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Gene Review

FSHR  -  follicle stimulating hormone receptor

Homo sapiens

Synonyms: FSH-R, FSHRO, Follicle-stimulating hormone receptor, Follitropin receptor, LGR1, ...
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Disease relevance of FSHR

  • Although the functional interaction of hCG and TSHR has been recognized in gestational hyperthyroidism, there are no reports linking hCG to FSHR activation [1].
  • In summary, the current study demonstrates the novel observation that both the FSHR and LHR are expressed by bovine OSE and selected ovarian cancers [2].
  • For the follicle-stimulating hormone (FSH) receptor (FSHR) loss-of-function mutations have been allocated to this region, a homozygous A189V mutation resulting in a resistant ovary syndrome and impaired spermatogenesis and a heterozygous N191I mutation with no apparent phenotype [3].
  • Activating mutations of the LHR cause familial male-limited precocious puberty (FMPP) while that of the FSHR has been shown to restore the reproductive capability of a hypophysectomized male [4].
  • We have engineered filamentous phages displaying mouse LHR and human FSHR decapeptides chosen in hormone binding regions [5].
  • Pediatric gonadal hyperstimulation associated with severe primary hypothyroidism is likely due to the actions of the elevated concentrations of TSH on the wild-type hFSHR, and this response is not dependent upon the hFSHR isoform [6].

High impact information on FSHR

  • Neither FSHbeta nor FSH receptor (FSHR) null mice have bone loss despite severe hypogonadism [7].
  • This 566C-->T mutation, predicting an alanine to valine substitution, is located in exon 7 of the FSHR gene, in the region encoding the extracellular domain of the receptor molecule [8].
  • We recently discovered that an inactivating point mutation in the FSH receptor (R) gene causes a recessively inherited form of hypergonadotropic ovarian failure in homozygous females [8].
  • A C566T transition in exon 7 of FSHR predicting an Ala to Val substitution at residue 189 in the extracellular ligand-binding domain segregated perfectly with the disease phenotype [9].
  • FSH receptor specificity is controlled primarily by residues encoded by exons 5 and 6 that prevent hCG binding but have little effect on hFSH binding [10].

Chemical compound and disease context of FSHR

  • Humans with FSH beta gene mutations tend to have a more severe phenotype than those with FSHR gene mutations, although infertility and varying degrees of impaired sex steroid production occur in both types of mutations [11].
  • One carcinoma showed two major transcripts of a follicle-stimulating hormone receptor (FSH-R) gene, 4.1 and 2.4 kb, whereas the other two carcinomas showed two major transcripts of the luteinizing hormone/human chorionic gonadotropin receptor (LH-R) gene, 5.4 and 2.4 kb [12].
  • This study was conducted to characterize the expression of the receptor (FSHR) for follicle-stimulating hormone (FSH) in androgen-independent prostate cancer cell lines and in human malignant prostate tissues [13].
  • These results indicate that infertility can be induced in adult male monkeys by interfering with the action of FSH using specific peptides of the extracellular domain of FSHR as antigens, without the risk of producing cross-reacting antibodies to the other glycoprotein hormones [14].
  • In a patient hypophysectomized because of a pituitary tumor, who, despite undetectable serum gonadotropin levels, had normal testis volume and semen parameters and fathered three children under testosterone substitution alone, we hypothesized an activating mutation of the FSH receptor [15].

Biological context of FSHR

  • Using transient transfections of luciferase reporter constructs, driven by various fragments of the murine (m) FSHR promoter, we identified a cell-specific promoter region [16].
  • An E box element within the proximal promoter is essential for activation of the FSHR promoter by SF-1 [17].
  • Only small amounts of FSH and the FSHR are routed to a lysosomal degradation pathway, and the extent of FSH-induced down-regulation of the cell surface and total FSHR is minimal [18].
  • To examine the ligand-independent gonadal actions of FSHR(+), the rat androgen-binding protein gene promoter was used to direct FSHR(+) transgene expression to Sertoli cells of gonadotropin-deficient hypogonadal (hpg) mice [19].
  • We created a novel transgenic model to investigate a mutant human FSH receptor (FSHR(+)) containing a single amino acid substitution (Asp567Gly) equivalent to activating mutations in related glycoprotein hormone receptors [19].

