The FSH Receptor: One Receptor with Multiple Forms or a Family of Receptors

  • Tim G. Rozell
  • Yonghai Li
  • Lisa C. Freeman

The follicle stimulating hormone (FSH) receptor (FSHR) is expressed within reproductive tissues and primarily allows for control of reproductive activity in response to secretion of FSH from the pituitary gland. Specific reproductive tissues within both males and females express the FSHR, and thus FSH has important roles in the reproductive process in both genders. This chapter will describe the location and expression of the FSHR gene within the gonads, post-transcriptional and post-translational modifications of FSHR protein, mechanisms of FSH binding and activation of the FSHR, and signaling events that occur within cells following FSH binding.


Granulosa Cell Follicle Stimulate Hormone Sertoli Cell Extracellular Domain Hormone Binding 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Glossary of Terms and Acronyms


cyclic adenosine monophosphate


complementary deoxyribonucleic acid


extracellular-regulated kinase


follicle stimulating hormone


follicle stimulating hormone receptor


human chorionic gonadotropin


luteinizing hormone


luteinizing hormone receptor


leucine-rich repeat


mitogen-activated protein kinase


protein kinase A


steroidogenic factor-1


Src-family kinases


thyroid stimulating hormone


thyroid stimulating hormone receptor


upstream regulatory factor-1/2


  1. 1.
    Xu Z, Garverick HA, Smith GW, et al. Expression of follicle stimulating hormone and luteinizing hormone receptor messenger ribonucleic acids in bovine follicles during the first follicular wave. Biol Reprod 1995; 53:951–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Sprengel R, Braun T, Nikolics K, et al. The testicular receptor for follicle stimulating hormone: structure and functional expression of cloned cDNA. Mol Endocrinol 1990; 4:525–30.PubMedCrossRefGoogle Scholar
  3. 3.
    McFarland KC, Sprengel R, Phillips HS, et al. Lutropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 1989; 245:494–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000; 289:739–45.PubMedCrossRefGoogle Scholar
  5. 5.
    Moyle WR, Xing Y, Lin W, et al. Model of glycoprotein hormone receptor ligand binding and signaling. J Biol Chem 2004; 279:44442–59.PubMedCrossRefGoogle Scholar
  6. 6.
    Davis D, Liu X, Segaloff DL. Identification of the sites of N-linked glycosylation on the follicle stimulating hormone (FSH) receptor and assessment of their role in FSH receptor function. Mol Endocrinol 1995; 9:159–70.PubMedCrossRefGoogle Scholar
  7. 7.
    Sairam MR, Babu PS. The tale of follitropin receptor diversity: a recipe for fine tuning gonadal responses? Mol Cell Endocrinol 2007; 260–262:163–71.PubMedCrossRefGoogle Scholar
  8. 8.
    Minegishi T, Hirakawa T, Kishi H, et al. A role of insulin-like growth factor I for follicle-stimulating hormone receptor expression in rat granulosa cells. Biol Reprod 2000; 62:325–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Sites CK, Patterson K, Jamison CS, et al. Follicle-stimulating hormone (FSH) increases FSH receptor messenger ribonucleic acid while decreasing FSH binding in cultured porcine granulosa cells. Endocrinology 1994; 134:411–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Heckert LL, Daggett MA, Chen J. Multiple promoter elements contribute to activity of the follicle-stimulating hormone receptor (FSHR) gene in testicular Sertoli cells. Mol Endocrinol 1998; 12:1499–512.PubMedCrossRefGoogle Scholar
  11. 11.
    Hermann BP, Heckert LL. Transcriptional regulation of the FSH receptor: New perspectives. Mol Cell Endocrinol 2007; 260–262:100–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Heckert LL, Griswold MD. The expression of the follicle-stimulating hormone receptor in spermatogenesis. Recent Prog Horm Res 2002; 57:129–48.PubMedCrossRefGoogle Scholar
  13. 13.
    Kash JC, Menon KMJ. Identification of a hormonally regulated luteinizing hormone/human chorionic gonadotropin receptor mRNA binding protein. J Biol Chem 1998; 273:10658–64.PubMedCrossRefGoogle Scholar
  14. 14.
