Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Empty Follicle Syndrome Following GnRHa Trigger in PCOS Patients Undergoing IVF Cycles

Authors
Department of Reproductive Medicine, Milann, The Fertility Center, A Unit of BACC Health care pvt Ltd, Karnataka, India
Abstract
Background: The objective of this study was to analyze the incidence and the underlying mechanisms of empty follicle syndrome (EFS) occurring in gonadotropin releasing hormone agonist (GnRHa) triggered in in vitro fertilization (IVF) cycles with GnRH antagonist protocol in women with polycystic ovary syndrome (PCOS) of Indian origin. The study also intended to evaluate the cycle outcome following a rescue trigger. Methods: Retrospective cohort analysis of data was extracted from the hospital database of 271 PCOS patients who underwent IVF in antagonist protocol triggered with GnRHa from August 2014 to December 2016. All cases with failure to obtain oocytes following retrieval were analyzed. Continuous variables were expressed as mean±SD using t-test and Chi-squared test for categorical variables. A p<0.05 was considered statistically significant. Results: Incidence of EFS following GnRHa trigger was found to be 3.3%. False empty follicle syndrome (FEFS) accounted for majority of the cases (8/9=88.8%). Of the nine EFS, six cases were salvaged with a rescue trigger, resulted in transfer of reasonably good quality embryos in a frozen-thawed embryo replacement cycle achieving clinical pregnancy in three cases (3/6=50%). Conclusion: Our experience with EFS cases following GnRHa, albeit small, given the rarity of its occurrence, suggests that majority of EFS are of false forms and can be effectively salvaged which results in reasonably favorable outcome.
Keywords

  1. Driscoll GL, Tyler JP, Knight DC, Cooke S, Kime L, Clark L, et al. Failure to collect oocytes in assisted reproductive technology: a retrospective. Hum Reprod. 1998;13(1):84-7.
  2. Mesen TB, Yu B, Richter KS, Widra E, DeCherney AH, Segars JH. The prevalence of genuine empty follicle syndrome. Fertil Steril. 2011;96(6):1375-7.
  3. Baum M, Machtinger R, Yerushalmi GM, Maman E, Seidman DS, Dor J, et al. Recurrence of empty follicle syndrome with stimulated IVF cycles. Gynecol Endocrinol. 2012;28(4):293-5.
  4. Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil Steril. 2010;94(2):389-400.
  5. Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J, et al. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab. 2002;87(2):709-15.
  6. Humaidan P, Kol S, Papanikolaou EG; Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011;17(4):510-24.
  7. Yen SS, Llerena O, Little B, Pearson OH. Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man. J Clin Endocrinol Metab. 1968;28(12):1763-7.
  8. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19-25.
  9. ALPHA Scientists In Reproductive Medicine; ESHRE Special Interest Group Embryology. Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Reprod Biomed Online. 2011;22(6):632-46.
  10. Coulam CB, Bustillo M, Schulman JD. Empty follicle syndrome. Fertil Steril. 1986;46:1153-5.
  11. Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril. 2008;89(1):84-91.
  12. Türkgeldi E, Türkgeldi L, Seyhan A, Ata B. Gonadotropin-releasing hormone agonist triggering of oocyte maturation in assisted reproductive technology cycles. Turk J Obstet Gynecol. 2015;12(2):96-101.
  13. Quintans CJ, Donaldson MJ, Blanco LA, Pasqualini RS. Empty follicle syndrome due to human errors: Its occurrence in an in vitro fertilization programme. Hum Reprod. 1998;13(10):2703-5.
  14. Awonuga A, Govindbhai J, Zierke S, Schnauffer K. Continuing the debate on empty follicle syndrome: can it be associated with normal bioavailability of beta human chorionic gonadotrophin on the day of oocyte recovery? Hum Reprod. 1998;13(5):1281-4.
  15. Ben-Shlomo I, Schiff E, Levran D, Ben Rafael Z, Mashiach S, Dor J. Failure of oocyte retrieval during in vitro fertilization: a sporadic event rather than a syndrome. Fertil Steril. 1991;55(2):324-7.
  16. Castillo JC, Garcia-Velasco J, Humaidan P. Empty follicle syndrome after GnRHa triggering versus hCG triggering in COS. J Assist Reprod Genet. 2012;29(3):249-53.
  17. Stevenson TL, Lashen H. Empty follicle syndrome: The reality of a controversial syndrome, a systematic review. Fertil Steril. 2008;90(3):691-8.
  18. Orvieto R, Rabinson J, Meltzer S, Zohav E, Anteby E, Homburg R. Substituting HCG with GnRH agonist to trigger final follicular maturation--a retrospective comparison of three different ovarian stimulation protocols. Reprod Biomed Online. 2006;13(2):198-201.