Anatomical context of FSHR

  • Both normal and hpg mouse testes expressed FSHR(+) mRNA [19].
  • Isolated transgenic Sertoli cells had significantly higher basal ( approximately 2-fold) and FSH-stimulated ( approximately 50%) cAMP levels compared with controls, demonstrating constitutive signaling and cell-surface expression of FSHR(+), respectively [19].
  • Testis weights of transgenic FSHR(+) hpg mice were increased approximately 2-fold relative to hpg controls (P < 0.02) and contained mature Sertoli cells and postmeiotic germ cells absent in controls, revealing FSHR(+)-initiated autonomous FSH-like testicular activity [19].
  • FSHR is essential for integrating the pituitary FSH signal to gonadal response, while SF-1 is an important transcriptional regulator of many genes that function within this axis and is essential for the development of gonads and adrenal glands [17].
  • Human granulosa cells, the site of FSHR expression in the ovary, were found to contain 14-3-3tau [20].

Associations of FSHR with chemical compounds

  • The FSHR(+) response was additive with a maximal testosterone dose on hpg testicular development, demonstrating FSHR(+) activity independent of androgen-specific actions [19].
  • Functional coupling of the rat FSHR to adenylate cyclase in insect cells was demonstrated [21].
  • Similar results were obtained with recombinant human FSHR in Y1 cells, measuring progesterone production as an end point [21].
  • 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 [22].
  • Selected analogues (2, 14, and 50) were also able to block FSHR-dependent estradiol production in rat primary ovarian granulosa cells and progesterone secretion in a clonal mouse adrenal Y1 cell line [23].

Physical interactions of FSHR

  • This gonadotropin, by binding to its specific G protein-coupled cell membrane receptor (FSHR), is important for normal gonadal function [24].
  • 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 [25].
  • The gene for the FSH receptor is large (greater than 85 kb) and complex (10 introns) and is structurally similar to the genes for the LH and TSH receptor [26].
  • Radioiodinated and alkylated hFSH-beta 33-53 binds to the FSH receptor with a Kd = (5.5 +/- 1.4) X 10(-5) M [27].
  • This report shows that, in addition to APPL1, FSHR interacts with FOXO1a and APPL2 [28].

Regulatory relationships of FSHR


Other interactions of FSHR

  • 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 [32].
  • Increases in basal cAMP production were also observed with YCG/TSHR and YCG/FSHR, e.g. 13- and 4-fold increases, respectively [1].
  • An oligogenic model including specific FSHR, ESR1 and ESR2 genotype patterns may partially explain the poor response to FSH hormone during controlled ovarian stimulation treatments [33].
  • The significantly lower expression of AR and FSHR mRNA in humans than in monkeys might therefore be either age- or species-related [34].
  • The receptor for the pituitary glycoprotein hormone FSH (FSHR) and the nuclear hormone receptor steroidogenic factor 1 (SF-1) play important roles in control of the hypothalamic-pituitary- gonadal axis [17].

Analytical, diagnostic and therapeutic context of FSHR

  • Confocal microscopy using antihuman FSHR R265-S296 demonstrated that recombinant human FSHR on Chinese hamster ovary cells existed as discrete patches on the surface [21].
  • Sequence analysis of this exon revealed an open reading frame corresponding to base positions 855-2085 of the FSHR cDNA, thereby coding for 410 amino acids [35].
  • Site directed mutagenesis of the FSHR and the expression of resulting mutants in HEK-293 cells were performed in order to corroborate the effects of these substitutions [36].
  • 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 [22].
  • In this retrospective study, we explored the impact and action of two distinct FSHR isoforms, Thr307/Asn680 and Ala307/Ser680, in a large group of men [37].


