GnRH-GnRH-Receptor System in the Mammalian Female Reproductive Tract

  • Indrajit Chowdhury
  • Rajagopala Sridaran

Reproduction in mammals is controlled by interactions between the hypothalamus, anterior pituitary, and gonads. The hypothalamus secretes synchronized pulses of gonadotropin-releasing hormone (GnRH) as the central initiator of the reproductive hormonal cascade from the diffusely arranged network of neuronal nerve endings of about 800 (rodents) to 1,500–2,000 (human) into the hypophyseal portal system every 30–120 min. GnRH stimulates the biosynthesis and secretion of the gonadotropic hormones, LH, and FSH by the anterior pituitary that in turn regulate the production of gametes and gonadal hormones as a key regulator of the reproductive functions. In the 1970 s, GnRH was first isolated from hypothalamus of pigs and sheep, and the subsequent realization that the decapeptide sequence was conserved across all mammals. This form of GnRH is referred as GnRH-I or type I mammalian GnRH (mGnRH). In 1977, Andrew Schally, Roger Guillemin, and co-workers shared the Nobel Prize in the field of Medicine for their discovery. In the early 1980 s, a second GnRH isoform from chickens was isolated (chicken GnRH; GnRH-II) [1] and a third isoform was identified in fish (salmon GnRH) [2]. Currently, a total of 23 different isoforms of chordate GnRH have been isolated [3–5]. All of these isoforms are decapeptides that share a high degree of sequence identity at both NH2- and COOH-terminals. This overview describes the recent literature regarding the GnRH primary structure, tissue distribution in female reproductive system, synthesis, secretion, and signaling pathways with current understanding on their cognate receptors and functional significance in relation to female reproductive system.


Granulosa Cell Ovarian Cancer Cell Corpus Luteum Ovarian Cancer Cell Line Ovarian Surface Epithelial 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


13.10Glossary of Terms and Acronyms


activator protein-1




Bcl-2 family member


ovarian cell line


CCAAT/enhancer binding protein


product of the proto-oncogene c-fos that dimerize with c-Jun (c-Fos/c-Jun heterodimer) to form the transcription factor AP-1


caspase inhibitor


caspase inhibitor


product of the proto-oncogene c-jun that dimerize with c-Fos to form the transcription factor AP-1.


cAMP response element




diagonal band of Broca


ovarian cancer cell line


ovarian cancer cell line


epidermal growth factor


epidermal growth factor receptor


extracellular loop


estrogen receptor


extracellular signal-regulated kinase


follicle stimulating hormone


GnRH-associated peptide region


somatolactotroph cells


granulosa luteal cells


gonadotropin-releasing hormone


gonadotropin-releasing hormone receptor


GnRHR-specific enhancer


G protein-coupled receptors


GnRHR activating sequence


glucocorticoid responsive element/ progesterone responsive element


G protein-coupled receptor kinases


human granulosa-luteal cells


high-performance liquid chromatography


immortalized extravillous trophoblast


inhibitor of kappa B


intracellular loop


in vitro fertilization


placental cell line


Jun N-terminal kinase


gonadotroph cell line


luteinizing hormone


mitogen activated protein kinases

MEK 1:

threonine and tyrosine recognition kinase


matrix metalloproteinase


melatonin receptor subtype


melatonin receptor subtype


nuclear factor-kappa B


negative regulatory element


ovarian epithelial cells


ovarian surface epithelial cells


ovarian cell line


plasminogen activator inhibitor


polymerase chain reaction


pan pituitary homeobox transcription factor


protein kinase C


preoptic area of the brain


preoptic area of anterior hypothalamus


progesterone receptor


progesterone receptor elements


oncogene of the Harvey (rasH) and Kristen (rasK) rat sarcoma viruses. These genes, which are frequently activated in human tumors, encode a 21 kD G-protein.


