH) - gene regulation - tissue-specific expression - ovary - placenta - breast - testes - prostate

REFERENCES

  • 1 Cheng C K, Leung P C. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans.  Endocr Rev. 2005;  26 283-306
    CrossrefPubMedGoogle Scholar
  • 2 Harrison G S, Wierman M E, Nett T M, Glode L M. Gonadotropin-releasing hormone and its receptor in normal and malignant cells.  Endocr Relat Cancer. 2004;  11 725-748
    CrossrefPubMedGoogle Scholar
  • 3 Limonta P, Moretti R M, Marelli M M, Motta M. The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans.  Front Neuroendocrinol. 2003;  24 279-295
    CrossrefPubMedGoogle Scholar
  • 4 Gore A C. Multiple GnRH Molecules Phylogeny and Evolution. In: Gore AC GnRH: the Master Molecule of Reproduction. Norwell, MA; Kluwer Academic 2002
    Google Scholar
  • 5 Fernald R D, White R B. Gonadotropin-releasing hormone genes: phylogeny, structure, and functions.  Front Neuroendocrinol. 1999;  20 224-240
    CrossrefPubMedGoogle Scholar
  • 6 Givens M L, Kurotani R, Rave-Harel N, Miller N L, Mellon P L. Phylogenetic footprinting reveals evolutionarily conserved regions of the gonadotropin-releasing hormone gene that enhance cell-specific expression.  Mol Endocrinol. 2004;  18 2950-2966
    CrossrefPubMedGoogle Scholar
  • 7 Eraly S A, Mellon P L. Regulation of gonadotropin-releasing hormone transcription by protein kinase C is mediated by evolutionarily conserved promoter-proximal elements.  Mol Endocrinol. 1995;  9 848-859
    CrossrefPubMedGoogle Scholar
  • 8 Belsham D D, Lovejoy D A. Gonadotropin-releasing hormone: gene evolution, expression, and regulation.  Vitam Horm. 2005;  71 59-94
    PubMedGoogle Scholar
  • 9 Chandran U R, DeFranco D B. Regulation of gonadotropin-releasing hormone gene transcription.  Behav Brain Res. 1999;  105 29-36
    CrossrefPubMedGoogle Scholar
  • 10 Seeburg P H, Adelman J P. Characterization of cDNA for precursor of human luteinizing hormone releasing hormone.  Nature. 1984;  311 666-668
    PubMedGoogle Scholar
  • 11 Gibbons Jr J M, Mitnick M, Chieffo V. In vitro biosynthesis of TSH- and LH-releasing factors by the human placenta.  Am J Obstet Gynecol. 1975;  121 127-131
    PubMedGoogle Scholar
  • 12 Khodr G S, Siler-Khodr T M. Placental luteinizing hormone-releasing factor and its synthesis.  Science. 1980;  207 315-317
    CrossrefPubMedGoogle Scholar
  • 13 Khodr G, Siler-Khodr T M. The effect of luteinizing hormone-releasing factor on human chorionic gonadotropin secretion.  Fertil Steril. 1978;  30 301-304
    PubMedGoogle Scholar
  • 14 Siler-Khodr T M, Khodr G S. Dose response analysis of gnRH stimulation of hCG release from human term placenta.  Biol Reprod. 1981;  25 353-358
    CrossrefPubMedGoogle Scholar
  • 15 Miyake A, Sakumoto T, Aono T, Kawamura Y, Maeda T, Kurachi K. Changes in luteinizing hormone-releasing hormone in human placenta throughout pregnancy.  Obstet Gynecol. 1982;  60 444-449
    PubMedGoogle Scholar
  • 16 Currie A J, Fraser H M, Sharpe R M. Human placental receptors for luteinizing hormone releasing hormone.  Biochem Biophys Res Commun. 1981;  99 332-338
    CrossrefPubMedGoogle Scholar
  • 17 Belisle S, Guevin J F, Bellabarba D, Lehoux J G. Luteinizing hormone-releasing hormone binds to enriched human placental membranes and stimulates in vitro the synthesis of bioactive human chorionic gonadotropin.  J Clin Endocrinol Metab. 1984;  59 119-126
    PubMedGoogle Scholar
  • 18 Wolfahrt S, Kleine B, Rossmanith W G. Detection of gonadotrophin releasing hormone and its receptor mRNA in human placental trophoblasts using in-situ reverse transcription-polymerase chain reaction.  Mol Hum Reprod. 1998;  4 999-1006
    CrossrefPubMedGoogle Scholar
  • 19 Rice G E, Smirnis M. Identification of luteinizing hormone releasing hormone-like immunoactivity in ovine cotyledons.  Regul Pept. 1990;  27 51-59
