Gonadotrophin-releasing hormone receptors: Introduction


Hypothalamic gonadotropin-releasing hormone (GnRH), also named luteinizing-hormone-releasing hormone (LHRH), was first isolated from porcine hypothalami in 1971 [17]. GnRH is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly.NH2) that plays an important role in the control of gonadal function and normal ovarian cyclicity. It is now called GnRH-I, as in man a second (GnRH-II) and third form (GnRH-III) of GnRH were later identified [24-25]. GnRH-II differs from GnRH-I by three amino acid residues (His5Trp7Tyr8GnRH-I) and is expressed at higher levels outside of the brain [20]. Like GnRH-I, it plays a role in a variety of reproductive and non-reproductive functions [1]. GnRH-III differs from GnRH-I by four amino acids (His5Asp6Trp7Lys8GnRH-I) and its distribution of expression in the brain indicates that it functions as a neurohormone at the hypothalamic-pituitary axis, next to other functions [25]. Moreover, it has been shown to have an antiproliferative effect on cancer cells [12] and it is not able to induce LH and FSH release in mammels [11].

The regulation of the ovarian cycle is dependent on a continuous interaction between the hypothalamus, the pituitary gland and the ovaries. GnRH is secreted by the hypothalamus in a pulsatile fashion [21]. Subsequently, GnRH is transported to the anterior pituitary, where it binds to specific receptors on the gonadotrope cells. This results in the biosynthesis and secretion of FSH and LH from the pituitary gonadotrope cells.

Receptor Structure

The cDNA sequence of the GnRH receptor was first elucidated in the early 1990's [2,9]. This receptor is a member of the rhodopsin-like (class A) G protein-coupled receptor (GPCR) superfamily. The receptor consists of seven α-helical transmembrane domains with typical sequence signatures of class A-like GPCRs and an extracellular amino terminal domain. A unique feature is the absence of an intracellular carboxy terminal domain [14]. A full length GnRH-II receptor transcript has not been identified in humans thus far, although it is present in other mammals. Thus in man there is one functional receptor with three endogenous ligands that all have a high affinity for the receptor [6,13,18].

The GnRH type I receptor is predominantly coupled to the Gq-protein, through which it regulates the biosynthesis and secretion of the gonadotropins, FSH and LH. However, signal transduction can also occur via other G-proteins or even in a G protein-independent manner [14].


Over the past decades several peptide agonists and antagonists for GnRH receptors have been developed [3-4,8]. In addition, quite a few non-peptide antagonists from various chemical classes have been reported, of which some were shown to be active in vivo after oral adminstration [16,22]. Combined site-directed mutagenesis and homology-based receptor modelling pointed to amino acids in the third and seventh transmembrane domains as being critically important for peptide and non-peptide ligand binding. The binding site of non-peptide GnRH antagonists is currently thought to partially overlap with the binding site of the endogenous ligand GnRH and may also use some of the residues that are crucial for peptide binding [7].

Recently, the first evidence arose that besides the traditional agonist recognition site there is an allosteric site that modulates orthosteric ligand binding and subsequent biological effects [19].

GnRH receptor agonists and antagonists have been shown to be beneficial in IVF procedures. It should be noted that (peptide) agonists are used to desensitize the receptor, which in turn also results in a decreased gonadotrope function [15]. In addition, GnRH receptor ligands may also be applied in a number of sex hormone-dependent conditions [10,23]. Notably, various peptide GnRH receptor agonists and antagonists are marketed for the treatment of prostate, breast, uterine and ovarian cancer, leiomyomas, infertility, benign prostatic hyperplasia (BPH), IVF, premenstrual syndrome and endometriosis [5].


Show »

1. Cheng CK, Leung PC. (2005) Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev, 26 (2): 283-306. [PMID:15561800]

2. Chi L, Zhou W, Prikhozhan A, Flanagan C, Davidson JS, Golembo M, Illing N, Millar RP, Sealfon SC. (1993) Cloning and characterization of the human GnRH receptor. Mol Cell Endocrinol, 91 (1-2): R1-6. [PMID:8386108]

3. Conn PM, Crowley Jr WF. (1994) Gonadotropin-releasing hormone and its analogs. Annu Rev Med, 45: 391-405. [PMID:8198390]

4. Davidson JS, Assefa D, Pawson A, Davies P, Hapgood J, Becker I, Flanagan C, Roeske R, Millar R. (1997) Irreversible activation of the gonadotropin-releasing hormone receptor by photoaffinity cross-linking: localization of attachment site to Cys residue in N-terminal segment. Biochemistry, 36 (42): 12881-9. [PMID:9335546]

5. Engel JB, Schally AV. (2007) Drug Insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone. Nat Clin Pract Endocrinol Metab, 3 (2): 157-67. [PMID:17237842]