  1. 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]
  2. Expression and actions of both the follicle stimulating hormone receptor and the luteinizing hormone receptor in normal ovarian surface epithelium and ovarian cancer. Parrott, J.A., Doraiswamy, V., Kim, G., Mosher, R., Skinner, M.K. Mol. Cell. Endocrinol. (2001) [Pubmed]
  3. 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]
  4. Molecular genetic, biochemical, and clinical implications of gonadotropin receptor mutations. Chan, W.Y. Mol. Genet. Metab. (1998) [Pubmed]
  5. Immunization against exon 1 decapeptides from the lutropin/choriogonadotropin receptor or the follitropin receptor as potential male contraceptive. Remy, J.J., Couture, L., Rabesona, H., Haertle, T., Salesse, R. J. Reprod. Immunol. (1996) [Pubmed]
  6. Evaluating the roles of follicle-stimulating hormone receptor polymorphisms in gonadal hyperstimulation associated with severe juvenile primary hypothyroidism. Ryan, G.L., Feng, X., d'Alva, C.B., Zhang, M., Van Voorhis, B.J., Pinto, E.M., Kubias, A.E., Antonini, S.R., Latronico, A.C., Segaloff, D.L. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  7. FSH directly regulates bone mass. Sun, L., Peng, Y., Sharrow, A.C., Iqbal, J., Zhang, Z., Papachristou, D.J., Zaidi, S., Zhu, L.L., Yaroslavskiy, B.B., Zhou, H., Zallone, A., Sairam, M.R., Kumar, T.R., Bo, W., Braun, J., Cardoso-Landa, L., Schaffler, M.B., Moonga, B.S., Blair, H.C., Zaidi, M. Cell (2006) [Pubmed]
  8. Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Tapanainen, J.S., Aittomäki, K., Min, J., Vaskivuo, T., Huhtaniemi, I.T. Nat. Genet. (1997) [Pubmed]
  9. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Aittomäki, K., Lucena, J.L., Pakarinen, P., Sistonen, P., Tapanainen, J., Gromoll, J., Kaskikari, R., Sankila, E.M., Lehväslaiho, H., Engel, A.R., Nieschlag, E., Huhtaniemi, I., de la Chapelle, A. Cell (1995) [Pubmed]
  10. Co-evolution of ligand-receptor pairs. Moyle, W.R., Campbell, R.K., Myers, R.V., Bernard, M.P., Han, Y., Wang, X. Nature (1994) [Pubmed]
  11. Mutations in the follicle-stimulating hormone-beta (FSH beta) and FSH receptor genes in mice and humans. Layman, L.C. Seminars in reproductive medicine. (2000) [Pubmed]
  12. 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]
  13. Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR). Ben-Josef, E., Yang, S.Y., Ji, T.H., Bidart, J.M., Garde, S.V., Chopra, D.P., Porter, A.T., Tang, D.G. J. Urol. (1999) [Pubmed]
  14. Induction of infertility in adult male bonnet monkeys by immunization with phage-expressed peptides of the extracellular domain of FSH receptor. Rao, A.J., Ramachandra, S.G., Ramesh, V., Couture, L., Abdennebi, L., Salesse, R., Remy, J.J. Reprod. Biomed. Online (2004) [Pubmed]
  15. An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. Gromoll, J., Simoni, M., Nieschlag, E. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  16. The promoter of murine follicle-stimulating hormone receptor: functional characterization and regulation by transcription factor steroidogenic factor 1. Levallet, J., Koskimies, P., Rahman, N., Huhtaniemi, I. Mol. Endocrinol. (2001) [Pubmed]
  17. Activation of the rat follicle-stimulating hormone receptor promoter by steroidogenic factor 1 is blocked by protein kinase a and requires upstream stimulatory factor binding to a proximal E box element. Heckert, L.L. Mol. Endocrinol. (2001) [Pubmed]
  18. Postendocytotic trafficking of the follicle-stimulating hormone (FSH)-FSH receptor complex. Krishnamurthy, H., Kishi, H., Shi, M., Galet, C., Bhaskaran, R.S., Hirakawa, T., Ascoli, M. Mol. Endocrinol. (2003) [Pubmed]