    CrossrefPubMedGoogle Scholar
  • 20 Gautron J P, Pattou E, Kordon C. Occurrence of higher molecular forms of LHRH in fractionated extracts from rat hypothalamus, cortex and placenta.  Mol Cell Endocrinol. 1981;  24 1-15
    CrossrefPubMedGoogle Scholar
  • 21 Nowak R A, Bahr J M. Secretion of a gonadotrophin-releasing hormone- (GnRH-)like factor by the rabbit fetal placenta in vitro.  Placenta. 1987;  8 299-304
    PubMedGoogle Scholar
  • 22 Gohar J, Mazor M, Leiberman J R. GnRH in pregnancy.  Arch Gynecol Obstet. 1996;  259 1-6
    PubMedGoogle Scholar
  • 23 Bercu B B, Hyashi A, Poth M, Alexandrova M, Soloff M S, Donahoe P K. Luteinizing hormone-releasing hormone-induced delay of parturition.  Endocrinology. 1980;  107 504-508
    PubMedGoogle Scholar
  • 24 Kang I S, Koong M K, Forman J, Siler-Khodr T M. Dose-related action of gonadotropin-releasing hormone on basal prostanoid production from the human term placenta.  Am J Obstet Gynecol. 1991;  165 1771-1776
    PubMedGoogle Scholar
  • 25 Chou C S, Beristain A G, MacCalman C D, Leung P C. Cellular localization of gonadotropin-releasing hormone (GnRH) I and GnRH II in first-trimester human placenta and decidua.  J Clin Endocrinol Metab. 2004;  89 1459-1466
    CrossrefPubMedGoogle Scholar
  • 26 Chou C S, Zhu H, MacCalman C D, Leung P C. Regulatory effects of gonadotropin-releasing hormone (GnRH) I and GnRH II on the levels of matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinases-1 in primary cultures of human extravillous cytotrophoblasts.  J Clin Endocrinol Metab. 2003;  88 4781-4790
    CrossrefPubMedGoogle Scholar
  • 27 Chou C S, MacCalman C D, Leung P C. Differential effects of gonadotropin-releasing hormone I and II on the urokinase-type plasminogen activator/plasminogen activator inhibitor system in human decidual stromal cells in vitro.  J Clin Endocrinol Metab. 2003;  88 3806-3815
    CrossrefPubMedGoogle Scholar
  • 28 Chou C S, Tai C J, MacCalman C D, Leung P C. Dose-dependent effects of gonadotropin releasing hormone on matrix metalloproteinase (MMP)-2, and MMP-9 and tissue specific inhibitor of metalloproteinases-1 messenger ribonucleic acid levels in human decidual Stromal cells in vitro.  J Clin Endocrinol Metab. 2003;  88 680-688
    CrossrefPubMedGoogle Scholar
  • 29 Radovick S, Wondisford F E, Nakayama Y, Yamada M, Cutler Jr G B, Weintraub B D. Isolation and characterization of the human gonadotropin-releasing hormone gene in the hypothalamus and placenta.  Mol Endocrinol. 1990;  4 476-480
    PubMedGoogle Scholar
  • 30 Dong K W, Yu K L, Roberts J L. Identification of a major up-stream transcription start site for the human progonadotropin-releasing hormone gene used in reproductive tissues and cell lines.  Mol Endocrinol. 1993;  7 1654-1666
    CrossrefPubMedGoogle Scholar
  • 31 Wong B C, Wang X, Oehninger S, Gibbons W E, Dong K W. Estrogen down-regulates GnRH gene expression in human placental cytotrophoblast cells.  Mol Cell Endocrinol. 2004;  213 199-210
    CrossrefPubMedGoogle Scholar
  • 32 Dong K W, Yu K L, Chen Z G, Chen Y D, Roberts J L. Characterization of multiple promoters directing tissue-specific expression of the human gonadotropin-releasing hormone gene.  Endocrinology. 1997;  138 2754-2762
    CrossrefPubMedGoogle Scholar
  • 33 Wolfe A, Kim H H, Tobet S, Stafford D E, Radovick S. Identification of a discrete promoter region of the human GnRH gene that is sufficient for directing neuron-specific expression: a role for POU homeodomain transcription factors.  Mol Endocrinol. 2002;  16 435-449
    CrossrefPubMedGoogle Scholar
  • 34 Clark M E, Mellon P L. The POU homeodomain transcription factor Oct-1 is essential for activity of the gonadotropin-releasing hormone neuron-specific enhancer.  Mol Cell Biol. 1995;  15 6169-6177