    Dunkel L, Tilly JL, Shikone T, et al. Follicle-stimulating hormone receptor expression in the rat ovary: increases during prepubertal development and regulation by the opposing actions of transforming growth factors beta and alpha. Biol Reprod 1994; 50:940–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Otsuka F, Moore RK, Wang X, et al. Essential role of the oocyte in estrogen amplification of follicle-stimulating hormone signaling in granulosa cells. Endocrinology 2005; 146:3362–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Otsuka F, Yamamoto S, Erickson GF, et al. Bone morphogenetic protein-15 inhibits follicle-stimulating hormone (FSH) action by suppressing FSH receptor expression. J Biol Chem 2001; 276:11387–92.PubMedCrossRefGoogle Scholar
  17. 17.
    Jin X, Han CS, Zhang XS, et al. Stem cell factor modulates the expression of steroidogenesis related proteins and FSHR during ovarian follicular development. Front Biosci 2005; 10:1573–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Camp TA, Rahal JO, Mayo KE. Cellular localization and hormonal regulation of follicle-stimulating hormone and luteinizing hormone receptor messenger RNAs in the rat ovary. Mol Endocrinol 1991; 5:1405–17.PubMedCrossRefGoogle Scholar
  19. 19.
    LaPolt PS, Tilly JL, Aihara T, et al. Gonadotropin-induced up- and down-regulation of ovarian follicle-stimulating hormone (FSH) receptor gene expression in immature rats: effects of pregnant mare's serum gonadotropin, human chorionic gonadotropin, and recombinant FSH. Endocrinology 1992; 130:1289–95.PubMedCrossRefGoogle Scholar
  20. 20.
    Tilly JL, LaPolt PS, Hsueh AJ. Hormonal regulation of follicle-stimulating hormone receptor messenger ribonucleic acid levels in cultured rat granulosa cells. Endocrinology 1992; 130:1296–302.PubMedCrossRefGoogle Scholar
  21. 21.
    Themmen AP, Blok LJ, Post M, et al. Follitropin receptor down-regulation involves a cAMP-dependent post-transcriptional decrease of receptor mRNA expression. Mol Cell Endocrinol 1991; 78:R7–13.PubMedCrossRefGoogle Scholar
  22. 22.
    Maguire SM, Tribley WA, Griswold MD. Follicle-stimulating hormone (FSH) regulates the expression of FSH receptor messenger ribonucleic acid in cultured Sertoli cells and in hypophysectomized rat testis. Biol Reprod 1997; 56:1106–11.PubMedCrossRefGoogle Scholar
  23. 23.
    Griswold MD, Kim JS, Tribley WA. Mechanisms involved in the homologous down-regulation of transcription of the follicle-stimulating hormone receptor gene in Sertoli cells. Mol Cell Endocrinol 2001; 173:95–107.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhu C, Tian H, Xiong Z, et al. Follicle-stimulating hormone (FSH) induced internalization of porcine FSH receptor in cultured porcine granulosa cells and Chinese hamster ovary cells transfected with recombinant porcine FSH receptor cDNA. J Tongji Med Univ 2001; 21:188–90.PubMedCrossRefGoogle Scholar
  25. 25.
    Manna PR, Pakarainen P, Rannikko AS, et al. Mechanisms of desensitization of follicle-stimulating hormone (FSH) action in a murine granulosa cell line stably transfected with the human FSH receptor complementary deoxyribonucleic acid. Mol Cell Endocrinol 1998; 146:163–76.PubMedCrossRefGoogle Scholar
  26. 26.
    Rannikko A, Penttila TL, Zhang FP, et al. Stage-specific expression of the FSH receptor gene in the prepubertal and adult rat seminiferous epithelium. J Endocrinol 1996; 151:29–35.PubMedCrossRefGoogle Scholar
  27. 27.
    Griswold MD, Heckert L, Linder C. The molecular biology of the FSH receptor. J Steroid Biochem Mol Biol 1995; 53:215–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Johnston H, Baker PJ, Abel M, et al. Regulation of Sertoli cell number and activity by follicle-stimulating hormone and androgen during postnatal development in the mouse. endocrinology 2004; 145:318–29.PubMedCrossRefGoogle Scholar
  29. 29.
    Einstein R, Jordan H, Zhou W, et al. Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors. Proc Natl Acad Sci U S A 2008; 105:5230–5.Google Scholar
  30. 30.
    Khan H, Jiang LG, Jayashree GN, et al. Recognition of follicle stimulating hormone (alpha-subunit) by a recombinant receptor protein domain coded by an alternately spliced mRNA and expressed in Escherichia coli. J Mol Endocrinol 1997; 19:183–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Ulloa-Aguirre A, Zarinan T, Pasapera AM, et al. Multiple facets of follicle-stimulating hormone receptor function. Endocrine 2007; 32:251–63.PubMedCrossRefGoogle Scholar
