Skip to main content

Advertisement

SpringerLink
Log in

The Extrapituitary Effects of GnRH Antagonists and Their Potential Clinical Implications: A Narrated Review

  • Reviews
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Potential roles of gonadotropin-releasing hormone (GnRH) antagonists on GnRH/GnRH receptor systems and their effects on the extrapituitary tissues are largely elusive. In this narrated review, we summarized the systemic effects of GnRH antagonists on ovary, endometrium, embryo implantation, placental development, fetal teratogenicity, reproductive tissue cancer cells, and heart while briefly reviewing the GnRH and GnRH receptor system. GnRH antagonists may have direct effects on ovarian granulosa cells. Data are conflicting regarding their effects on endometrial receptivity. The GnRH antagonists may potentially have detrimental effect on early placentation by decreasing the invasive ability of cytotrophoblasts if the exposure to them occurs during early pregnancy. The GnRH antagonists were not found to increase the rates of congenital malformations. Comparative clinical data are required to explore their systemic effects on various extrapituitary tissues such as on cardiac function in the long term as well as their potential use in other human cancers that express GnRH receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Yao B, Liu HY, Gu YC, et al. Gonadotropin-releasing hormone positively regulates steroidogenesis via extracellular signal-regulated kinase in rat Leydig cells. Asian J Androl. 2011; 13(3):438–445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kim YA, Kim MR, Lee JH, et al. Gonadotropin-releasing hormone agonist reduces aromatase cytochrome P450 and cyclooxygenase-2 in ovarian endometrioma and eutopic endometrium of patients with endometriosis. Gynecol Obstet Invest. 2009;68(2):73–81.

    Article  CAS  PubMed  Google Scholar 

  3. Levens E, Luo X, Ding L, Williams RS, Chegini N. Fibromodulin is expressed in leiomyoma and myometrium and regulated by gonadotropin-releasing hormone analogue therapy and TGF-beta through Smad and MAPK-mediated signalling. Mol Hum Reprod. 2005;11(7):489–494.

    Article  CAS  PubMed  Google Scholar 

  4. Casan EM, Raga F, Bonilla-Musoles F, Polan ML. Human oviductal gonadotropin-releasing hormone: possible implications in fertilization, early embryonic development, and implantation. J Clin Endocrinol Metab. 2000;85(4): 1377–1381.

    CAS  PubMed  Google Scholar 

  5. Kang SK, Choi KC, Tai CJ, Auersperg N, Leung PC. Estradiol regulates gonadotropin-releasing hormone (GnRH) and its receptor gene expression and antagonizes the growth inhibitory effects of GnRH in human ovarian surface epithelial and ovarian cancer cells. Endocrinology. 2001;142(2):580–588.

    Article  CAS  PubMed  Google Scholar 

  6. Weiss JM, Krautmacher B, Polack S, Diedrich K, Ortmann O. Actions of GnRH antagonists on IGF-II, IGF-binding protein-2 and pregnancy-associated plasma protein-A in human granulosa-lutein cells. Eur J Endocrinol. 2003;149(1):31–37.

    Article  CAS  PubMed  Google Scholar 

  7. Jelodar GA, Gholami S, Jafarpour F. Effect of GnRH on guinea pig endometrium at preimplantation stage. Indian J Exp Biol. 2007;45(3):242–246.

    CAS  PubMed  Google Scholar 

  8. Chou CS, Beristain AG, MacCalman CD, Leung PC. Cellular localization of gonadotropin-releasing hormone (GnRH) I and GnRH II in first-trimester human placenta and decidua. J Clin Endocrinol Metab. 2004;89(3):1459–1466.

    Article  CAS  PubMed  Google Scholar 

  9. White RB, Eisen JA, Kasten TL, Fernald RD. Second gene for gonadotropin-releasing hormone in humans. Proc Natl Acad Sci U S A. 1998;95(1):305–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cheon KW, Lee HS, Parhar IS, Kang IS. Expression of the second isoform of gonadotrophin-releasing hormone (GnRH-II) in human endometrium throughout the menstrual cycle. Mol Hum Reprod. 2001;7(5):447–452.

