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Luteinizing hormone/choriogonadotropin receptor

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Available structures
PDBOrtholog search: PDBe RCSB
AliasesLHCGR, HHG, LCGR, LGR2, LH/CG-R, LH/CGR, LHR, LHRHR, LSH-R, ULG5, Luteinizing hormone/choriogonadotropin receptor
External IDsOMIM: 152790; MGI: 96783; HomoloGene: 37276; GeneCards: LHCGR; OMA:LHCGR - orthologs
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 2: 48.69 – 48.76 MbChr 17: 89.02 – 89.1 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

The luteinizing hormone/choriogonadotropin receptor (LHCGR), also lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor (LHR), is a transmembrane receptor found predominantly in the ovary and testis, but also many extragonadal organs such as the uterus and breasts. The receptor interacts with both luteinizing hormone (LH) and chorionic gonadotropins (such as hCG in humans) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning during reproduction.

LHCGR gene[edit]

The gene for the LHCGR is found on chromosome 2 p21 in humans, close to the FSH receptor gene. It consists of 70 kbp (versus 54 kpb for the FSHR).[5] The gene is similar to the gene for the FSH receptor and the TSH receptor.

Receptor structure[edit]

The LHCGR consists of 674 amino acids and has a molecular mass of about 85–95 kDA based on the extent of glycosylation.[6]

Like other GPCRs, the LHCG receptor possess seven membrane-spanning domains or transmembrane helices.[7] The extracellular domain of the receptor is heavily glycosylated. These transmembrane domains contain two highly conserved cysteine residues, which build disulfide bonds to stabilize the receptor structure. The transmembrane part is highly homologous with other members of the rhodopsin family of GPCRs.[8] The C-terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation.

Ligand binding and signal transduction[edit]

Upon binding of LH to the external part of the membrane spanning receptor, a transduction of the signal takes place. This process results in the activation of a heterotrimeric G protein. Binding of LH to the receptor shifts its conformation. The activated receptor promotes the binding of GTP to the G protein and its subsequent activation. After binding GTP, the G protein heterotrimer detaches from the receptor and disassembles. The alpha-subunit Gs binds adenylate cyclase and activates the cAMP system.[9]

It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of LH (or CG) to the receptor shifts the equilibrium towards the active form of the receptor. For a cell to respond to LH only a small percentage (≈1%) of receptor sites need to be activated.

Phosphorylation by cAMP-dependent protein kinases[edit]

Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal cascade originated by the activation of the G protein Gs by the LHCG-receptor. Activated Gs binds the enzyme adenylate cyclase and this leads to the production of cyclic AMP (cAMP). Cyclin AMP-dependent protein kinases are present as tetramers with two regulatory subunits and two catalytic subunits. Upon binding of cAMP to the regulatory subunits, the catalytic units are released and initiate the phosphorylation of proteins leading to the physiologic action. Cyclic AMP is degraded by phosphodiesterase and release 5’AMP. One of the targets of protein kinase A is the Cyclic AMP Response Element Binding Protein, CREB, which binds DNA in the cell nucleus via direct interactions with specific DNA sequences called cyclic AMP response elements (CRE); this process results in the activation or inactivation of gene transcription.[5]

The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by prostaglandins. Other cellular regulators that participate are the intracellular calcium concentration regulated by phospholipase C activation, nitric oxide, and other growth factors.

Other pathways of signaling exist for the LHCGR.[6]


Luteinizing hormone up-regulates cholesterol side chain cleaving enzyme in sensitive tissues, the first step of all human steroidogenesis.

The LHCG receptor's main function is the regulation of steroidogenesis. This is accomplished by increasing the intracellular levels of the enzyme cholesterol side chain cleaving enzyme, a member of the cytochrome P450 family. This leads to increased conversion of cholesterol into androgen precursors required to make many steroid hormones, including testosterone and estrogens.[10]


In the ovary, the LHCG receptor is necessary for follicular maturation and ovulation, as well as luteal function. Its expression requires appropriate hormonal stimulation by FSH and estradiol. The LHCGR is present on granulosa cells, theca cells, luteal cells, and interstitial cells[6] The LCGR is restimulated by increasing levels of chorionic gonadotropins in case a pregnancy is developing. In turn, luteal function is prolonged and the endocrine milieu is supportive of the nascent pregnancy.


In the male the LHCGR has been identified on the Leydig cells that are critical for testosterone production, and support spermatogenesis.

Normal LHCGR functioning is critical for male fetal development, as the fetal Leydig cells produce androstenedione which is converted to testosterone in fetal Sertoli cells to induce masculinization.


LHCGR have been found in many types of extragonadal tissues, and the physiologic role of some has remained largely unexplored. Thus receptors have been found in the uterus, sperm, seminal vesicles, prostate, skin, breast, adrenals, thyroid, neural retina, neuroendocrine cells, and (rat) brain.[6]

Receptor regulation[edit]

The seven transmembrane α-helix structure of a G protein-coupled receptor such as LHCGR


Upregulation refers to the increase in the number of receptor sites on the membrane. Estrogen and FSH upregulate LHCGR sites in preparation for ovulation. After ovulation, the luteinized ovary maintains LHCGR s that allow activation in case there is an implantation. Upregulation in males requires gene transcription to synthesize LH receptors within the cell cytoplasm. Some reasons as to why downregulated LH receptors are not upregulated are: lack of gene transcription, lack of RNA to protein conversion and lack of cell membrane targeted shipments from Golgi.


The LHCGRs become desensitized when exposed to LH for some time. A key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases. This process uncouples Gs protein from the LHCGR.