  19. An activated human follicle-stimulating hormone (FSH) receptor stimulates FSH-like activity in gonadotropin-deficient transgenic mice. Haywood, M., Tymchenko, N., Spaliviero, J., Koch, A., Jimenez, M., Gromoll, J., Simoni, M., Nordhoff, V., Handelsman, D.J., Allan, C.M. Mol. Endocrinol. (2002) [Pubmed]
  20. Human follitropin receptor (FSHR) interacts with the adapter protein 14-3-3tau. Cohen, B.D., Nechamen, C.A., Dias, J.A. Mol. Cell. Endocrinol. (2004) [Pubmed]
  21. Accessibility of rat and human follitropin receptor primary sequence (R265-S296) in situ. Liu, X., DePasquale, J.A., Griswold, M.D., Dias, J.A. Endocrinology (1994) [Pubmed]
  22. 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]
  23. Synthesis of (bis)sulfonic acid, (bis)benzamides as follicle-stimulating hormone (FSH) antagonists. Wrobel, J., Green, D., Jetter, J., Kao, W., Rogers, J., Pérez, M.C., Hardenburg, J., Deecher, D.C., López, F.J., Arey, B.J., Shen, E.S. Bioorg. Med. Chem. (2002) [Pubmed]
  24. Follicle-stimulating hormone ligand and receptor mutations, and gonadal dysfunction. Levallet, J., Pakarinen, P., Huhtaniemi, I.T. Arch. Med. Res. (1999) [Pubmed]
  25. 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]
  26. Expression of the FSH receptor in the testis. Heckert, L., Griswold, M.D. Recent Prog. Horm. Res. (1993) [Pubmed]
  27. A synthetic peptide corresponding to human FSH beta-subunit 33-53 binds to FSH receptor, stimulates basal estradiol biosynthesis, and is a partial antagonist of FSH. Santa Coloma, T.A., Dattatreyamurty, B., Reichert, L.E. Biochemistry (1990) [Pubmed]
  28. APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling complex. Nechamen, C.A., Thomas, R.M., Dias, J.A. Mol. Cell. Endocrinol. (2007) [Pubmed]
  29. Human follicle-stimulating hormone receptor (FSH-R) promoter/enhancer activity is inhibited by transcriptional factors, from the upstream stimulating factors family, via E-box and newly identified initiator element (Inr) in FSH-R non-expressing cells. Putowski, L.T., Schillings, W.J., Lee, C.M., Reddy, E.P., Jakowicki, J.A. Gynecol. Endocrinol. (2004) [Pubmed]
  30. Role of G protein-coupled receptor kinases on the agonist-induced phosphorylation and internalization of the follitropin receptor. Lazari, M.F., Liu, X., Nakamura, K., Benovic, J.L., Ascoli, M. Mol. Endocrinol. (1999) [Pubmed]
  31. Cellular mechanisms and modulation of activin A- and transforming growth factor beta-mediated differentiation in cultured hen granulosa cells. Johnson, A.L., Bridgham, J.T., Woods, D.C. Biol. Reprod. (2004) [Pubmed]
  32. 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]
  33. Human controlled ovarian hyperstimulation outcome is a polygenic trait. de Castro, F., Morón, F.J., Montoro, L., Galán, J.J., Hernández, D.P., Padilla, E.S., Ramírez-Lorca, R., Real, L.M., Ruiz, A. Pharmacogenetics (2004) [Pubmed]
  34. Quantification of androgen receptor and follicle-stimulating hormone receptor mRNA levels in human and monkey testes by a ribonuclease-protection assay. Dankbar, B., Sohn, M., Nieschlag, E., Gromoll, J. Int. J. Androl. (1995) [Pubmed]
  35. Localization of the human FSH receptor to chromosome 2 p21 using a genomic probe comprising exon 10. Gromoll, J., Ried, T., Holtgreve-Grez, H., Nieschlag, E., Gudermann, T. J. Mol. Endocrinol. (1994) [Pubmed]
  36. Structural determinants in the second intracellular loop of the human follicle-stimulating hormone receptor are involved in G(s) protein activation. Timossi, C., Maldonado, D., Vizcaíno, A., Lindau-Shepard, B., Conn, P.M., Ulloa-Aguirre, A. Mol. Cell. Endocrinol. (2002) [Pubmed]
  37. Distribution and function of FSH receptor genetic variants in normal men. Asatiani, K., Gromoll, J., Eckardstein, S.V., Zitzmann, M., Nieschlag, E., Simoni, M. Andrologia (2002) [Pubmed]
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