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Gene Review

LHCGR  -  luteinizing hormone/choriogonadotropin...

Homo sapiens

Synonyms: HHG, LCGR, LGR2, LH/CG-R, LH/CGR, ...
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Disease relevance of LHCGR


Psychiatry related information on LHCGR

  • All four spectral indices showed significant differences between OSA patients and normals in both wakefulness and sleep, although the changes in MLHR and GRSA were substantially larger and less variable: MLHR (p < 0.0003) and GRSA (p < 0.0001) vs. LHR (p < 0.005) and NHFP (p < 0.004) [6].

High impact information on LHCGR


Chemical compound and disease context of LHCGR


Biological context of LHCGR

  • FSHR and LHCGR were closely linked in sheep with no recombinants and neither receptor was linked to the Booroola fecundity gene (FecB) [16].
  • The steady-state synthesis of LHCGR mRNA (exons 1-5) in DS pregnancies was significantly higher than that of controls, but the expression of full-length LHCGR mRNA (exons 1-11) in DS was comparable to that of uncompromised pregnancies [1].
  • Increasing amounts of Ad-hLHR, used at a multiplicity of infection (MOI) of 20 or 200 viable viral particles/cell, increased human chorionic gonadotropin (hCG) binding and hCG-induced cAMP and Akt phosphorylation, but inositol phosphates only increased in response to hCG in cells infected with 200 MOI Ad-hLHR [17].
  • The luteinizing hormone receptor (LHR), a member of the G protein-coupled, seven transmembrane receptor family, is essential for normal sexual development and reproductive function [18].
  • Our studies have demonstrated that orphan receptor-ERE complexes, and the HDAC1-HDAC2-mSin3A complex have important roles in the regulation of LHR gene transcription by interaction with Sp1/Sp3, and by region-specific changes in histone acetylation and Pol II recruitment within the LHR promoter [18].

Anatomical context of LHCGR

  • The current studies investigated the differential binding of orphan receptors to rat (rLHR) and hLHR promoters, and their modulation of rLHR gene transcription in rat granulosa cells [19].
  • This suggests that in the presence of mutant-LHR, hFSHR, which is trapped in the ER and associated with hLHR(exon 9), is unable to come up to the plasma membrane [20].
  • Our recent studies on the marmoset monkey testis LHR cDNA indicated that an 81 bp nucleotide sequence, encoding the complete exon 10 of the LHR gene in other mammalian species, is absent in this species without affecting the LHR function [21].
  • For comparison, chinese hamster ovary (CHO) cells transfected with FSH-R or LH-R were also assessed [22].
  • LHR are expressed primarily in the gonads, but also are found in non-gonadal and cancer tissues [18].

Associations of LHCGR with chemical compounds

  • Previously, we have shown that the beta-strands of hLH-R leucine-rich repeats 3 and 6 can confer full hCG/hLH responsiveness and binding when simultaneously introduced into a hFSH-R background without affecting the receptor's responsiveness to hFSH [23].
  • Cyclic AMP stimulation was not detectable in CHO-LHR and CHO-FSHR cells after incubation with M22 IgG, whereas incubation with hCG or FSH, respectively, caused dose-dependent cyclic AMP stimulation [24].
  • In both myometrium and cervix, LH activates both the adenylate cyclase and phospholipase C pathways, and the effect of LH on both pathways at each stage of the cycle is correlated with the amount of LH-R present in the tissue [25].
  • Consequently, TSA and the DNA demethylating reagent 5-azacytidine (5-AzaC) caused marked synergistic activation of the LHR gene in JAR but not in MCF-7 cells [26].
  • Multiple site-specific lysine acetylation of H3/H4 is associated with such LHR gene activation [26].
  • These findings reveal the importance of phosphatases in the control of LHR transcription, where the balance between phosphatidylinositol 3-kinase/PKCzeta and phosphatases could be critical for up- and down-regulation of LHR gene expression in physiological and pathological settings [27].

Physical interactions of LHCGR

  • A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein [28].
  • Chemical modification of the parent compound combined with prior mutagenesis of TSHR provided compelling experimental evidence in support of computational models of 3 binding to TSHR and LHCGR within their transmembrane cores [29].
  • The C-terminal truncation studies of the alpha 26-46 peptide revealed that Lys44 contributes to FSH receptor binding activity but does not contribute to the LH-receptor interaction [30].
  • 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 [31].
  • EGF treatment paradoxically stabilized hCG/LH receptor protein [32].