    PubMedGoogle Scholar
  • 35 Dong K W, Zheng H M, Wen Z Y, Chen Z G. The POU homeodomain protein Oct-1 binds Cis-regulatory element essential for the human GnRH upstream promoter activity in JEG-3 cells.  J Clin Endocrinol Metab. 2001;  86 2838-2844
    CrossrefPubMedGoogle Scholar
  • 36 Chen Z G, Chou C S, Hsu M I, Dong K W. Glucocorticoids modulate human gonadotrophin releasing hormone upstream promoter activity in transfected human placental cells (JEG-3).  Mol Hum Reprod. 1998;  4 93-99
    CrossrefPubMedGoogle Scholar
  • 37 Radovick S, Ticknor C M, Nakayama Y et al.. Evidence for direct estrogen regulation of the human gonadotropin-releasing hormone gene.  J Clin Invest. 1991;  88 1649-1655
    PubMedGoogle Scholar
  • 38 Wierman M E, Kepa J K, Sun W, Gordon D F, Wood W M. Estrogen negatively regulates rat gonadotropin releasing hormone (rGnRH) promoter activity in transfected placental cells.  Mol Cell Endocrinol. 1992;  86 1-10
    CrossrefPubMedGoogle Scholar
  • 39 Dong K W, Chen Z G, Cheng K W, Yu K L. Evidence for estrogen receptor-mediated regulation of human gonadotropin-releasing hormone promoter activity in human placental cells.  Mol Cell Endocrinol. 1996;  117 241-246
    CrossrefPubMedGoogle Scholar
  • 40 Chen Z, Zheng H, Dong K W. Identification of negative and positive estrogen response elements in human GnRH upstream promoter in the placental JEG-3 cells.  Mol Cell Endocrinol. 2001;  184 125-134
    CrossrefPubMedGoogle Scholar
  • 41 Janssens R M, Brus L, Cahill D J, Huirne J A, Schoemaker J, Lambalk C B. Direct ovarian effects and safety aspects of GnRH agonists and antagonists.  Hum Reprod Update. 2000;  6 505-518
    CrossrefPubMedGoogle Scholar
  • 42 Kang S K, Choi K C, Yang H S, Leung P C. Potential role of gonadotrophin-releasing hormone (GnRH)-I and GnRH-II in the ovary and ovarian cancer.  Endocr Relat Cancer. 2003;  10 169-177
    CrossrefPubMedGoogle Scholar
  • 43 Takekida S, Deguchi J, Samoto T, Matsuo H, Maruo T. Comparative analysis of the effects of gonadotropin-releasing hormone agonist on the proliferative activity, apoptosis, and steroidogenesis in cultured porcine granulosa cells at varying stages of follicular growth.  Endocrine. 2000;  12 61-67
    CrossrefPubMedGoogle Scholar
  • 44 Saragueta P E, Lanuza G M, Baranao J L. Inhibitory effect of gonadotrophin-releasing hormone (GnRH) on rat granulosa cell deoxyribonucleic acid synthesis.  Mol Reprod Dev. 1997;  47 170-174
    CrossrefPubMedGoogle Scholar
  • 45 Billig H, Furuta I, Hsueh A J. Gonadotropin-releasing hormone directly induces apoptotic cell death in the rat ovary: biochemical and in situ detection of deoxyribonucleic acid fragmentation in granulosa cells.  Endocrinology. 1994;  134 245-252
    CrossrefPubMedGoogle Scholar
  • 46 Zhao S, Saito H, Wang X, Saito T, Kaneko T, Hiroi M. Effects of gonadotropin-releasing hormone agonist on the incidence of apoptosis in porcine and human granulosa cells.  Gynecol Obstet Invest. 2000;  49 52-56
    CrossrefPubMedGoogle Scholar
  • 47 Goto T, Endo T, Henmi H et al.. Gonadotropin-releasing hormone agonist has the ability to induce increased matrix metalloproteinase (MMP)-2 and membrane type 1-MMP expression in corpora lutea, and structural luteolysis in rats.  J Endocrinol. 1999;  161 393-402
    CrossrefPubMedGoogle Scholar
  • 48 Tilly J L, LaPolt P S, Hsueh A J. Hormonal regulation of follicle-stimulating hormone receptor messenger ribonucleic acid levels in cultured rat granulosa cells.  Endocrinology. 1992;  130 1296-1302
    CrossrefPubMedGoogle Scholar
  • 49 Hsueh A J, Erickson G F. Extrapituitary action of gonadotropin-releasing hormone: direct inhibition ovarian steroidogenesis.  Science. 1979;  204 854-855
    CrossrefPubMedGoogle Scholar
