International Journal of Infertility & Fetal Medicine

Register      Login

VOLUME 11 , ISSUE 2 ( May-August, 2020 ) > List of Articles

REVIEW ARTICLE

Current Knowledge on the Use of Letrozole in Ovarian Stimulation

Suchika Mangal

Keywords : Letrozole, Ovulation induction, Protocols,Aromatase inhibitor

Citation Information : Mangal S. Current Knowledge on the Use of Letrozole in Ovarian Stimulation. Int J Infertil Fetal Med 2020; 11 (2):48-53.

DOI: 10.5005/jp-journals-10016-1205

License: CC BY-NC-ND 4.0

Published Online: 09-03-2021

Copyright Statement:  Copyright © 2020; Jaypee Brothers Medical Publishers (P) Ltd.


Abstract

Androgens are converted to estrogens by the enzyme called aromatase. This process called aromatization is inhibited by a group of drugs called aromatase inhibitors (AIs). Letrozole is a nonsteroidal inhibitor that reversibly binds aromatase. Decrease in circulating estradiol level leads to release of negative feedback at hypothalamus pituitary level, thereby increasing follicle stimulating hormone (FSH) secretion resulting in stimulation of growth of ovarian follicles. Letrozole is well tolerated and is used in different protocols of ovarian stimulation. The extended spectrum of uses includes addition with gonadotrophins in poor responders, ovarian hyperstimulation syndrome (OHSS) prevention, fertility preservation in cancer patients. Due to its wide range of use, easy availability, affordability and good tolerability, Letrozole has emerged as a first line drug for ovulation induction.