    Article  CAS  PubMed  Google Scholar 

  11. Fister S, Gunthert AR, Aicher B, Paulini KW, Emons G, Grundker C. GnRH-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells via activation of stress-induced MAPKs p38 and JNK and proapoptotic protein Bax. Cancer Res. 2009;69(16):6473–6481.

    Article  CAS  PubMed  Google Scholar 

  12. Leung PC, Cheng CK, Zhu XM. Multi-factorial role of GnRH-I and GnRH-II in the human ovary. Mol Cell Endocrinol. 2003; 202(1–2):145–153.

    Article  CAS  PubMed  Google Scholar 

  13. Choi JH, Gilks CB, Auersperg N, Leung PC. Immunolocaliza-tion of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and type I GnRH receptor during follicular development in the human ovary. J Clin Endocrinol Metab. 2006;91(11): 4562–4570.

    Article  CAS  PubMed  Google Scholar 

  14. Stewart AJ, Katz AA, Millar RP, Morgan K. Retention and silencing of prepro-GnRH-II and type II GnRH receptor genes in mammals. Neuroendocrinology. 2009;90(4):416–432.

    Article  CAS  PubMed  Google Scholar 

  15. Yahalom D, Chen A, Ben-Aroya N, et al. The gonadotropin-releasing hormone family of neuropeptides in the brain of human, bovine and rat: identification of a third isoform. FEBS Lett. 1999; 463(3):289–294.

    Article  CAS  PubMed  Google Scholar 

  16. La Rosa S, Celato N, Uccella S, Capella C. Detection of gonadotropin-releasing hormone receptor in normal human pituitary cells and pituitary adenomas using immunohistochemistry. Virchows Arch. 2000;437(3):264–269.

    Article  PubMed  Google Scholar 

  17. Neill JD, Duck LW, Sellers JC, Musgrove LC. A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem Biophys Res Commun. 2001;282(4):1012–1018.

    Article  CAS  PubMed  Google Scholar 

  18. Borroni R, Di Blasio AM, Gaffuri B, et al. Expression of GnRH receptor gene in human ectopic endometrial cells and inhibition of their proliferation by leuprolide acetate. Mol Cell Endocrinol. 2000;159(1–2):37–43.

    Article  CAS  PubMed  Google Scholar 

  19. Kim KY, Choi KC, Park SH, Chou CS, Auersperg N, Leung PC. Type II gonadotropin-releasing hormone stimulates p38 mitogen-activated protein kinase and apoptosis in ovarian cancer cells. J Clin Endocrinol Metab. 2004;89(6):3020–3026.

    Article  CAS  PubMed  Google Scholar 

  20. van Biljon W, Wykes S, Scherer S, Krawetz SA, Hapgood J. Type II gonadotropin-releasing hormone receptor transcripts in human sperm. Biol Reprod. 2002;67(6):1741–1749.

    Article  PubMed  CAS  Google Scholar 

  21. Ata B, Urman B. Single dose GnRH agonist administration in the luteal phase of assisted reproduction cycles: is the effect dependent on the type of GnRH analogue used for pituitary suppression? Reprod Biomed Online. 2010;20(1):165–166.

    Article  CAS  PubMed  Google Scholar 

  22. Kiesel LA, Rody A, Greb RR, Szilagyi A. Clinical use of GnRH analogues. Clin Endocrinol (Oxf). 2002;56(6):677–687.

    Article  CAS  Google Scholar 

  23. Shalev E, Leung PC. Gonadotropin-releasing hormone and reproductive medicine. J Obstet Gynaecol Can. 2003;25(2):98–113.

    Article  PubMed  Google Scholar 

  24. Tan O, Bukulmez O. Biochemistry, molecular biology and cell biology of gonadotropin-releasing hormone antagonists. Curr Opin Obstet Gynecol. 2011;23(4):238–244.

    Article  PubMed  Google Scholar 

  25. FDA DA. Abarelix (Praecis Pharmaceuticals / Schering AG’s Ple-naxis) http://www.accessdata.fda.gov. 2005.

  26. Festuccia C, Dondi D, Piccolella M, et al. Ozarelix, a fourth generation GnRH antagonist, induces apoptosis in hormone refractory androgen receptor negative prostate cancer cells modulating expression and activity of death receptors. Prostate. 2010;70(12):1340–1349.