6. Fromme BJ, Katz AA, Roeske RW, Millar RP, Flanagan CA. (2001) Role of aspartate7.32(302) of the human gonadotropin-releasing hormone receptor in stabilizing a high-affinity ligand conformation. Mol Pharmacol, 60: 1280-1287. [PMID:11723235]

7. Herbst KL. (2003) Gonadotropin-releasing hormone antagonists. Curr Opin Pharmacol, 3 (6): 660-6. [PMID:14644020]

8. Huirne JA, Lambalk CB. (2001) Gonadotropin-releasing-hormone-receptor antagonists. Lancet, 358 (9295): 1793-803. [PMID:11734258]

9. Kakar SS, Musgrove LC, Devor DC, Sellers JC, Neill JD. (1992) Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. Biochem Biophys Res Commun, 189 (1): 289-95. [PMID:1333190]

10. Kiesel LA, Rody A, Greb RR, Szilágyi A. (2002) Clinical use of GnRH analogues. Clin Endocrinol (Oxf), 56 (6): 677-87. [PMID:12072036]

11. Kovacs M, Seprodi J, Koppan M, Horvath JE, Vincze B, Teplan I, Flerko B. (2002) Lamprey gonadotropin hormone-releasing hormone-III has no selective follicle-stimulating hormone-releasing effect in rats. J Neuroendocrinol, 14 (8): 647-55. [PMID:12153467]

12. Lovas S, Pályi I, Vincze B, Horváth J, Kovács M, Mezö I, Tóth G, Teplán I, Murphy RF. (1998) Direct anticancer activity of gonadotropin-releasing hormone-III. J Pept Res, 52 (5): 384-9. [PMID:9894843]

13. Mezo G, Czajlik A, Manea M, Jakab A, Farkas V, Majer Z, Vass E, Bodor A, Kapuvári B, Boldizsár M et al.. (2007) Structure, enzymatic stability and antitumor activity of sea lamprey GnRH-III and its dimer derivatives. Peptides, 28 (4): 806-20. [PMID:17254668]

14. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. (2004) Gonadotropin-releasing hormone receptors. Endocr Rev, 25 (2): 235-75. [PMID:15082521]

15. Papanikolaou EG, Kolibianakis E, Devroey P. (2005) Emerging drugs in assisted reproduction. Expert Opin Emerg Drugs, 10 (2): 425-40. [PMID:15934877]

16. Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M. (2003) Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor. J Med Chem, 46 (1): 113-24. [PMID:12502365]

17. Schally AV, Arimura A, Kastin AJ, Matsuo H, Baba Y, Redding TW, Nair RM, Debeljuk L, White WF. (1971) Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science, 173 (4001): 1036-8. [PMID:4938639]

18. Stewart AJ, Sellar R, Wilson DJ, Millar RP, Lu ZL. (2008) Identification of a novel ligand binding residue Arg38(1.35) in the human gonadotropin-releasing hormone receptor. Mol Pharmacol, 73 (1): 75-81. [PMID:17942747]

19. Sullivan SK, Brown MS, Gao Y, Loweth CJ, Lio FM, Crowe PD, Struthers RS, Betz SF. (2006) Allosteric and orthosteric binding modes of two nonpeptide human gonadotropin-releasing hormone receptor antagonists. Biochemistry, 45 (51): 15327-37. [PMID:17176055]

20. Tan O, Bukulmez O. (2011) Biochemistry, molecular biology and cell biology of gonadotropin-releasing hormone antagonists. Curr Opin Obstet Gynecol, 23 (4): 238-44. [PMID:21666463]

21. Themmen APN, Huhtaniemi IT. (2000) Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev, 21 (5): 551-83. [PMID:11041448]

22. Tucci FC, Zhu YF, Struthers RS, Guo Z, Gross TD, Rowbottom MW, Acevedo O, Gao Y, Saunders J, Xie Q et al.. (2005) 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization. J Med Chem, 48 (4): 1169-78. [PMID:15715483]

23. Weckermann D, Harzmann R. (2004) Hormone therapy in prostate cancer: LHRH antagonists versus LHRH analogues. Eur Urol, 46 (3): 279-83; discussion 283-4. [PMID:15306097]

24. White RB, Eisen JA, Kasten TL, Fernald RD. (1998) Second gene for gonadotropin-releasing hormone in humans. Proc Natl Acad Sci USA, 95 (1): 305-9. [PMID:9419371]

25. Yahalom D, Chen A, Ben-Aroya N, Rahimipour S, Kaganovsky E, Okon E, Fridkin M, Koch Y. (1999) The gonadotropin-releasing hormone family of neuropeptides in the brain of human, bovine and rat: identification of a third isoform. FEBS Lett, 463 (3): 289-94. [PMID:10606740]

How to cite this page

To cite this family introduction, please use the following:

Database page citation (select format):