PDF Share
  1. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol 2001;45(3):116–124. DOI: 10.1067/mjd.2001.117432.
  2. Gruber CJ, Tschugguel W, Schneeberger C, et al. Production and actions of estrogens. N Engl J Med 2002;346(5):340–352. DOI: 10.1056/NEJMra000471.
  3. Thompson EA, Siiteri PK. Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J Biol Chem 1974;249(17):5364–5372. DOI: 10.1016/S0021-9258(20)79735-8.
  4. Chen S, Besman MJ, Sparkes RS, et al. Human aromatase: CDNA cloning, southern blot analysis, and assignment of the gene to chromosome 15. DNA 1988;7(1):27–38. DOI: 10.1089/dna.1988.7.27.
  5. Santen RJ, Brodie H, Simpson ER, et al. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev 2009;30(4):343–375. DOI: 10.1210/er.2008-0016.
  6. Novartis, Femara (letrozole) tablets prescribing information. East Hanover, NJ.
  7. Fabian CJ. The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer. Int J Clin Pract 2007;61(12):2051–2063. DOI: 10.1111/j.1742-1241.2007.01587.x.
  8. Janicke F. Are all aromatase inhibitors the same? A review of the current evidence. Breast 2004;13(Suppl 1):S10–S18. DOI: 10.1016/j.breast.2004.09.003.
  9. Requena A. Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Hum Reprod Update 2008;14(6):571–582. DOI: 10.1093/humupd/dmn033.
  10. Casper RF, Mohamed FM. Mitwally review: aromatase inhibitors for ovulation induction. J Clin Endocrinol Metabol 2006;91(3):760–771. DOI: 10.1210/jc.2005-1923.
  11. Kar S. Current evidence supporting “letrozole” for ovulation induction. J Hum Reprod Sci 2013;6(2):93–98. DOI: 10.4103/0974-1208.117166.
  12. Weil SJ, Vendola K, Zhou J, et al. Androgen receiptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab 1998;837(7):2479–2485. DOI: 10.1210/jcem.83.7.4917.
  13. Kamat A, Hinshelwood MM, Murry BA, et al. Mechanisms in tissue-specific regulation of estrogen biosynthesis in humans. Trends Endocrionol Metab 2002;133(3):122–128. DOI: 10.1016/S1043-2760(02)00567-2.
  14. Bhatnagar AS, Häusler A, Schieweck K, et al. Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol 1990;37(6):1021–1027. DOI: 10.1016/0960-0760(90)90460-3.
  15. Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of 2.5 and 5.0 mg of letrozole (LE) on follicular development, endometrial thickness and pregnancy rate in patients undergoing superovulation. Fertil Steril 2002;78:S55. DOI: 10.1016/S0015-0282(02)03524-0.
  16. Healey S, Tan SL, Tulandi T, et al. Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination. Fertil Steril 2003;806(6):1325–1329. DOI: 10.1016/j.fertnstert.2003.03.001.
  17. Rahmani E. Dosage optimization for letrozole treatment in clomiphene-resistant patients with Ppolycystic ovary syndrome: a prospective interventional study. Obstet Gynecol Int 2012;2012:758508.
  18. Mitwally MFM, Casper RF. Aromatase inhibition: a novel method of ovulation induction in women with polycystic ovarian syndrome. Reprod Technol 2001;10:244–247.
  19. Mitwally MF, Biljan MM, Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol 2005;192(2):381–386. DOI: 10.1016/j.ajog.2004.08.013.
  20. Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial. Fert Steril 2009;92(3):849–852. DOI: 10.1016/j.fertnstert.2007.02.062.
  21. Mitwally MFM, Casper RF. Single dose administration of the aromatase inhibitor, letrozole: a simple and convenient effective method of ovulation induction. Fertil Steril 2001;76(3):S94–S95. DOI: 10.1016/S0015-0282(01)02281-6.
  22. Badawy A, Mosbah A, Tharwat A, et al. Extended letrozole therapy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a novel protocol. Fertil Steril 2009;92(1):236–239. DOI: 10.1016/j.fertnstert.2008.04.065.
  23. Holzer H, Casper R, Tulandi T. A new era in ovulation induction. Fertil Steril 2006;85(2):277–284. DOI: 10.1016/j.fertnstert.2005.05.078.
  24. Fouda UM. Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: a randomized controlled trial. Reprod Biol Endocrinol 2011;9(1):84. DOI: 10.1186/1477-7827-9-84.
  25. Mitwally MF, Said T, Galal A, et al. Letrozole step-up protocol: a successful superovulation protocol. Poster Presentat 2008;89(4):S23–S24.
  26. Malhotra N, Karmakar D, Kumar S. Letrozole alone or letrozole gonadotropin combination as first line for superovulation in women with unexplained infertility undergoing intrauterine insemination (IUI): a prospective randomized trial, fertility and sterility. 2012;98(3):S258.
  27. Haas J, Bassil R, Meriano J, et al. Does daily co-administration of letrozole and gonadotropins during ovarian stimulation improve IVF outcome? Reprod Biol Endocrinol 2011;15(1):70. DOI: 10.1186/s12958-017-0288-8.
  28. Pereira N, Hancock K, Cordeiro CN, et al. Comparison of ovarian stimulation response in patients with breast cancer undergoing ovarian stimulation with letrozole and gonadotropins to patients undergoing ovarian stimulation with gonadotropins alone for elective cryopreservation of oocytes. Gynecol Endocrinol 2016;32(10):823–826. DOI: 10.1080/09513590.2016.1177013.
  29. Quinn MM, Cakmak H, Letourneau JM, et al. Response to ovarian stimulation is not impacted by a breast cancer diagnosis. Hum Reprod 2017;32(3):568–574. DOI: 10.1093/humrep/dew355.
  30. Mai Q, Hu X, Yang G, et al. Effect of letrozole on moderate and severe early-onset ovarian hyperstimulation syndrome in high-risk women: a prospective randomized trial. Am J Obstet Gynecol 2017;216(1):42.e1–42.e10. DOI: 10.1016/j.ajog.2016.08.018.