  32. 32.
    Themmen APN, Huhtaniemi IT. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 2000; 21:551–83.PubMedCrossRefGoogle Scholar
  33. 33.
    Sairam MR, Jiang LG, Yarney TA, et al. Follitropin signal transduction: alternative splicing of the FSH receptor gene produces a dominant negative form of receptor which inhibits hormone action. Biochem Biophys Res Commun 1996; 226:717–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Li Y, Ganta S, Cheng C, et al. FSH stimulates ovarian cancer cell growth by action on growth factor variant receptor. Mol Cell Endocrinol 2007; 267:26–37.PubMedCrossRefGoogle Scholar
  35. 35.
    Fan QR, Hendrickson WA. Structure of human follicle-stimulating hormone in complex with its receptor. Nature 2005; 433:269–77.PubMedCrossRefGoogle Scholar
  36. 36.
    Delidow BC, White BA, Peluso JJ. Gonadotropin induction of c-fos and c-myc expression and deoxyribonucleic acid synthesis in rat granulosa cells. Endocrinology 1990; 126:2302–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Yarney TA, Fahmy MH, Sairam MR, et al. Ontogeny of FSH receptor messenger ribonucleic acid transcripts in relation to FSH secretion and testicular function in sheep. J Mol Endocrinol 1997; 18:113–25.PubMedCrossRefGoogle Scholar
  38. 38.
    Lusson J, Vieau D, Hamelin J, et al. cDNA structure of the mouse and rat subtilisin/kexin-like PC5: a candidate proprotein convertase expressed in endocrine and nonendocrine cells. Proc Natl Acad Sci U S A 1993; 90:6691–5.Google Scholar
  39. 39.
    Nachtigal MW, Ingraham HA. Bioactivation of Mullerian inhibiting substance during gonadal development by a kex2/subtilisin-like endoprotease. Proc Natl Acad Sci U S A 1996; 93:7711–6.Google Scholar
  40. 40.
    Ellgaard L, Helenius A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 2003; 4:181–91.PubMedCrossRefGoogle Scholar
  41. 41.
    Rozell TG, Davis DP, Chai Y, et al. Association of gonadotropin receptor precursors with the protein folding chaperone calnexin. Endocrinology 1998; 139:1588–93.PubMedCrossRefGoogle Scholar
  42. 42.
    Mizrachi D, Segaloff DL. Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors. Mol Endocrinol 2004; 18:1768–77.PubMedCrossRefGoogle Scholar
  43. 43.
    Smits G, Campillo M, Govaerts C, et al. Glycoprotein hormone receptors: determinants in leucine-rich repeats responsible for ligand specificity. EMBO J 2003; 22:2692–703.PubMedCrossRefGoogle Scholar
  44. 44.
    Hunzicker-Dunn M, Maizels ET. FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A. Cell Signal 2006; 18:1351–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Wayne CM, Fan HY, Cheng X, et al. Follicle-stimulating hormone induces multiple signaling cascades: evidence that activation of Rous sarcoma oncogene, RAS, and the epidermal growth factor receptor are critical for granulosa cell differentiation. Mol Endocrinol 2007; 21:1940–57.PubMedCrossRefGoogle Scholar
  46. 46.
    Gonzalez-Robayna IJ, Falender AE, Ochsner S, et al. Follicle-Stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-lnduced kinase (Sgk): evidence for A kinase-independent signaling by FSH in granulosa cells. Mol Endocrinol 2000; 14:1283–300.PubMedCrossRefGoogle Scholar
  47. 47.
    Richards JS. New signaling pathways for hormones and cyclic adenosine 3',5'-monophosphate action in endocrine cells. Mol Endocrinol 2001; 15:209–18.PubMedCrossRefGoogle Scholar
  48. 48.
    Latronico AC, Segaloff DL. Naturally occurring mutations of the luteinizing-hormone receptor: lessons learned about reproductive physiology and G protein-coupled receptors. Am J Hum Genet 1999; 65:949–58.PubMedCrossRefGoogle Scholar
  49. 49.
    Gromoll J, Simoni M, Nieschlag E. An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab 1996; 81:1367–70.PubMedCrossRefGoogle Scholar
  50. 50.
    Laue L, Chan WY, Hsueh AJ, et al. Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty. Proc Natl Acad Sci U S A 1995; 92:1906–10.Google Scholar
  51. 51.
    Vassart G, Pardo L, Costagliola S. A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci 2004; 29:119–26.PubMedCrossRefGoogle Scholar
  52. 52.