  • 50 Vaananen J E, Tong B L, Vaananen C M, Chan I H, Yuen B H, Leung P C. Interaction of prostaglandin F2alpha and gonadotropin-releasing hormone on progesterone and estradiol production in human granulosa-luteal cells.  Biol Reprod. 1997;  57 1346-1353
    CrossrefPubMedGoogle Scholar
  • 51 Leung P C, Cheng C K, Zhu X M. Multi-factorial role of GnRH-I and GnRH-II in the human ovary.  Mol Cell Endocrinol. 2003;  202 145-153
    PubMedGoogle Scholar
  • 52 Piquette G N, LaPolt P S, Oikawa M, Hsueh A J. Regulation of luteinizing hormone receptor messenger ribonucleic acid levels by gonadotropins, growth factors, and gonadotropin-releasing hormone in cultured rat granulosa cells.  Endocrinology. 1991;  128 2449-2456
    PubMedGoogle Scholar
  • 53 Lynch J P, Lala D S, Peluso J J, Luo W, Parker K L, White B A. Steroidogenic factor 1, an orphan nuclear receptor, regulates the expression of the rat aromatase gene in gonadal tissues.  Mol Endocrinol. 1993;  7 776-786
    CrossrefPubMedGoogle Scholar
  • 54 Sridaran R, Philip G H, Li H et al.. GnRH agonist treatment decreases progesterone synthesis, luteal peripheral benzodiazepine receptor mRNA, ligand binding and steroidogenic acute regulatory protein expression during pregnancy.  J Mol Endocrinol. 1999;  22 45-54
    CrossrefPubMedGoogle Scholar
  • 55 Clayton R N, Harwood J P, Catt K J. Gonadotropin-releasing hormone analogue binds to luteal cells and inhibits progesterone production.  Nature. 1979;  282 90-92
    PubMedGoogle Scholar
  • 56 Macdonald G J, Beattie C W. Pregnancy failure in hypophysectomized rats following LH-RH administration.  Life Sci. 1979;  24 1103-1110
    CrossrefPubMedGoogle Scholar
  • 57 Jones P B, Hsueh A J. Direct inhibitory effect of gonadotropin-releasing hormone upon luteal luteinizing hormone receptor and steroidogenesis in hypophysectomized rats.  Endocrinology. 1980;  107 1930-1936
    PubMedGoogle Scholar
  • 58 Corbin A, Bex F J. Luteinizing hormone releasing hormone agonists induce ovulation in hypophysectomized proestrous rats: direct ovarian effect.  Life Sci. 1981;  29 185-192
    CrossrefPubMedGoogle Scholar
  • 59 Ekholm C, Hillensjo T, Isaksson O. Gonadotropin releasing hormone agonists stimulate oocyte meiosis and ovulation in hypophysectomized rats.  Endocrinology. 1981;  108 2022-2024
    CrossrefPubMedGoogle Scholar
  • 60 Wong W Y, Richards J S. Induction of prostaglandin H synthase in rat preovulatory follicles by gonadotropin-releasing hormone.  Endocrinology. 1992;  130 3512-3521
    CrossrefPubMedGoogle Scholar
  • 61 Morris J K, Richards J S. Hormone induction of luteinization and prostaglandin endoperoxide synthase-2 involves multiple cellular signaling pathways.  Endocrinology. 1993;  133 770-779
    CrossrefPubMedGoogle Scholar
  • 62 Natraj U, Richards J S. Hormonal regulation, localization, and functional activity of the progesterone receptor in granulosa cells of rat preovulatory follicles.  Endocrinology. 1993;  133 761-769
    CrossrefPubMedGoogle Scholar
  • 63 Ny T, Liu Y X, Ohlsson M, Jones P B, Hsueh A J. Regulation of tissue-type plasminogen activator activity and messenger RNA levels by gonadotropin-releasing hormone in cultured rat granulosa cells and cumulus-oocyte complexes.  J Biol Chem. 1987;  262 11790-11793
    PubMedGoogle Scholar
  • 64 Hillensjo T, LeMaire W J. Gonadotropin releasing hormone agonists stimulate meiotic maturation of follicle-enclosed rat oocytes in vitro.  Nature. 1980;  287 145-146
    PubMedGoogle Scholar
  • 65 Magnusson C, LeMaire W J. A gonadotrophin-releasing hormone agonist stimulates oxygen consumption and maturation of follicle-enclosed rat oocytes in vitro.  Acta Physiol Scand. 1981;  111 377-379
    PubMedGoogle Scholar