    CAS  PubMed  Google Scholar 

  27. Schneider A, Lang A, Naumann W. Fluorescence spectroscopic determination of the critical aggregation concentration of the GnRH antagonists Cetrorelix, Teverelix and Ozarelix. J Fluoresc. 2010;20(6):1233–1240.

    Article  CAS  PubMed  Google Scholar 

  28. Struthers RS, Nicholls AJ, Grundy J, et al. Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix. J Clin Endocrinol Metab. 2009;94(2): 545–551.

    Article  CAS  PubMed  Google Scholar 

  29. Chen C, Wu D, Guo Z, et al. Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]be nzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem. 2008;51(23):7478–7485.

    Article  CAS  PubMed  Google Scholar 

  30. Metallinou C, Asimakopoulos B, Schroer A, Nikolettos N. Gonadotropin-releasing hormone in the ovary. Reprod Sci. 2007;14(8):737–749.

    Article  CAS  PubMed  Google Scholar 

  31. Choi JH, Choi KC, Auersperg N, Leung PC. Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid by gonadotropins in human immortalized ovarian surface epithelium and ovarian cancer cells. Endocr Relat Cancer. 2006;13(2):641–651.

    Article  CAS  PubMed  Google Scholar 

  32. Weiss JM, Oltmanns K, Gurke EM, et al. Actions of gonadotropin-releasing hormone antagonists on steroidogenesis in human granulosa lutein cells. Eur J Endocrinol. 2001;144(6):677–685.

    Article  CAS  PubMed  Google Scholar 

  33. Asimakopoulos B, Nikolettos N, Nehls B, Diedrich K, Al-Hasani S, Metzen E. Gonadotropin-releasing hormone antagonists do not influence the secretion of steroid hormones but affect the secretion of vascular endothelial growth factor from human granulosa luteinized cell cultures. Fertil Steril. 2006;86(3):636–641.

    Article  CAS  PubMed  Google Scholar 

  34. Giampietro F, Sancilio S, Tiboni GM, Rana RA, Di Pietro R. Levels of apoptosis in human granulosa cells seem to be comparable after therapy with a gonadotropin-releasing hormone agonist or antagonist. Fertil Steril. 2006;85(2):412–419.

    Article  CAS  PubMed  Google Scholar 

  35. Garcia-Velasco JA, Isaza V, Vidal C, et al. Human ovarian steroid secretion in vivo: effects of GnRH agonist versus antagonist (cetrorelix). Hum Reprod. 2001;16(12):2533–2539.

    Article  CAS  PubMed  Google Scholar 

  36. Winkler N, Bukulmez O, Hardy DB, Carr BR. Gonadotropin releasing hormone antagonists suppress aromatase and anti-Mullerian hormone expression in human granulosa cells. Fertil Steril. 2010;94(5):1832–1839.

    Article  CAS  PubMed  Google Scholar 

  37. Gordon K. Gonadotropin-releasing hormone antagonists implications for oocyte quality and uterine receptivity. Ann N Y Acad Sci. 20011;943:49–54.

    Article  CAS  PubMed  Google Scholar 

  38. Horcajadas JA, Minguez P, Dopazo J, et al. Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. J Clin Endocrinol Metab. 2008;93(11):4500–4510.

    Article  CAS  PubMed  Google Scholar 

  39. Cheng CK, Leung PC. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev. 2005;26(2):283–306.

    Article  CAS  PubMed  Google Scholar 

  40. Oehninger S. Revealing the enigmas of implantation: what is the true impact of ovarian hyperstimulation? Fertil Steril. 2008;89(1): 27–30.

    Article  PubMed  Google Scholar 

  41. Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception: a Cochrane review. Reprod Biomed Online. 2007;14(5):640–649.

    Article  CAS  PubMed  Google Scholar 

  42. Bourgain C, Devroey P. The endometrium in stimulated cycles for IVF. Hum Reprod Update. 2003;9(6):515–522.

    Article  PubMed  Google Scholar 

  43. Borthwick JM, Charnock-Jones DS, Tom BD, et al. Determination of the transcript profile of human endometrium. Mol Hum Reprod. 2003;9(1):19–33.