RNA-binding motif protein-8A


reverse transcriptase polymerase chain reaction


steroidogenic factor-1


ovarian cell line


name of the first described retroviral oncogene (v-src), from the chicken Rous sarcoma retrovirus and its precursor (c-src), which encode a membrane-associated protein kinase.


sequence underlying responsiveness to GnRH element


human ovarian granulosa-luteal cell line


theca luteal cells


human ovarian granulosa-luteal cell line


neuronal cell line




untranslated region


inositol 1,4,5-triphosphate


ovarian cell line


  1. 1.
    Miyamoto K, Hasegawa Y, Nomura M, et al. Identification of a second gonadotropin releasing hormone in chicken hypothalamus: evidence that gonadotropin secretion is probably controlled by two distinct gonadotropin-releasing hormones in avian species. Proc Natl Acad Sci USA 1984; 81:3874–8.Google Scholar
  2. 2.
    Sherwood NM, Harvey B, Brownstein MJ, et al. Gonadotropin-releasing hormone (Gn-RH) in striped mullet (Mugil cephalus), milkfish (Chanos chanos), and rainbow trout (Salmo gairdneri): comparison with salmon GnRH. Gen Comp Endocrinol 1984; 55:174–81.PubMedCrossRefGoogle Scholar
  3. 3.
    Guilgur LG, Moncaut NP, Canário AV, et al. Evolution of GnRH ligands and receptors in gnathostomata. Comp Biochem Physiol A Mol Integr Physiol 2006; 144:272–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Morgan K, Millar RP. Evolution of GnRH ligand precursors and GnRH receptors in protochordate and vertebrate species. Gen Comp Endocrinol 2004; 139:191–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Kah O, Lethimonier C, Somoza G, et al. GnRH and GnRH receptors in metazoa: a historical, comparative, and evolutive perspective. Gen Comp Endocrinol 2007; 153:346–64.PubMedCrossRefGoogle Scholar
  6. 6.
    Seeburg PH, Adelman JP. Characterization of cDNA for precursor of human luteinizing hormone releasing hormone. Nature 1984; 311:666–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Millar RP. GnRHs and GnRH receptors. Anim Reprod Sci 2005; 88:5–28.PubMedCrossRefGoogle Scholar
  8. 8.
    Rispoli LA, Nett TM. Pituitary gonadotropin-releasing hormone (GnRH) receptor: structure, distribution and regulation of expression. Anim Reprod Sci 2005; 88:57–74.PubMedCrossRefGoogle Scholar
  9. 9.
    Choi JH, Gilks CB, Auersperg N, et al. Immunolocalization of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and type I GnRH receptor during follicular development in the human ovary. J Clin Endocrinol Metab 2006; 91:4562–70.PubMedCrossRefGoogle Scholar
  10. 10.
    Choi JH, Choi KC, Auersperg N, et al. Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid by gonadotropins in human immortalized ovarian surface epithelium and ovarian cancer cells. Endocrinol Relat Cancer 2006; 13:641–51.CrossRefGoogle Scholar
  11. 11.
    Cheng CK, Leung PC. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev 2005; 26:283–306.PubMedCrossRefGoogle Scholar
  12. 12.
    Chakrabarti N, Subbarao T, Sengupta A, et al. Expression of mRNA and proteins for GnRH I and II and their receptors in primate corpus luteum during menstrual cycle. Mol Reprod Dev 2008; 75:1567–1577.Google Scholar
  13. 13.
    Leung PC, Cheng CK, Zhu XM. Multi-factorial role of GnRH-I and GnRH-II in the human ovary. Mol Cell Endocrinol 2003; 202:145–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Metallinou C, Asimakopoulos B, Schröer A, et al. Gonadotropin-releasing hormone in the ovary. Reprod Sci 2007; 14:737–49.PubMedCrossRefGoogle Scholar
  15. 15.
    Ramakrishnappa N, Rajamahendran R, Lin YM, et al. GnRH in non-hypothalamic reproductive tissues. Anim Reprod Sci 2005; 88:95–113.PubMedCrossRefGoogle Scholar
  16. 16.
    Sengupta A, Baker T, Chakrabarti N, et al. Localization of immunoreactive gonadotropin-releasing hormone and relative expression of its mRNA in the oviduct during pregnancy in rats. J Histochem Cytochem 2007; 55:525–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Sengupta A, Chakrabarti N, Sridaran R. Presence of immunoreactive gonadotropin releasing hormone (GnRH) and its receptor (GnRHR) in rat ovary during pregnancy. Mol Reprod Dev 2008; 75:1031–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Clarke IJ, Pompolo S. Synthesis and secretion of GnRH. Animal Reprod Sci 2005; 88:29–55.CrossRefGoogle Scholar