Regulatory relationships of LHCGR

  • A number of activating and inactivating mutations of the LHR have been found while only one activating and three inactivating mutations of the FSHR are known [4].
  • Conversely, TR4 activated the hLHR promoter activity up to 2.5-fold through binding to the same cis-element [33].
  • In summary, EGF treatment up-regulates hCG subunits gene expression and down-regulates hCG/LH receptor mRNAs involving transcriptional and posttranscriptional mechanisms in JEG-3 human choriocarcinoma cells [32].
  • Flow cytometry showed that the expression of LH-R on the cell surface of luteinizing granulosa cells was enhanced by HCG, but was unaffected by TNFalpha [34].
  • We hypothesised that an abnormal configuration of the LH receptor might autonomously activate G protein coupling, and thereby cause the overproduction of testosterone in this condition [35].

Other interactions of LHCGR

  • We further demonstrated that EAR3 specifically decreased association of TFIIB to the Sp1(I) site without interfering on its interaction with the hLHR core promoter [36].
  • Whereas the affinity and specificity of hCG for LHR are extraordinarily high, the hormone is capable of binding to and activating both TSHR and FSHR under these conditions that mimic high ligand concentrations [37].
  • Dual mechanisms of regulation of transcription of luteinizing hormone receptor gene by nuclear orphan receptors and histone deacetylase complexes [18].
  • An imperfect estrogen receptor half-site response element direct-repeat within the LHR promoter is an inhibitory locus [18].
  • A multiprotein complex is recruited to the hLHR promoter via interaction with Sp1/Sp3: HDACs dock directly to Sp1-1 bound DNA and indirectly to Sp3-1 bound DNA through RbAp48, while mSin3A interacts HDACs and potentiates HDAC1-mediated repression [18].

Analytical, diagnostic and therapeutic context of LHCGR

  • FSH-R and LH-R expression were detected by flow cytometry [22].
  • Methods: CHO-TSHR, CHO-LHR, and CHO-FSHR cells were incubated with bovine TSH (0.1-25mU/mL), human recombinant chorionic gonadotropin (hCG; 0.5-10mU/mL) or human recombinant FSH (100-5000mU/mL) or with M22 IgG (0.001-5.0 microg/mL), and the extracellular cyclic AMP was measured by radioimmunoassay [24].
  • Electrophoresis mobility shift assays demonstrated that the in vitro translated nuclear orphan receptors specifically bound the direct-repeat motif of the hLHR promoter [33].
  • Although Western blot analyses demonstrated both mutant receptors to be stably expressed, little or no hCG binding activity could be detected in detergent solubilized extracts of 293 cells expressing either nonglycosylated LHR mutant [38].
  • Sequence analysis of part of the cfLH-R gene revealed the presence of an intron typically found in other vertebrate LH-R genes [39].