    Meduri G, Bachelot A, Cocca MP, et al. Molecular pathology of the FSH receptor: new insights into FSH physiology. Mol Cell Endocrinol 2008; 282:130–42.PubMedCrossRefGoogle Scholar
  53. 53.
    De Leener A, Montanelli L, Van Durme J, et al. Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology. J Clin Endocrinol Metab 2006; 91:555–62.PubMedCrossRefGoogle Scholar
  54. 54.
    Montanelli L, Delbaere A, Di Carlo C, et al. A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 2004; 89:1255–8.CrossRefGoogle Scholar
  55. 55.
    Smits G, Olatunbosun O, Delbaere A, et al. Ovarian hyperstimulation syndrome due to a mutation in the follicle-stimulating hormone receptor. N Engl J Med 2003; 349:760–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Vasseur C, Rodien P, Beau I, et al. A chorionic gonadotropin-sensitive mutation in the follicle-stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyperstimulation syndrome. N Engl J Med 2003; 349:753–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Fuller PJ, Verity K, Shen Y, et al. No evidence of a role for mutations or polymorphisms of the follicle-stimulating hormone receptor in ovarian granulosa cell tumors. J Clin Endocrinol Metab 1998; 83:274–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Ligtenberg MJ, Siers M, Themmen AP, et al. Analysis of mutations in genes of the follicle-stimulating hormone receptor signaling pathway in ovarian granulosa cell tumors. J Clin Endocrinol Metab 1999; 84:2233–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Montgomery GW, Duffy DL, Hall J, et al. Mutations in the follicle-stimulating hormone receptor and familial dizygotic twinning. Lancet 2001; 357:773–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Zhang M, Tao YX, Ryan GL, et al. Intrinsic differences in the response of the human lutropin receptor versus the human follitropin receptor to activating mutations. J Biol Chem 2007; 282:25527–39.PubMedCrossRefGoogle Scholar
  61. 61.
    Rozell TG, Wang H, Liu X, et al. Intracellular retention of mutant gonadotropin receptors results in loss of hormone binding activity of the follitropin receptor but not the lutropin/choriogonadotropin receptor. Mol Endocrinol 1995; 9:1727–36.CrossRefGoogle Scholar
  62. 62.
    Choi JH, Wong AS, Huang HF, et al. Gonadotropins and ovarian cancer. Endocr Rev 2007; 28:440–61.PubMedCrossRefGoogle Scholar
  63. 63.
    Leung PC, Choi JH. Endocrine signaling in ovarian surface epithelium and cancer. Hum Reprod Update 2007; 13:143–62.PubMedCrossRefGoogle Scholar
  64. 64.
    Halperin R, Hadas E, Langer R, et al. Peritoneal fluid gonadotropins and ovarian hormones in patients with ovarian cancer. Int J Gynecol Cancer 1999; 9:502–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Chudecka-Glaz A, Rzepka-Gorska I. Concentrations of follicle stimulating hormone are increased in ovarian tumor fluid: implications for the management of ovarian cancer. Eur J Gynaecol Oncol 2008; 29:37–42.PubMedGoogle Scholar
  66. 66.
    Bose CK. Follicle stimulating hormone receptor (FSHR) antagonist and epithelial ovarian cancer (EOC). J Exp Ther Oncol 2007; 6:201–4.PubMedGoogle Scholar
  67. 67.
    Ho SM, Lau KM, Mok SC, et al. Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells. Oncogene 2003; 22:4243–56.PubMedCrossRefGoogle Scholar
  68. 68.
    Ji Q, Liu PI, Chen PK, et al. Follicle stimulating hormone-induced growth promotion and gene expression profiles on ovarian surface epithelial cells. Int J Cancer 2004; 112:803–14.PubMedCrossRefGoogle Scholar
  69. 69.
    Gromoll J, Simoni M. Genetic complexity of FSH receptor function. Trends Endocrinol Metab 2005; 16:368–73.PubMedCrossRefGoogle Scholar
  70. 70.
    Yang CQ, Chan KY, Ngan HY, et al. Single nucleotide polymorphisms of follicle-stimulating hormone receptor are associated with ovarian cancer susceptibility. Carcinogenesis 2006; 27:1502–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Chen CL, Cheung LW, Lau MT, et al. Differential role of gonadotropin-releasing hormone on human ovarian epithelial cancer cell invasion. Endocrine 2007; 31:311–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Animal Sciences & IndustryKansas State UniversityManhattanUSA
  2. 2.Department of Anatomy & PhysiologyKansas State University College of Veterinary MedicineManhattanUSA

Personalised recommendations