  • 66 Yoshimura Y, Nakamura Y, Ando M, Shiokawa S, Koyama N, Nanno T. Direct effect of gonadotropin-releasing hormone agonists on the rabbit ovarian follicle.  Fertil Steril. 1992;  57 1091-1097
    PubMedGoogle Scholar
  • 67 Schirman-Hildesheim T D, Bar T, Ben-Aroya N, Koch Y. Differential gonadotropin-releasing hormone (GnRH) and GnRH receptor messenger ribonucleic acid expression patterns in different tissues of the female rat across the estrous cycle.  Endocrinology. 2005;  146 3401-3408
    CrossrefPubMedGoogle Scholar
  • 68 Reeves J J, Seguin C, Lefebvre F A, Kelly P A, Labrie F. Similar luteinizing hormone-releasing hormone binding sites in rat anterior pituitary and ovary.  Proc Natl Acad Sci USA. 1980;  77 5567-5571
    CrossrefPubMedGoogle Scholar
  • 69 Jones P B, Conn P M, Marian J, Hsueh A J. Binding of gonadotropin releasing hormone agonist to rat ovarian granulosa cells.  Life Sci. 1980;  27 2125-2132
    CrossrefPubMedGoogle Scholar
  • 70 Seguin C, Pelletier G, Dube D, Labrie F. Distribution of luteinizing hormone-releasing hormone receptors in the rat ovary.  Regul Pept. 1982;  4 183-190
    CrossrefPubMedGoogle Scholar
  • 71 Olofsson J I, Conti C C, Leung P C. Homologous and heterologous regulation of gonadotropin-releasing hormone receptor gene expression in preovulatory rat granulosa cells.  Endocrinology. 1995;  136 974-980
    CrossrefPubMedGoogle Scholar
  • 72 Minaretzis D, Jakubowski M, Mortola J F, Pavlou S N. Gonadotropin-releasing hormone receptor gene expression in human ovary and granulosa-lutein cells.  J Clin Endocrinol Metab. 1995;  80 430-434
    CrossrefPubMedGoogle Scholar
  • 73 Kang S K, Choi K C, Cheng K W, Nathwani P S, Auersperg N, Leung P C. Role of gonadotropin-releasing hormone as an autocrine growth factor in human ovarian surface epithelium.  Endocrinology. 2000;  141 72-80
    CrossrefPubMedGoogle Scholar
  • 74 Ramakrishnappa N, Rajamahendran R, Lin Y M, Leung P C. GnRH in non-hypothalamic reproductive tissues.  Anim Reprod Sci. 2005;  88 95-113
    CrossrefPubMedGoogle Scholar
  • 75 Bull P, Morales P, Huyser C, Socias T, Castellon E A. Expression of GnRH receptor in mouse and rat testicular germ cells.  Mol Hum Reprod. 2000;  6 582-586
    CrossrefPubMedGoogle Scholar
  • 76 Moumni M, Kottler M L, Counis R. Nucleotide sequence analysis of mRNAs predicts that rat pituitary and gonadal gonadotropin-releasing hormone receptor proteins have identical primary structure.  Biochem Biophys Res Commun. 1994;  200 1359-1366
    CrossrefPubMedGoogle Scholar
  • 77 Peng C, Fan N C, Ligier M, Vaananen J, Leung P C. Expression and regulation of gonadotropin-releasing hormone (GnRH) and GnRH receptor messenger ribonucleic acids in human granulosa-luteal cells.  Endocrinology. 1994;  135 1740-1746
    CrossrefPubMedGoogle Scholar
  • 78 Hsueh A J, Jones P B. Extrapituitary actions of gonadotropin-releasing hormone.  Endocr Rev. 1981;  2 437-461
    PubMedGoogle Scholar
  • 79 Nett T M, Akbar A M, Niswender G D. Serum levels of luteinizing hormone and gonadotropin-releasing hormone in cycling, castrated and anestrous ewes.  Endocrinology. 1974;  94 713-718
    PubMedGoogle Scholar
  • 80 Oikawa M, Dargan C, Ny T, Hsueh A J. Expression of gonadotropin-releasing hormone and prothymosin-alpha messenger ribonucleic acid in the ovary.  Endocrinology. 1990;  127 2350-2356
    PubMedGoogle Scholar
  • 81 Clayton R N, Eccleston L, Gossard F, Thalbard J C, Morel G. Rat granulosa cells express the gonadotrophin-releasing hormone gene: evidence from in-situ hybridization histochemistry.  J Mol Endocrinol. 1992;  9 189-195
    PubMedGoogle Scholar
  • 82 Nathwani P S, Kang S K, Cheng K W, Choi K C, Leung P C. Regulation of gonadotropin-releasing hormone and its receptor gene expression by 17beta-estradiol in cultured human granulosa-luteal cells.  Endocrinology. 2000;  141 1754-1763
    CrossrefPubMedGoogle Scholar