  1. A link between high serum levels of human chorionic gonadotrophin and chorionic expression of its mature functional receptor (LHCGR) in Down's syndrome pregnancies. Banerjee, S., Smallwood, A., Chambers, A.E., Papageorghiou, A., Loosfelt, H., Spencer, K., Campbell, S., Nicolaides, K. Reprod. Biol. Endocrinol. (2005) [Pubmed]
  2. Expression of gonadotropin and activin receptor messenger ribonucleic acid in human ovarian epithelial neoplasms. Minegishi, T., Kameda, T., Hirakawa, T., Abe, K., Tano, M., Ibuki, Y. Clin. Cancer Res. (2000) [Pubmed]
  3. Intracellular calcium mobilization in response to the activation of human wild-type and chimeric gonadotropin receptors. Lee, P.S., Buchan, A.M., Hsueh, A.J., Yuen, B.H., Leung, P.C. Endocrinology (2002) [Pubmed]
  4. Molecular genetic, biochemical, and clinical implications of gonadotropin receptor mutations. Chan, W.Y. Mol. Genet. Metab. (1998) [Pubmed]
  5. Homozygous mutation within the conserved Ala-Phe-Asn-Glu-Thr motif of exon 7 of the LH receptor causes male pseudohermaphroditism. Gromoll, J., Schulz, A., Borta, H., Gudermann, T., Teerds, K.J., Greschniok, A., Nieschlag, E., Seif, F.J. Eur. J. Endocrinol. (2002) [Pubmed]
  6. Spectral indices of cardiac autonomic function in obstructive sleep apnea. Khoo, M.C., Kim, T.S., Berry, R.B. Sleep. (1999) [Pubmed]
  7. Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. Latronico, A.C., Anasti, J., Arnhold, I.J., Rapaport, R., Mendonca, B.B., Bloise, W., Castro, M., Tsigos, C., Chrousos, G.P. N. Engl. J. Med. (1996) [Pubmed]
  8. Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene. Kremer, H., Kraaij, R., Toledo, S.P., Post, M., Fridman, J.B., Hayashida, C.Y., van Reen, M., Milgrom, E., Ropers, H.H., Mariman, E. Nat. Genet. (1995) [Pubmed]
  9. Rapid GDP release from Gs alpha in patients with gain and loss of endocrine function. Iiri, T., Herzmark, P., Nakamoto, J.M., van Dop, C., Bourne, H.R. Nature (1994) [Pubmed]
  10. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Shenker, A., Laue, L., Kosugi, S., Merendino, J.J., Minegishi, T., Cutler, G.B. Nature (1993) [Pubmed]
  11. Gonadotrophin receptors. Clayton, R.N. Baillieres Clin. Endocrinol. Metab. (1996) [Pubmed]
  12. Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. Kero, J., Poutanen, M., Zhang, F.P., Rahman, N., McNicol, A.M., Nilson, J.H., Keri, R.A., Huhtaniemi, I.T. J. Clin. Invest. (2000) [Pubmed]
  13. A common polymorphism renders the luteinizing hormone receptor protein more active by improving signal peptide function and predicts adverse outcome in breast cancer patients. Piersma, D., Berns, E.M., Verhoef-Post, M., Uitterlinden, A.G., Braakman, I., Pols, H.A., Themmen, A.P. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  14. Elevated expression of luteinizing hormone receptor in aldosterone-producing adenomas. Saner-Amigh, K., Mayhew, B.A., Mantero, F., Schiavi, F., White, P.C., Rao, C.V., Rainey, W.E. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  15. A missense mutation in the second transmembrane segment of the luteinizing hormone receptor causes familial male-limited precocious puberty. Kraaij, R., Post, M., Kremer, H., Milgrom, E., Epping, W., Brunner, H.G., Grootegoed, J.A., Themmen, A.P. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  16. The follicle-stimulating hormone receptor and luteinizing hormone receptor genes are closely linked in sheep and deer. Montgomery, G.W., Tate, M.L., Henry, H.M., Penty, J.M., Rohan, R.M. J. Mol. Endocrinol. (1995) [Pubmed]
  17. The differential effects of the gonadotropin receptors on aromatase expression in primary cultures of immature rat granulosa cells are highly dependent on the density of receptors expressed and the activation of the inositol phosphate cascade. Donadeu, F.X., Ascoli, M. Endocrinology (2005) [Pubmed]
  18. Dual mechanisms of regulation of transcription of luteinizing hormone receptor gene by nuclear orphan receptors and histone deacetylase complexes. Zhang, Y., Dufau, M.L. J. Steroid Biochem. Mol. Biol. (2003) [Pubmed]
  19. EAR2 and EAR3/COUP-TFI regulate transcription of the rat LH receptor. Zhang, Y., Dufau, M.L. Mol. Endocrinol. (2001) [Pubmed]
  20. Association of human follitropin (FSH) receptor with splicing variant of human lutropin/choriogonadotropin receptor negatively controls the expression of human FSH receptor. Yamashita, S., Nakamura, K., Omori, Y., Tsunekawa, K., Murakami, M., Minegishi, T. Mol. Endocrinol. (2005) [Pubmed]
