A Prospective Randomised Comparative Clinical Trial Study of Luteal PhaseLetrozole versus Ganirelix Acetate Administration to Prevent Severity of Early Onset OHSS in ARTs

Document Type : Original Article


1 Ankoor Fertility Clinic, Mumbai, India

2 Panache Hospital, Nashik, Maharashtra, India

3 Seema Hospital and Eva Fertility Clinic, Atraulia, Uttar Pradesh, India


Background: Ovarian hyperstimulation syndrome (OHSS) is the most notable complication in ovulation induction for assisted reproductive techniques (ARTs) like in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Hence, we decided to evaluate the effect of the aromatase inhibitor, letrozole, versus gonadotrophin-releasing hormone (GnRH)-antagonist (ganirelix acetate) on prevention of severity of OHSS and reduction in serum estradiol (E2) levels when administered during the luteal phase after oocyte retrieval in IVF/ICSI cycles.
Materials and Methods: In this prospective single-centred, randomized, parallel-arm study, 122 patients were randomized to receive oral letrozole (n=61, 2.5 mg twice daily) or ganirelix acetate (n=61, 0.25 mg subcutaneously daily) from the day of egg retrieval for the next 7 days. Incidence and severity of early OHSS were the primary endpoints assessed by the signs, symptoms, and laboratory findings of OHSS (e.g., serum E2 levels). The secondary endpoints were patient satisfaction and the additional cost of therapy to prevent the severity of OHSS.
Results: Letrozole group had lower incidence of OHSS (13.1%) compared to 19.6% in ganirelix acetate group (P=0.32). Serum E2 levels on post-pick up days 5 and 7 were significantly lower in the letrozole group when compared to the ganirelix acetate group (P=0.001). The majority of the patients in both groups had no major complications. No significant difference was found between the study groups with respect to the incidence of OHSS (P=0.33). The additional cost per IVF cycle for prevention of severity of early-onset OHSS in the letrozole group was 5.32 USD compared to 267.26 USD in the ganirelix acetate group, which was almost fifty times costlier.
Conclusion: Letrozole and ganirelix acetate have the same efficiency for the overall prevention of OHSS, whereas letrozole was more effective in preventing moderate OHSS. Letrozole had better patient satisfaction and is cheaper compared to GnRH antagonists (Registration number: CTRI/2020/10/028674).