  19. 19.
    Yang-Feng TL, Seeburg PH, Francke U. Human luteinizing hormone-releasing hormone gene (LHRH) is located on short arm of chromosome 8 (region 8p11.2----p21). Somat Cell Mol Genet 1986; 12:95–100.PubMedCrossRefGoogle Scholar
  20. 20.
    Schirman-Hildesheim TD, Bar T, Ben-Aroya N, et al. 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; 146:3401–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Hapgood JP, Sadie H, van Biljon W, et al. Regulation of expression of mammalian gonadotrophin-releasing hormone receptor genes. J Neuroendocrinol 2005; 17:619–38.PubMedCrossRefGoogle Scholar
  22. 22.
    Millar RP, Lu ZL, Pawson AJ, et al. Gonadotropin-releasing hormone receptors. Endocr Rev 2004; 25:235–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Faurholm B, Millar RP, Katz AA. The genes encoding the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genomic loci. Genomics 2001; 78:15–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Sengupta A, Sridaran R. Expression and localization of gonadotropin-releasing hormone receptor in the rat oviduct during pregnancy. J Histochem Cytochem 2008; 56:25–31.PubMedCrossRefGoogle Scholar
  25. 25.
    Ruf F, Fink MY, Sealfon SC. Structure of the GnRH receptor-stimulated signaling network: insights from genomics. Front Neuroendocrinol 2003; 24:181–99.PubMedCrossRefGoogle Scholar
  26. 26.
    Caunt CJ, Finch AR, Sedgley KR, et al. GnRH receptor signalling to ERK: kinetics and compartmentalization. Trends Endocrinol Metab 2006; 17:308–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Motola S, Cao X, Ashkenazi H, et al. GnRH actions on rat preovulatory follicles are mediated by paracrine EGF-like factors. Mol Reprod Dev 2006; 73:1271–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Pawson AJ, McNeilly AS. The pituitary effects of GnRH. Anim Reprod Sci 2005; 88:75–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Chen A, Laskar-Levy O, Ben-Aroya N, et al. Transcriptional regulation of the human GnRH II gene is mediated by a putative cAMP response element. Endocrinology 2001; 142: 3483–92.PubMedCrossRefGoogle Scholar
  30. 30.
    Chen A, Ziv K, Laskar-Levy O, et al. The transcription of the hGnRH-I and hGnRH-II genes in human neuronal cells is differentially regulated by estrogen. J Mol Neurosci 2002; 18:67–76.PubMedCrossRefGoogle Scholar
  31. 31.
    Stocco C, Telleria C, Gibori G. The molecular control of corpus luteum formation, function, and regression. Endocr Rev 2007; 28:117–49.PubMedCrossRefGoogle Scholar
  32. 32.
    Lareu RR, Lacher MD, Bradley CK, et al. Regulated expression of inhibitor of apoptosis protein 3 in the rat corpus luteum. Biol Reprod 2003; 68:2232–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Papadopoulos V, Dharmarajan AM, Li H, et al. Mitochondrial peripheral-type benzodiazepine receptor expression. Correlation with gonadotropin-releasing hormone (GnRH) agonist-induced apoptosis in the corpus luteum. Biochem Pharmacol 1999; 58:1389–93.PubMedCrossRefGoogle Scholar
  34. 34.
    Sridaran R, Hisheh S, Dharmarajan AM. Induction of apoptosis by a gonadotropin-releasing hormone agonist during early pregnancy in the rat. Apoptosis 1998; 3:51–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Sridaran R, Philip GH, 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.PubMedCrossRefGoogle Scholar
  36. 36.
    Sridaran R, Lee MA, Haynes L, et al. GnRH action on luteal steroidogenesis during pregnancy. Steroids 1999; 64: 618–23.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Indrajit Chowdhury
    • 1
    • 2
  • Rajagopala Sridaran
    • 2
  1. 1.Department of Obstetrics and GynecologyMorehouse School of MedicineAtlantaUSA
  2. 2.Department of PhysiologyMorehouse School of MedicineAtlantaUSA

Personalised recommendations