  • 83 Chen Z G, Yu K L, Zheng H M, Dong K W. Estrogen receptor-mediated repression of gonadotropin-releasing hormone (GnRH) promoter activity in transfected CHO-K1 cells.  Mol Cell Endocrinol. 1999;  158 131-142
    CrossrefPubMedGoogle Scholar
  • 84 Goubau S, Bond C T, Adelmaln J P et al.. Partial characterization of the gonadotropin-releasing hormone (GNRH) gene transcript in the rat ovary.  Endocrinology. 1992;  130 3098-3100
    CrossrefPubMedGoogle Scholar
  • 85 Kim H H, Wolfe A, Smith G R, Tobet S A, Radovick S. Promoter sequences targeting tissue-specific gene expression of hypothalamic and ovarian gonadotropin-releasing hormone in vivo.  J Biol Chem. 2002;  277 5194-5202
    CrossrefPubMedGoogle Scholar
  • 86 Kim H H, Wolfe A, Cohen R N et al.. In vivo identification of a 107-base pair promoter element mediating neuron-specific expression of mouse gonadotropin-releasing hormone.  Mol Endocrinol. 2007;  21 457-471
    PubMedGoogle Scholar
  • 87 Lawson M A, Macconell L A, Kim J, Powl B T, Nelson S B, Mellon P L. Neuron-specific expression in vivo by defined transcription regulatory elements of the GnRH gene.  Endocrinology. 2002;  143 1404-1412
    CrossrefPubMedGoogle Scholar
  • 88 Wolfe A M, Wray S, Westphal H, Radovick S. Cell-specific expression of the human gonadotropin-releasing hormone gene in transgenic animals.  J Biol Chem. 1996;  271 20018-20023
    CrossrefPubMedGoogle Scholar
  • 89 Baram T, Koch Y, Hazum E, Fridkin M. Gonadotropin-releasing hormone in milk.  Science. 1977;  198 300-302
    CrossrefPubMedGoogle Scholar
  • 90 Palmon A, Ben Aroya N, Tel-Or S, Burstein Y, Fridkin M, Koch Y. The gene for the neuropeptide gonadotropin-releasing hormone is expressed in the mammary gland of lactating rats.  Proc Natl Acad Sci USA. 1994;  91 4994-4996
    CrossrefPubMedGoogle Scholar
  • 91 Ikeda M, Taga M, Sakakibara H, Minaguchi H, Vonderhaar B K. Detection of messenger RNA for gonadotropin-releasing hormone (GnRH) but not for GnRH receptors in mouse mammary glands.  Biochem Biophys Res Commun. 1995;  207 800-806
    CrossrefPubMedGoogle Scholar
  • 92 Amarant T, Fridkin M, Koch Y. Luteinizing hormone-releasing hormone and thyrotropin-releasing hormone in human and bovine milk.  Eur J Biochem. 1982;  127 647-650
    PubMedGoogle Scholar
  • 93 Smith S S, Ojeda S R. Maternal modulation of infantile ovarian development and available ovarian luteinizing hormone-releasing hormone (LHRH) receptors via milk LHRH.  Endocrinology. 1984;  115 1973-1983
    PubMedGoogle Scholar
  • 94 Levi L N, Ben-Aroya N, Tel-Or S, Palmon A, Burstein Y, Koch Y. Expression of the gene for the receptor of gonadotropin-releasing hormone in the rat mammary gland.  FEBS Lett. 1996;  379 186-190
    CrossrefPubMedGoogle Scholar
  • 95 Kakar S S, Grizzle W E, Neill J D. The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary.  Mol Cell Endocrinol. 1994;  106 145-149
    CrossrefPubMedGoogle Scholar
  • 96 Seppala M, Wahlstrom T. Identification of luteinizing hormone-releasing factor and alpha subunit of glycoprotein hormones in ductal carcinoma of the mammary gland.  Int J Cancer. 1980;  26 267-268
    CrossrefPubMedGoogle Scholar
  • 97 Harris N, Dutlow C, Eidne K, Dong K W, Roberts J, Millar R. Gonadotropin-releasing hormone gene expression in MDA-MB-231 and ZR-75-1 breast carcinoma cell lines.  Cancer Res. 1991;  51 2577-2581
    PubMedGoogle Scholar
  • 98 Kottler M L, Starzec A, Carre M C, Lagarde J P, Martin A, Counis R. The genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer.  Int J Cancer. 1997;  71 595-599
    CrossrefPubMedGoogle Scholar
  • 99 Chen A, Kaganovsky E, Rahimipour S, Ben-Aroya N, Okon E, Koch Y. Two forms of gonadotropin-releasing hormone (GnRH) are expressed in human breast tissue and overexpressed in breast cancer: a putative mechanism for the antiproliferative effect of GnRH by down-regulation of acidic ribosomal phosphoproteins P1 and P2.  Cancer Res. 2002;  62 1036-1044