    Article  CAS  PubMed  Google Scholar 

  44. Bukulmez O, Rehman KS, Langley M, et al. Precycle administration of GnRH antagonist and microdose HCG decreases clinical pregnancy rates without affecting embryo quality and blastulation. Reprod Biomed Online. 2006;13(4):465–475.

    Article  CAS  PubMed  Google Scholar 

  45. Bukulmez O, Carr BR, Doody KM, Doody KJ. Serum cetrorelix concentrations do not affect clinical pregnancy outcome in assisted reproduction. Fertil Steril. 2008;89(1):74–83.

    Article  CAS  PubMed  Google Scholar 

  46. Haouzi D, Assou S, Dechanet C, et al. Controlled ovarian hyper-stimulation for in vitro fertilization alters endometrial receptivity in humans: protocol effects. Biol Reprod. 2010;82(4):679–686.

    Article  CAS  PubMed  Google Scholar 

  47. Prapas N, Tavaniotou A, Panagiotidis Y, et al. GnRH antagonists and endometrial receptivity in oocyte recipients: a prospective randomized trial. Reprod Biomed Online. 2009;18(2):276–281.

    Article  PubMed  Google Scholar 

  48. Martinez F, Latre L, Clua E, Rodriguez I, Coroleu B. Replacing GnRH agonists with GnRH antagonists in oocyte recipient cycle did not adversely affect the pregnancy rates. Eur J Obstet Gynecol Reprod Biol. 2011;159(2):355–358.

    Article  CAS  PubMed  Google Scholar 

  49. Rackow BW, Kliman HJ, Taylor HS. GnRH antagonists may affect endometrial receptivity. Fertil Steril. 2008;89(5): 1234–1239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Simon C, Oberye J, Bellver J, et al. Similar endometrial development in oocyte donors treated with either high- or standard-dose GnRH antagonist compared to treatment with a GnRH agonist or in natural cycles. Hum Reprod. 2005;20(12):3318–3327.

    Article  CAS  PubMed  Google Scholar 

  51. Van Vaerenbergh I, Van Lommel L, Ghislain V, et al. In GnRH antagonist/rec-FSH stimulated cycles, advanced endometrial maturation on the day of oocyte retrieval correlates with altered gene expression. Hum Reprod. 2009;24(5):1085–1091.

    Article  PubMed  CAS  Google Scholar 

  52. Albano C, Felberbaum RE, Smitz J, et al. Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin. European Cetrorelix Study Group. Hum Reprod. 2000;15(3):526–531.

    Article  CAS  PubMed  Google Scholar 

  53. Borm G, Mannaerts B. Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group. Hum Reprod. 2000;15(7):1490–1498.

    Article  CAS  PubMed  Google Scholar 

  54. Fluker M, Grifo J, Leader A, et al. Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertil Steril. 2001;75(1):38–45.

    Article  CAS  PubMed  Google Scholar 

  55. Blumenfeld Z. Gonadotropin-releasing hormone antagonists instead of agonists: a change for the etter? Fertil Steril. 2001; 76(3):443–444.

    Article  CAS  PubMed  Google Scholar 

  56. Kolibianakis EM, Collins J, Tarlatzis BC, Devroey P, Diedrich K, Griesinger G. Among patients treated for IVF with gonadotro-phins and GnRH analogues, is the probability of live birth dependent on the type of analogue used? A systematic review and metaanalysis. Hum Reprod Update. 2006;12(6):651–671.

    Article  CAS  PubMed  Google Scholar 

  57. Bodri D, Sunkara SK, Coomarasamy A. Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis. Fertil Steril. 2011;95(1):164–169.

    Article  CAS  PubMed  Google Scholar 

  58. Al-Inany HG, Youssef MA, Aboulghar M, et al. GnRH antagonists are safer than agonists: an update of a Cochrane review. Hum Reprod Update. 2011;17(4):435.