  31. Goldrat O, Gervy C, Englert Y, et al. Progesterone levels in letrozole associated controlled ovarian stimulation for fertility preservation in breast cancer patients. Hum Reprod 2015;30(9):2184–2189. DOI: 10.1093/humrep/dev155.
  32. Al-Omari WR, Sulaiman WR, Al-Hadithi N. Comparison of two aromatase inhibitors in women with clomiphene-resistant polycystic ovary syndrome. Int J Gynaecol Obstet 2004;85(3):289–291. DOI: 10.1016/j.ijgo.2003.11.010.
  33. Atay V, Cam C, Muhcu M, et al. Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation. J Int Med Res 2006;34(1):73–76. DOI: 10.1177/147323000603400109.
  34. Bayar Ü, Tanrıverdi HA, Barut A, et al. Letrozole vs clomiphene citrate in patients with ovulatory infertility. Fertil Steril 2006;85(4):1045–1048. DOI: 10.1016/j.fertnstert.2005.09.045.
  35. Sohrabvand F, Ansari SH, Bagheri M. Efficacy of combined metformin letrozole in comparison with metformin clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease. Hum Reprod 2006;21(6):1432–1435. DOI: 10.1093/humrep/del020.
  36. Cantineau AE, Cohlen BJ, Heineman MJ. Ovarian stimulation protocols (antioestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility. Cochrane Database Syst Rev 2007(2):CD005356.
  37. Pourali L, Ayati S, Tavakolizadeh S, et al. Clomiphene citrate versus letrozole with gonadotropins in intrauterine insemination cycles: a prospective randomized trial. Int J Reproduct Biomedic 2017;15(1):49–54.
  38. Al-Fozan H, Al-Khadouri M, Tan SL, et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004;82(6):1561–1563. DOI: 10.1016/j.fertnstert.2004.04.070.
  39. Fatemi HM, Kolibianakis E, Tournaye H, et al. Clomiphene citrate versus letrozole for ovarian stimulation: a pilot study. Reprod Biomed Online 2003;7(5):543–546. DOI: 10.1016/S1472-6483(10)62070-6.
  40. Nasseri S, Ledger WL. Clomiphene citrate in the twenty-first century. Am Fam Physician 2000;62(5):1079–1088, 1090.
  41. Homburg R. Polycystic ovary syndrome – induction of ovulation. Human Rreproduction 1996;11(1):29–39. DOI: 10.1093/oxfordjournals.humrep.a019031.
  42. Biljan MM, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril 2005;84(Suppl 1):S95. DOI: 10.1016/j.fertnstert.2005.07.230.
  43. Tulandi T, Martin J, Al-Fadhli R, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85(6):1761–1765. DOI: 10.1016/j.fertnstert.2006.03.014.
  44. Legro RS, Kunselman AR, Brzyski RG, et al. The pregnancy in polycystic ovary syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials 2012;33(3):470–481. DOI: 10.1016/j.cct.2011.12.005.
  45. Diamond MP, Mitwally M, Casper R, et al. Estimating rates of multiple gestation pregnancies: sample size calculation from the assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial. Contemp Clin Trials 2011;32(6):902–908. DOI: 10.1016/j.cct.2011.07.009.
  46. Badawy A, Shokeir T, Allam AF, et al. Pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility. Acta Obstetricia et Gynecologica 2009;88(2):187–191. DOI: 10.1080/00016340802638199.
  47. Dicken CL, Nakhuda GS, Guarnaccia MM, et al. Triplet pregnancy after ovulation induction with an aromatase inhibitor. Fertil Steril 2008;90(4):1199.e9-11. DOI: 10.1016/j.fertnstert.2007.08.065.
  48. Bishai R, Arbour L, Lyons C, et al. Intrauterine exposure to clomiphene and neonatal persistent hyperplastic primary vitreous. Teratology 1999;60(3):143–145. DOI: 10.1002/(SICI)1096-9926(199909)60:3<143::AID-TERA9>3.0.CO;2-#.
  49. Tiboni GM. Aromatase inhibitors and teratogenesis. Fertil Steril 2004;81(4):1158–1159. DOI: 10.1016/j.fertnstert.2004.01.006.
  50. Akman L, Akdogan A, Erbas O, et al. Effect of letrozole for prevention of ovarian hyperstimulation syndrome (OHSS) in a rat model. Fertil Steril 2013;100(3):S258. DOI: 10.1016/j.fertnstert.2013. 07.1086.
  51. He Q, Liang L, Zhang C, et al. Effects of different doses of letrozole on the incidence of early-onset ovarian hyperstimulation syndrome after oocyte retrieval. Syst Biol Reprod Med 2014;60(6):355. DOI: 10.3109/19396368.2014.957879.
  52. Thomas K, Thomson A, Wood S, et al. Endometrial integrin expression in women undergoing in vitro fertilization and the association with subsequent treatment outcome. Fertil Steril 2003;80(3):502–507. DOI: 10.1016/S0015-0282(03)00792-1.
  53. Miller PB, Parnell BA, Bushnell G, et al. Endometrial receptivity defects during IVF cycles with and without letrozole. Hum Reprod 2012;27(3):881–888. DOI: 10.1093/humrep/der452.
  54. Goswami SK, Das T, Chattopadhyay R, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004;19(9):2031–2035. DOI: 10.1093/humrep/deh359.
  55. Garcia-Velasco JA, Moreno L, Pacheco A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril 2005;84(1):82–87. DOI: 10.1016/j.fertnstert.2005.01.117.
  56. Ozmen B, Sönmezer M, Atabekoglu CS, et al. Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocols. Reprod Biomed Online 2009;19(4):478–485. DOI: 10.1016/j.rbmo.2009.05.007.
  57. Davar R, Oskouian H, Ahmadi S, et al. GnRH antagonist/letrozole versus microdose GnRH agonist flare protocol in poor responders undergoing in vitro fertilization. Taiwan J Obstet Gynecol 2010;49(3):297–301. DOI: 10.1016/S1028-4559(10)60064-2.
  58. Ersahin A, Gorgen B, Kahraman S. Letrozole in poor responders: a comparative study with previous cycles. Fertil Steril 2013;100(3):S508. DOI: 10.1016/j.fertnstert.2013.07.208.
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.