  21. The unique exon 10 of the human luteinizing hormone receptor is necessary for expression of the receptor protein at the plasma membrane in the human luteinizing hormone receptor, but deleterious when inserted into the human follicle-stimulating hormone receptor. Zhang, F.P., Kero, J., Huhtaniemi, I. Mol. Cell. Endocrinol. (1998) [Pubmed]
  22. Gonadotrophin receptor expression on human granulosa cells of low and normal responders to FSH. Thiruppathi, P., Shatavi, S., Dias, J.A., Radwanska, E., Luborsky, J.L. Mol. Hum. Reprod. (2001) [Pubmed]
  23. Opposite contribution of two ligand-selective determinants in the N-terminal hormone-binding exodomain of human gonadotropin receptors. Vischer, H.F., Granneman, J.C., Bogerd, J. Mol. Endocrinol. (2003) [Pubmed]
  24. Effects of a Thyroid-Stimulating Human Monoclonal Autoantibody (M22) on Functional Activity of LH and FSH Receptors. Tonacchera, M., Ferrarini, E., Dimida, A., Agretti, P., Marco, G.D., Pinchera, A., Sanders, J., Evans, M., Richards, T., Furmaniak, J., Smith, B.R. Thyroid (2006) [Pubmed]
  25. Functional importance of bovine myometrial and vascular LH receptors and cervical FSH receptors. Shemesh, M., Mizrachi, D., Gurevich, M., Stram, Y., Shore, L.S., Fields, M.J. Seminars in reproductive medicine. (2001) [Pubmed]
  26. Coordinated changes in DNA methylation and histone modifications regulate silencing/derepression of luteinizing hormone receptor gene transcription. Zhang, Y., Fatima, N., Dufau, M.L. Mol. Cell. Biol. (2005) [Pubmed]
  27. Unlocking repression of the human luteinizing hormone receptor gene by trichostatin A-induced cell-specific phosphatase release. Zhang, Y., Liao, M., Dufau, M.L. J. Biol. Chem. (2008) [Pubmed]
  28. A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein. Puett, D., Li, Y., Demars, G., Angelova, K., Fanelli, F. Mol. Cell. Endocrinol. (2007) [Pubmed]
  29. Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: structure-activity relationships and selective binding patterns. Moore, S., Jaeschke, H., Kleinau, G., Neumann, S., Costanzi, S., Jiang, J.K., Childress, J., Raaka, B.M., Colson, A., Paschke, R., Krause, G., Thomas, C.J., Gershengorn, M.C. J. Med. Chem. (2006) [Pubmed]
  30. Contribution of specific amino acid residues within the hFSH alpha 26-46 sequence region to FSH receptor-binding activity. Cattini-Schultz, S.V., Stanton, P.G., Robertson, D.M., Hearn, M.T. Pept. Res. (1995) [Pubmed]
  31. 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. Hirakawa, T., Galet, C., Kishi, M., Ascoli, M. J. Biol. Chem. (2003) [Pubmed]
  32. Transcriptional and posttranscriptional mechanisms in epidermal growth factor regulation of human chorionic gonadotropin (hCG) subunits and hCG receptor gene expression in human choriocarcinoma cells. Cao, H., Lei, Z.M., Rao, C.V. Endocrinology (1994) [Pubmed]
  33. Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. Zhang, Y., Dufau, M.L. J. Biol. Chem. (2000) [Pubmed]
  34. Immunohistochemical localization of the LH/HCG receptor in human ovary: HCG enhances cell surface expression of LH/HCG receptor on luteinizing granulosa cells in vitro. Takao, Y., Honda, T., Ueda, M., Hattori, N., Yamada, S., Maeda, M., Fujiwara, H., Mori, T., Wimalasena, J. Mol. Hum. Reprod. (1997) [Pubmed]
  35. Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty. Kremer, H., Mariman, E., Otten, B.J., Moll, G.W., Stoelinga, G.B., Wit, J.M., Jansen, M., Drop, S.L., Faas, B., Ropers, H.H. Hum. Mol. Genet. (1993) [Pubmed]
  36. Repression of the luteinizing hormone receptor gene promoter by cross talk among EAR3/COUP-TFI, Sp1/Sp3, and TFIIB. Zhang, Y., Dufau, M.L. Mol. Cell. Biol. (2003) [Pubmed]
  37. Specificity of cognate ligand-receptor interactions: fusion proteins of human chorionic gonadotropin and the heptahelical receptors for human luteinizing hormone, thyroid-stimulating hormone, and follicle-stimulating hormone. Schubert, R.L., Narayan, P., Puett, D. Endocrinology (2003) [Pubmed]
  38. The six N-linked carbohydrates of the lutropin/choriogonadotropin receptor are not absolutely required for correct folding, cell surface expression, hormone binding, or signal transduction. Davis, D.P., Rozell, T.G., Liu, X., Segaloff, D.L. Mol. Endocrinol. (1997) [Pubmed]
  39. Cloning and functional characterization of a gonadal luteinizing hormone receptor complementary DNA from the African catfish (Clarias gariepinus). Vischer, H.F., Bogerd, J. Biol. Reprod. (2003) [Pubmed]
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