    Article  PubMed  Google Scholar 

  59. Lin LS, Roberts VJ, Yen SS. Expression of human gonadotropin-releasing hormone receptor gene in the placenta and its functional relationship to human chorionic gonadotropin secretion. J Clin Endocrinol Metab. 1995;80(2):580–585.

    CAS  PubMed  Google Scholar 

  60. Wolfahrt S, Kleine B, Jarry H, Rossmanith WG. Endogenous regulation of the GnRH receptor by GnRH in the human placenta. Mol Hum Reprod. 2001;7(1):89–95.

    Article  CAS  PubMed  Google Scholar 

  61. Sasaki K, Norwitz ER. Gonadotropin-releasing hormone/ gonadotropin-releasing hormone receptor signaling in the placenta. Curr Opin Endocrinol Diabetes Obes. 2011;18(6): 401–408.

    Article  CAS  PubMed  Google Scholar 

  62. Chou CS, Zhu H, Shalev E, MacCalman CD, Leung PC. The effects of gonadotropin-releasing hormone (GnRH) I and GnRH II on the urokinase-type plasminogen activator/plasmi-nogen activator inhibitor system in human extravillous cytotro-phoblasts in vitro. J Clin Endocrinol Metab. 2002;87(12): 5594–5603.

    Article  CAS  PubMed  Google Scholar 

  63. Chou CS, Zhu H, MacCalman CD, Leung PC. Regulatory effects of gonadotropin-releasing hormone (GnRH) I and GnRH II on the levels of matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinases-1 in primary cultures of human extravillous cytotrophoblasts. J Clin Endocrinol Metab. 2003; 88(10):4781–4790.

    Article  CAS  PubMed  Google Scholar 

  64. Liu J, Cao B, Li YX, Wu XQ, Wang YL. GnRH I and II up-regulate MMP-26 expression through the JNK pathway in human cytotrophoblasts. Reprod Biol Endocrinol. 2010;8:5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Casan EM, Raga F, Polan ML. GnRH mRNA and protein expression in human preimplantation embryos. Mol Hum Reprod. 1999; 5(3):234–239.

    Article  CAS  PubMed  Google Scholar 

  66. Tug N, Uslu U, Cumbul A, et al. Effects of the gonadotropin-releasing hormone antagonist cetrorelix in the early postimplantation period on rat pregnancy. Eur J Obstet Gynecol Reprod Biol. 2011;155(2):166–170.

    Article  CAS  PubMed  Google Scholar 

  67. Olivennes F, Mannaerts B, Struijs M, Bonduelle M, Devroey P. Perinatal outcome of pregnancy after GnRH antagonist (ganirelix) treatment during ovarian stimulation for conventional IVF or ICSI: a preliminary report. Hum Reprod. 2001;16(8):1588–1591.

    Article  CAS  PubMed  Google Scholar 

  68. Boerrigter PJ, de Bie JJ, Mannaerts BM, van Leeuwen BP, Passier-Timmermans DP. Obstetrical and neonatal outcome after controlled ovarian stimulation for IVF using the GnRH antagonist ganirelix. Hum Reprod. 2002;17(8):2027–2034.

    Article  CAS  PubMed  Google Scholar 

  69. Elizur SE, Tulandi T. Drugs in infertility and fetal safety. Fertil Steril. 2008;89(6): 1595–1602.

    Article  CAS  PubMed  Google Scholar 

  70. Bonduelle M, Oberye J, Mannaerts B, Devroey P. Large prospective, pregnancy and infant follow-up trial assures the health of 1000 fetuses conceived after treatment with the GnRH antagonist ganirelix during controlled ovarian stimulation. Hum Reprod. 2010;25(6):1433–1440.

    Article  CAS  PubMed  Google Scholar 

  71. Kyrou D, Verpoest W, Staessen C, et al. No relationship between the type of pituitary suppression for IVF and chromosomal abnormality rates of blastomeres: an observational study. Fertil Steril. 2011;95(2):563–567.

    Article  PubMed  Google Scholar 

  72. Dondi D, Festuccia C, Piccolella M, Bologna M, Motta M. GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting the plasminogen activator system. Oncol Rep. 2006;15(2):393–400.