Downregulation refers to the decrease in the number of receptor molecules. This is usually the result of receptor endocytosis. In this process, the bound LCGR-hormone complex binds arrestin and concentrates in clathrin coated pits. Clathrin coated pits recruit dynamin and pinch off from the cell surface, becoming clathrin-coated vesicles. Clathrin-coated vesicles are processed into endosomes, some of which are recycled to the cell surface while others are targeted to lysosomes. Receptors targeted to lysosomes are degraded. Use of long-acting agonists will downregulate the receptor population by promoting their endocytosis.


Antibodies to LHCGR can interfere with LHCGR activity.

LHCGR antagonists and agonists[edit]

In 2019, the discovery of potent, and selective antagonists of the Luteinizing Hormone Receptor (BAY-298 and BAY-899) were reported which were able to reduce sex hormone levels in vivo.[11] The latter fulfils the quality criteria for a 'Donated Chemical Probe' as defined by the Structural Genomics Consortium.[12]

A series of thienopyr(im)idine-based compounds[13] leading to optimized Org 43553 were described as the first Luteinizing Hormone Receptor agonists.[14][15]

LHCGR abnormalities[edit]

Loss-of-function mutations in females can lead to infertility. In 46, XY individuals severe inactivation can cause male pseudohermaphroditism, as fetal Leydig cells during may not respond and thus interfere with masculinization.[16] Less severe inactivation can result in hypospadias or a micropenis.[6]


Alfred G. Gilman and Martin Rodbell received the 1994 Nobel Prize in Medicine and Physiology for the discovery of the G Protein System.


Luteinizing hormone/choriogonadotropin receptor has been shown to interact with GIPC1.[17]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000138039Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024107Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Simoni M, Gromoll J, Nieschlag E (Dec 1997). "The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology". Endocrine Reviews. 18 (6): 739–73. doi:10.1210/edrv.18.6.0320. PMID 9408742.
  6. ^ a b c d e Ascoli M, Fanelli F, Segaloff DL (Apr 2002). "The lutropin/choriogonadotropin receptor, a 2002 perspective". Endocrine Reviews. 23 (2): 141–74. doi:10.1210/edrv.23.2.0462. PMID 11943741.
  7. ^ Dufau ML (1998). "The luteinizing hormone receptor". Annual Review of Physiology. 60: 461–96. doi:10.1146/annurev.physiol.60.1.461. PMID 9558473.
  8. ^ Jiang X, Dias JA, He X (Jan 2014). "Structural biology of glycoprotein hormones and their receptors: insights to signaling". Molecular and Cellular Endocrinology. 382 (1): 424–51. doi:10.1016/j.mce.2013.08.021. PMID 24001578.
  9. ^ Ryu KS, Gilchrist RL, Koo YB, Ji I, Ji TH (Apr 1998). "Gene, interaction, signal generation, signal divergence and signal transduction of the LH/CG receptor". International Journal of Gynaecology and Obstetrics. 60 (Suppl 1): S9-20. doi:10.1016/S0020-7292(98)80001-5. PMID 9833610. S2CID 4798893.
  10. ^ Dufau ML, Cigorraga S, Baukal AJ, Sorrell S, Bator JM, Neubauer JF, Catt KJ (Dec 1979). "Androgen biosynthesis in Leydig cells after testicular desensitization by luteinizing hormone-releasing hormone and human chorionic gonadotropin". Endocrinology. 105 (6): 1314–21. doi:10.1210/endo-105-6-1314. PMID 227658.
  11. ^ Wortmann L, Lindenthal B, Muhn P, et al. (2019). "Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent, and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels in Vivo". Journal of Medicinal Chemistry. 62 (22): 10321–10341. doi:10.1021/acs.jmedchem.9b01382. PMID 31670515. S2CID 204967109.
  12. ^ "Donated Chemical Probes". thesgc.org. Retrieved July 31, 2023.
  13. ^ van Straten NC, Schoonus-Gerritsma GG, van Someren RG, Draaijer J, Adang AE, Timmers CM, Hanssen RG, van Boeckel CA (2002-10-04). "The First Orally Active Low Molecular Weight Agonists for the LH Receptor: Thienopyr(im)idines with Therapeutic Potential for Ovulation Induction". ChemBioChem. 3 (10): 1023–1026. doi:10.1002/1439-7633(20021004)3:10<1023::AID-CBIC1023>3.0.CO;2-9. PMID 12362369. S2CID 8732411.
  14. ^ Heitman LH, Oosterom J, Bonger KM, Timmers CM, Wiegerinck PH, IJzerman AP (2008-02-01). "[3H]Org 43553, the First Low-Molecular-Weight Agonistic and Allosteric Radioligand for the Human Luteinizing Hormone Receptor". Molecular Pharmacology. 73 (2): 518–524. doi:10.1124/mol.107.039875. hdl:1887/3209412. ISSN 0026-895X. PMID 17989351. S2CID 34584880.
  15. ^ van de Lagemaat R, Timmers CM, Kelder J, van Koppen C, Mosselman S, Hanssen RG (March 2009). "Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor". Human Reproduction (Oxford, England). 24 (3): 640–648. doi:10.1093/humrep/den412. ISSN 1460-2350. PMID 19088107.
  16. ^ Wu SM, Chan WY (1999). "Male pseudohermaphroditism due to inactivating luteinizing hormone receptor mutations". Archives of Medical Research. 30 (6): 495–500. doi:10.1016/S0188-4409(99)00074-0. PMID 10714363.
  17. ^ Hirakawa T, Galet C, Kishi M, Ascoli M (Dec 2003). "GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR". The Journal of Biological Chemistry. 278 (49): 49348–57. doi:10.1074/jbc.M306557200. PMID 14507927.

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