    PubMedGoogle Scholar
  • 100 Grundker C, Huschmand Nia A, Emons G. Gonadotropin-releasing hormone receptor-targeted gene therapy of gynecologic cancers.  Mol Cancer Ther. 2005;  4 225-231
    PubMedGoogle Scholar
  • 101 Petersen S L, Ottem E N, Carpenter C D. Direct and indirect regulation of gonadotropin-releasing hormone neurons by estradiol.  Biol Reprod. 2003;  69 1771-1778
    CrossrefPubMedGoogle Scholar
  • 102 Clayton R N, Katikineni M, Chan V, Dufau M L, Catt K J. Direct inhibition of testicular function by gonadotropin-releasing hormone: mediation by specific gonadotropin-releasing hormone receptors in interstitial cells.  Proc Natl Acad Sci USA. 1980;  77 4459-4463
    CrossrefPubMedGoogle Scholar
  • 103 Lefebvre F A, Reeves J J, Seguin C, Massicotte J, Labrie F. Specific binding of a potent LHRH agonist in rat testis.  Mol Cell Endocrinol. 1980;  20 127-134
    CrossrefPubMedGoogle Scholar
  • 104 Sharpe R M, Fraser H M. Leydig cell receptors for luteinizing hormone releasing hormone and its agonists and their modulation by administration or deprivation of the releasing hormone.  Biochem Biophys Res Commun. 1980;  95 256-262
    CrossrefPubMedGoogle Scholar
  • 105 Fasano S, de Leeuw R, Pierantoni R, Chieffi G, van Oordt P G. Characterization of gonadotropin-releasing hormone (GnRH) binding sites in the pituitary and testis of the frog, Rana esculenta .  Biochem Biophys Res Commun. 1990;  168 923-932
    CrossrefPubMedGoogle Scholar
  • 106 Yu K L, He M L, Chik C C, Lin X W, Chang J P, Peter R E. mRNA expression of gonadotropin-releasing hormones (GnRHs) and GnRH receptor in goldfish.  Gen Comp Endocrinol. 1998;  112 303-311
    CrossrefPubMedGoogle Scholar
  • 107 Botte M C, Chamagne A M, Carre M C, Counis R, Kottler M L. Fetal expression of GnRH and GnRH receptor genes in rat testis and ovary.  J Endocrinol. 1998;  159 179-189
    CrossrefPubMedGoogle Scholar
  • 108 Bahk J Y, Hyun J S, Chung S H et al.. Stage specific identification of the expression of GnRH mRNA and localization of the GnRH receptor in mature rat and adult human testis.  J Urol. 1995;  154 1958-1961
    CrossrefPubMedGoogle Scholar
  • 109 Tieva A, Stattin P, Wikstrom P, Bergh A, Damber J E. Gonadotropin-releasing hormone receptor expression in the human prostate.  Prostate. 2001;  47 276-284
    CrossrefPubMedGoogle Scholar
  • 110 Sharpe R M, Fraser H M. HCG stimulation of testicular LHRH-like activity.  Nature. 1980;  287 642-643
    PubMedGoogle Scholar
  • 111 Sharpe R M, Fraser H M, Cooper I, Rommerts F F. Sertoli-Leydig cell communication via an LHRH-like factor.  Nature. 1981;  290 785-787
    PubMedGoogle Scholar
  • 112 Paull W K, Turkelson C M, Thomas C R, Arimura A. Immunohistochemical demonstration of a testicular substance related to luteinizing hormone-releasing hormone.  Science. 1981;  213 1263-1264
    CrossrefPubMedGoogle Scholar
  • 113 Azad N, Uddin S, La Paglia N et al.. Luteinizing hormone-releasing hormone (LHRH) in rat prostate: characterization of LHRH peptide, messenger ribonucleic acid expression, and molecular processing of LHRH in intact and castrated male rats.  Endocrinology. 1993;  133 1252-1257
    CrossrefPubMedGoogle Scholar
  • 114 Uzbekova S, Lareyre J, Guiguen Y, Ferriere F, Bailhache T, Breton B. Expression of sGnRH mRNA in gonads during rainbow trout gametogenesis.  Comp Biochem Physiol B Biochem Mol Biol. 2001;  129 457-465
    PubMedGoogle Scholar
  • 115 Soverchia L, Carotti M, Andreu-Vieyra C et al.. Role of gonadotropin-releasing hormone (GnRH) in the regulation of gonadal differentiation in the gilthead seabream (Sparus aurata).  Mol Reprod Dev. 2007;  74 57-67