    CAS  PubMed  Google Scholar 

  73. Maudsley S, Davidson L, Pawson AJ, Chan R, Lopez de Maturana R, Millar RP. Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a Galphai-coupling state of the type I GnRH receptor. Cancer Res. 2004;64(20):7533–7544.

    Article  CAS  PubMed  Google Scholar 

  74. Grundker C, Schlotawa L, Viereck V, et al. Antiproliferative effects of the GnRH antagonist cetrorelix and of GnRH-II on human endometrial and ovarian cancer cells are not mediated through the GnRH type I receptor. Eur J Endocrinol. 2004;151:141–149.

    Article  PubMed  Google Scholar 

  75. Emons G, Grundker C, Gunthert AR, Westphalen S, Kavanagh J, Verschraegen C. GnRH antagonists in the treatment of gynecological and breast cancers. Endocr Relat Cancer. 2003;10(2):291–299.

    Article  CAS  PubMed  Google Scholar 

  76. So WK, Cheng JC, Poon SL, Leung PC. Gonadotropin-releasing hormone and ovarian cancer: a functional and mechanistic overview. FEBS J. 2008;275(22):5496–5511.

    Article  CAS  PubMed  Google Scholar 

  77. Vincze B, Palyi I, Daubner D, et al. Antitumour effect of a gonadotropin-releasing-hormone antagonist (MI-1544) and its conjugate on human breast cancer cells and their xenografts. J Cancer Res Clin Oncol. 1994;120(10):578–584.

    Article  CAS  PubMed  Google Scholar 

  78. Neves SR, Ram PT, Iyengar R. G protein pathways. Science. 2002;296(5573):1636–1639.

    Article  CAS  PubMed  Google Scholar 

  79. White CD, Stewart AJ, Lu ZL, Millar RP, Morgan K. Antiproliferative effects of GnRH agonists: prospects and problems for cancer therapy. Neuroendocrinology. 2008;88(2):67–79.

    Article  CAS  PubMed  Google Scholar 

  80. Kakar SS, Jennes L. Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues. Cancer Lett. 1995; 98(1):57–62.

    Article  CAS  PubMed  Google Scholar 

  81. Lee CY, Ho J, Chow SN, Yasojima K, Schwab C, McGeer PL. Immunoidentification of gonadotropin releasing hormone receptor in human sperm, pituitary and cancer cells. Am J Reprod Immunol. 2000;44(3):170–177.

    Article  CAS  PubMed  Google Scholar 

  82. Tandler R, Kondruweit M, Fischlein T, Weyand M. Hormone therapy in men-increased risk of cardiac allograft rejection? J Heart Lung Transplant. 2003;22(7):831.

    Article  CAS  PubMed  Google Scholar 

  83. D’Amico AV, Denham JW, Crook J, et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol. 2007;25(17): 2420–2425.

    Article  PubMed  CAS  Google Scholar 

  84. Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 2007; 99(20):1516–1524.

    Article  PubMed  Google Scholar 

  85. Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102(1):39–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Dong F, Skinner DC, Wu TJ, Ren J. The heart: a novel gonadotrophin-releasing hormone target. J Neuroendocrinal. 2011;23(5):456–463.

    Article  CAS  Google Scholar 

  87. Smith MR, Klotz L, van der Meulen E, Colli E, Tanko LB. Gonadotropin-releasing hormone blockers and cardiovascular disease risk: analysis of prospective clinical trials of degarelix. J Urol. 2011;186(5):1835–1842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cheung LW, Wong AS. Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues. FEBS J. 2008; 275(22):5479–5495.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. J6, 75390, Dallas, TX, USA

    Orkun Tan MD, Bruce R. Carr MD, Victor E. Beshay MD & Orhan Bukulmez MD

Authors
  1. Orkun Tan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruce R. Carr MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor E. Beshay MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Orhan Bukulmez MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Orkun Tan MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tan, O., Carr, B.R., Beshay, V.E. et al. The Extrapituitary Effects of GnRH Antagonists and Their Potential Clinical Implications: A Narrated Review. Reprod. Sci. 20, 16–25 (2013). https://doi.org/10.1177/1933719112459244

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719112459244

Keywords

Search

Navigation