  1. Beall SA, DeCherney A. History and challenges surrounding ovarian stimulation in the treatment of infertility. Fertil Steril. 2012; 97(4): 795-801.
  2. Depalo R, Jayakrishan K, Garruti G, Totaro I, Panzarino M, Giorgino F, et al. GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET). Reprod Biol Endocrinol. 2012; 10: 26.
  3. Erb K, Klipping C, Duijkers I, Pechstein B, Schueler A, Hermann R. Pharmacodynamic effects and plasma pharmacokinetics of single doses of cetrorelix acetate in healthy premenopausal women. Fertil Steril. 2001; 75(2): 316-323.
  4. Song M, Liu C, Hu R, Wang F, Huo Z. Administration effects of single-dose GnRH agonist for luteal support in females undertaking IVF/ICSI cycles: a meta-analysis of randomized controlled trials. Exp Ther Med. 2020; 19(1): 786-796.
  5. Blumenfeld Z. The ovarian hyperstimulation syndrome. Vitam Horm. 2018; 107: 423-451.
  6. Nastri CO, Teixeira DM, Moroni RM, Leitão VM, Martins WP. Ovarian hyperstimulation syndrome: pathophysiology, staging, prediction and prevention. Ultrasound Obstet Gynecol. 2015; 45(4): 377-393.
  7. Choi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles. Gynecol Endocrinol. 2014; 30(3): 174-181.
  8. Peigne M, Lobert M, Tintillier V, Trillot N, Catteau-Jonard S, Dewailly D. Prevalence of ovarian hyperstimulation syndrome (OHSS) and hypercoagulability in patients triggered by GnRH agonist for excessive follicular response: a systematic follow-up. Fertil Steril. 2017; 108(3): e227.
  9. Toftager M, Bogstad J, Bryndorf T, Løssl K, Roskær J, Holland T, et al. Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles. Hum Reprod. 2016; 31(6): 1253-1264.
  10. D'Angelo A, Davies R, Salah E, Nix BA, Amso NN. Value of the serum estradiol level for preventing ovarian hyperstimulation syndrome: a retrospective case control study. Fertil Steril. 2004; 81(2): 332-336.
  11. Corbett S, Shmorgun D, Claman P; Reproductive Endocrinology Infertility Committee; Special Contributor. The prevention of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can. 2014; 36(11): 1024-1033.
  12. Namavar Jahromi B, Parsanezhad ME, Shomali Z, Bakhshai P, Alborzi M, Moin Vaziri N, et al. Ovarian hyperstimulation syndrome: a narrative review of its pathophysiology, risk factors, prevention, classification, and management. Iran J Med Sci. 2018; 43(3): 248- 260.
  13. Huang H, Takai Y, Samejima K, Narita T, Ichinose S, Itaya Y, et al. Late-onset ovarian hyperstimulation syndrome developing during ovarian stimulation in an ectopic pregnancy: a case report. J Med Case Rep. 2020; 14(1): 110.
  14. Bosch E, Ezcurra D. Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patients. Reprod Biol Endocrinol. 2011; 9: 82.
  15. Lainas GT, Kolibianakis EM, Sfontouris IA, Zorzovilis IZ, Petsas GK, Tarlatzi TB, et al. Outpatient management of severe early OHSS by administration of GnRH antagonist in the luteal phase: an observational cohort study. Reprod Biol Endocrinol. 2012; 10: 69.
  16. Wang Yq, Yang J, Xu Wm, Xie Qz, Yan Wj, Yin Tl, et al. Luteal letrozole administration decreases serum estrogen level but not the risk of ovarian hyperstimulation syndrome. Beijing Da Xue Xue Bao Yi Xue Ban. 2013; 45(6): 869-872.
  17. Chen Y, Yang T, Hao C, Zhao J. A retrospective study of letrozole treatment prior to human chorionic gonadotropin in women with polycystic ovary syndrome undergoing in vitro fertilization at risk of ovarian hyperstimulation syndrome. Med Sci Monit. 2018; 24: 4248-4253.
  18. Hawthorne G, Sansoni J, Hayes L, Marosszeky N, Sansoni E. Measuring patient satisfaction with health care treatment using the short assessment of patient satisfaction measure delivered superior and robust satisfaction estimates. J Clin Epidemiol. 2014; 67(5): 527-537.
  19. Garcia-Velasco JA, Quea G, Piró M, Mayoral M, Ruiz M, Toribio M, et al. Letrozole administration during the luteal phase after ovarian stimulation impacts corpus luteum function: a randomized, placebo-controlled trial. Fertil Steril. 2009; 92(1): 222-225.
  20. Garcia-Velasco JA, Moreno L, Pacheco A, Guillén A, Duque L, Requena 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.
  21. Pereira N, Hancock K, Cordeiro CN, Lekovich JP, Schattman GL, Rosenwaks Z. 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.
  22. Goldrat O, Gervy C, Englert Y, Delbaere A, Demeestere I. Progesterone levels in letrozole associated controlled ovarian stimulation for fertility preservation in breast cancer patients. Hum Reprod. 2015; 30(9): 2184-2189.
  23. Danastas K, Whittington CM, Dowland SN, Combes V, Murphy CR, Lindsay LA. Ovarian hyperstimulation reduces vascular endothelial growth factor-A during uterine receptivity. Reprod Sci. 2019; 26(2): 259-268.
  24. He Q, Liang L, Zhang C, Li H, Ge Z, Wang L, 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): 355-360.
  25. Azmoodeh A, Pejman Manesh M, Akbari Asbagh F, Ghaseminejad A, Hamzehgardeshi Z. Effects of letrozole-HMG and clomiphene- HMG on incidence of luteinized unruptured follicle syndrome in infertile women undergoing induction ovulation and intrauterine insemination: a randomised trial. Glob J Health Sci. 2015; 8(4): 244-252.
  26. D'Amato G, Caringella AM, Stanziano A, Cantatore C, Palini S, Caroppo E. Mild ovarian stimulation with letrozole plus fixed dose human menopausal gonadotropin prior to IVF/ICSI for infertile non-obese women with polycystic ovarian syndrome being pre-treated with metformin: a pilot study. Reprod Biol Endocrinol. 2018; 16(1): 89.
  27. Behnoud N, Farzaneh F, Ershadi S. The effect of clomiphene citrate versus letrozole on pregnancy rate in women with polycystic ovary syndrome: a randomized clinical trial. Crescent J Medical Biol Sci. 2019; 6(3): 335-340.
  28. Wang YQ, Luo J, Xu WM, Xie QZ, Yan WJ, Wu GX, et al. Can steroidal ovarian suppression during the luteal phase after oocyte retrieval reduce the risk of severe OHSS? J Ovarian Res. 2015; 8: 63.
  29. Mai Q, Hu X, Yang G, Luo Y, Huang K, Yuan Y, 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.
  30. Lainas GT, Kolibianakis EM, Sfontouris IA, Zorzovilis IZ, Petsas GK, Lainas TG, et al. Pregnancy and neonatal outcomes following luteal GnRH antagonist administration in patients with severe early OHSS. Hum Reprod. 2013; 28(7): 1929-1942.