    CrossrefPubMedGoogle Scholar
  • 116 Lau H L, Zhu X M, Leung P C et al.. Detection of mRNA expression of gonadotropin-releasing hormone and its receptor in normal and neoplastic rat prostates.  Int J Oncol. 2001;  19 1193-1201
    PubMedGoogle Scholar
  • 117 Bahk J Y, Hyun J S, Lee H et al.. Expression of gonadotropin-releasing hormone (GnRH) and GnRH receptor mRNA in prostate cancer cells and effect of GnRH on the proliferation of prostate cancer cells.  Urol Res. 1998;  26 259-264
    CrossrefPubMedGoogle Scholar
  • 118 Arimura A, Serafini P, Talbot S, Schally A V. Reduction of testicular luteinizing hormone/human chorionic gonadotropin receptors by [D-Trp6]-luteinizing hormone releasing hormone in hypophysectomized rats.  Biochem Biophys Res Commun. 1979;  90 687-693
    CrossrefPubMedGoogle Scholar
  • 119 Hsueh A J, Erickson G F. Extra-pituitary inhibition of testicular function by luteinising hormone releasing hormone.  Nature. 1979;  281 66-67
    PubMedGoogle Scholar
  • 120 Hsueh A J, Schaeffer J M. Gonadotropin-releasing hormone as a paracrine hormone and neurotransmitter in extra-pituitary sites.  J Steroid Biochem. 1985;  23 757-764
    PubMedGoogle Scholar
  • 121 Bambino T H, Schreiber J R, Hsueh A J. Gonadotropin-releasing hormone and its agonist inhibit testicular luteinizing hormone receptor and steroidogenesis in immature and adult hypophysectomized rats.  Endocrinology. 1980;  107 908-917
    PubMedGoogle Scholar
  • 122 Sharpe R M, Cooper I. Stimulatory effect of LHRH and its agonists on Leydig cell steroidogenesis in vitro.  Mol Cell Endocrinol. 1982;  26 141-150
    CrossrefPubMedGoogle Scholar
  • 123 Sharpe R M, Doogan D G, Cooper I. Stimulation of Leydig cell testosterone secretion in vitro and in vivo in hypophysectomized rats by an agonist of luteinizing hormone releasing hormone.  Biochem Biophys Res Commun. 1982;  106 1210-1217
    CrossrefPubMedGoogle Scholar
  • 124 Andreu-Vieyra C V, Buret A G, Habibi H R. Gonadotropin-releasing hormone induction of apoptosis in the testes of goldfish (Carassius auratus).  Endocrinology. 2005;  146 1588-1596
    PubMedGoogle Scholar
  • 125 Minucci S, Di Matteo L, Pierantoni R, Varriale B, Rastogi R K, Chieffi G. In vivo and in vitro stimulatory effect of a gonadotropin-releasing hormone analog (HOE 766) on spermatogonial multiplication in the frog, Rana esculenta .  Endocrinology. 1986;  119 731-736
    PubMedGoogle Scholar
  • 126 Meistrich M L, Kangasniemi M. Hormone treatment after irradiation stimulates recovery of rat spermatogenesis from surviving spermatogonia.  J Androl. 1997;  18 80-87
    PubMedGoogle Scholar
  • 127 Meistrich M L, Wilson G, Huhtaniemi I. Hormonal treatment after cytotoxic therapy stimulates recovery of spermatogenesis.  Cancer Res. 1999;  59 3557-3560
    PubMedGoogle Scholar
  • 128 Morales P. Gonadotropin-releasing hormone increases ability of the spermatozoa to bind to the human zona pellucida.  Biol Reprod. 1998;  59 426-430
    CrossrefPubMedGoogle Scholar
  • 129 Clayton R N. Gonadotrophin-releasing hormone: its actions and receptors.  J Endocrinol. 1989;  120 11-19
    PubMedGoogle Scholar
  • 130 Kaiser U B, Conn P M, Chin W W. Studies of gonadotropin-releasing hormone (GnRH) action using GnRH receptor-expressing pituitary cell lines.  Endocr Rev. 1997;  18 46-70
    CrossrefPubMedGoogle Scholar
  • 131 Gupta R K, Flaws J A. Gonadotropin-releasing hormone (GnRH) analogues and the ovary: do GnRH antagonists destroy primordial follicles?.  Fertil Steril. 2005;  83 1339-1342
    CrossrefPubMedGoogle Scholar

Helen H KimM.D. 

Director, In Vitro Fertilization Program, Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology

The University of Chicago, 5841 South Maryland, MC 2050, Chicago, IL 60637

eMail: hkim@babies.bsd.uchicago.edu