Gonadotropin-releasing hormone receptor
Alt. symbolsGnRH-R; LRHR;
NCBI gene2798
Other data
LocusChr. 4 q21.2
Gonadotropin-releasing hormone (type 2) receptor 2
NCBI gene114814
Other data
LocusChr. 1 q12

The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin-releasing hormone (GnRH). The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate.

This receptor is a 60 kDa G protein-coupled receptor and resides primarily in the pituitary and is responsible for eliciting the actions of GnRH after its release from the hypothalamus.[1] Upon activation, the LHRHr stimulates tyrosine phosphatase and elicits the release of LH from the pituitary.

Evidence exists showing the presence of GnRH and its receptor in extrapituitary tissues as well as a role in progression of some cancers.[2]


Following binding of GnRH, the GnRHR associates with G-proteins that activate a phosphatidylinositol (PtdIns)-calcium second messenger system. Activation of the GnRHR ultimately causes the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH).


There are two major forms of the GNRHR, each encoded by a separate gene (GNRHR and GNRHR2).[3][4]

Alternative splicing of the GNRHR gene, GNRHR, results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5' region and multiple polyA signals in the 3' region have been identified for GNRHR.


The GnRHR responds to GnRH as well as to synthetic GnRH agonists. Agonists stimulate the receptor, however prolonged exposure leads to a downregulation effect resulting in hypogonadism, an effect that is often medically utilized. GnRH antagonists block the receptor and inhibit gonadotropin release. GnRHRs are further regulated by the presence of sex hormones as well as activin and inhibin.








Current research is looking into pharmacoperones, or chemical chaparones that promote the shuttling of mature Gonadotropin-releasing hormone receptor (GNRHR) protein to the cell surface, leading to a functional protein. Gonadotropin-releasing hormone receptor function has been shown to be deleteriously effected by point mutations in its gene. Some of these mutations, when expressed, cause the receptor to remain in the cytosol. An approach to rescue receptor function utilizes pharmacoperones or molecular chaperones, which are typically small molecules that rescue misfolded proteins to the cell surface. These interact with the receptor to restore cognate receptor function devoid of antagonist or agonist activity. This approach, when effective, should increase therapeutic reach. Pharmacoperones have been identified that restore function of Gonadotropin-releasing hormone receptor.[5][6]

Clinical implications

Defects in the GnRHR are a cause of hypogonadotropic hypogonadism (HH).[7]

Normal puberty begins between ages 8 and 14 in girls and between 9 and 14 in boys. Puberty, however, for some children can come much sooner or much later or in many cases never occurs and thereby contributes to the estimated 35-70 million infertile couples worldwide. Among children, the abnormally early or late onset of puberty exerts intense emotional and social stress that too often goes untreated.

The timely onset of puberty is regulated by many factors and one factor that is often referred to as the master regulator of puberty and reproduction is GnRH. This peptide hormone is produced in the hypothalamus but gets secreted and acts upon GnRHRs in the anterior pituitary to exert its effects on reproductive maturation.

Understanding how GnRHR functions has been key to developing clinical strategies to treat reproductive-related disorders.[8][9][10]

See also


  1. ^ Millar RP (2005). "GnRHs and GnRH receptors". Anim. Reprod. Sci. 88 (1–2): 5–28. doi:10.1016/j.anireprosci.2005.05.032. PMID 16140177.
  2. ^ Harrison GS, Wierman ME, Nett TM, Glode LM (2004). "Gonadotropin-releasing hormone and its receptor in normal and malignant cells". Endocr. Relat. Cancer. 11 (4): 725–48. doi:10.1677/erc.1.00777. PMID 15613448.
  3. ^ Neill JD, Musgrove LC, Duck LW (2004). "Newly recognized GnRH receptors: function and relative role". Trends Endocrinol. Metab. 15 (8): 383–92. doi:10.1016/j.tem.2004.08.005. PMID 15380810. S2CID 26829807.
  4. ^ 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. doi:10.1210/er.2003-0039. PMID 15561800.
  5. ^ Smith E, Janovick JA, Bannister T, Shumate J, Ganapathy V, Scampavia L, Spicer TP (June 2020). "Rescue of mutant gonadotropin-releasing hormone receptor function independent of cognate receptor activity". Scientific Reports. 10 (1): 10579. Bibcode:2020NatSR..1010579S. doi:10.1038/s41598-020-67473-w. PMC 7324376. PMID 32601341.
  6. ^ Conn PM, Smith E, Spicer TP, Chase P, Scampavia L, Janovick JA (May 2014). "A Phenotypic High Throughput Screening Assay for the Identification of Pharmacoperones for the Gonadotropin Releasing Hormone Receptor". Assay and Drug Development Technologies. 12 (4): 238–246. doi:10.1089/adt.2014.576. PMC 4025569. PMID 24831790.
  7. ^ Layman LC (2007). "Hypogonadotropic hypogonadism". Endocrinol. Metab. Clin. North Am. 36 (2): 283–96. doi:10.1016/j.ecl.2007.03.010. PMID 17543719.
  8. ^ Re M, Pampillo M, Savard M, Dubuc C, McArdle CA, Millar RP, Conn PM, Gobeil F, Bhattacharya M, Babwah AV (2010). Koch K (ed.). "The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane". PLOS ONE. 5 (7): e11489. Bibcode:2010PLoSO...511489R. doi:10.1371/journal.pone.0011489. PMC 2900216. PMID 20628612.
  9. ^ Balasubramanian R, Dwyer A, Seminara SB, Pitteloud N, Kaiser UB, Crowley WF (2010). "Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons". Neuroendocrinology. 92 (2): 81–99. doi:10.1159/000314193. PMC 3214927. PMID 20606386.
  10. ^ Viswanathan V, Eugster EA (December 2009). "Etiology and treatment of hypogonadism in adolescents". Endocrinol. Metab. Clin. North Am. 38 (4): 719–38. doi:10.1016/j.ecl.2009.08.004. PMC 4102132. PMID 19944289.