  19. Zegers-Hochschild F, Fernández E, Mackenna A, Fabres C, Altieri E, Lopez T. The empty follicle syndrome: a pharmaceutical industry syndrome. Hum Reprod. 1995;10(9):2262-5.
  20. Aktas M, Beckers NG, van Inzen WG, Verhoeff A, de Jong D. Oocytes in the empty follicle: A controversial syndrome. Fertil Steril. 2005;84(6):1643-8.
  21. Kummer NE, Feinn RS, Griffin DW, Nulsen JC, Benadiva CA, Engmann LL. Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger. Hum Reprod. 2013;28(1):152-9.
  22. Peluso JJ. Role of the amplitude of the gonadotropin surge in the rat. Fertil Steril. 1990;53(1):150-4.
  23. Itskovitz-Eldor J, Kol S, Mannaerts B. Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication. Hum Reprod. 2000;15(9):1965-8.
  24. Shapiro BS, Daneshmand ST, Restrepo H, Garner FC, Aguirre M, Hudson C. Efficacy of induced luteinizing hormone surge after "trigger" with gonadotropin-releasing hormone agonist. Fertil Steril. 2011;95(2):826-8.
  25. Shapiro BS, Andersen CY. Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related. Fertil Steril. 2015;103(4):874-8.
  26. Inan MS, Al-Hassan S, Ozand P, Coskun S. Transcriptional profiling of granulosa cells from a patient with recurrent empty follicle syndrome. Reprod Biomed Online. 2006;13(4):481-91.
  27. Yuan P, He Z, Zheng L, Wang W, Li Y, Zhao H, et al. Genetic evidence of ‘genuine’ empty follicle syndrome: a novel effective mutation in the LHCGR gene and review of the literature. Hum Reprod. 2017;32(4):944-53.
  28. Madani T, Jahangiri N. Empty follicle syndrome: the possible cause of occurrence. Oman Med J. 2015;30(6):417-20.
  29. Reichman DE, Hornstein MD, Jackson KV, Racowsky C. Empty follicle syndrome--does repeat administration of hCG really work? Fertil Steril. 2010;94(1):375-7.
  30. Wang JG, Lobo RA. The complex relationship between hypothalamic amenorrhea and polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93(4):1394-7.
  31. Dunaif A, Givens JR, Haseltine FP. Polycystic Ovarian Syndrome. Boston: Blackwell Scientific Publications; 1992. 377 p.
  32. Meyer L, Murphy LA, Gumer A, Reichman DE, Rosenwaks Z, Cholst IN. Risk factors for a suboptimal response to gonadotropin-releasing hormone agonist trigger during in vitro fertilization cycles. Fertil Steril. 2015;104(3):637-42.
  33. Chang FE, Beall SA, Cox JM, Richter KS, DeCherney AH, Levy MJ. Assessing the adequacy of gonadotropin-releasing hormone agonist leuprolide to trigger oocyte maturation and management of inadequate response. Fertil Steril. 2016;106(5):1093-100.
  34. Chevrier L, Guimiot F, de Roux N. GnRH receptor mutations in isolated gonadotropic deficiency. Mol Cell Endocrinol. 2011;346(1-2):21-8.
  35. Beranova M, Oliveira LM, Bédécarrats GY, Schipani E, Vallejo M, Ammini AC, et al. Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2001;86(4):1580-8.
  36. Alviggi C, Clarizia R, Pettersson K, Mollo A, Humaidan P, Strina I, et al. Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism. Reprod Biomed Online. 2011;22 Suppl 1:S67-72.
  37. Park JY, Su YQ, Ariga M, Law E, Jin SL, Conti M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science. 2004;303(5658):682-4.
  38. Ashkenazi H, Cao X, Motola S, Popliker M, Conti M, Tsafriri A. Epidermal growth factor family members: endogenous mediators of the ovulatory response. Endocrinology. 2005;146(1):77-84.
  39. Ndukwe G, Thornton S, Fishel S, Dowell K, Aloum M, Green S. 'Curing' empty follicle syndrome. Hum Reprod. 1997;12(1):21-3.
  40. Reichman DE, Greenwood E, Meyer L, Kligman I, Rosenwaks Z. Can in vitro fertilization cycles be salvaged by repeat administration of intramuscular human chorionic gonadotropin the day after failed injection? Fertil Steril. 2012;98(3):671-4.
  41. Blazquez A, Guillén JJ, Colomé C, Coll O, Vassena R, Vernaeve V. Empty follicle syndrome prevalence and management in oocyte donors. Hum Reprod. 2014;29(10):2221-7.
  42. Kim JH, Jee BC. Empty follicle syndrome. Clin Exp Reprod Med. 2012;39(4):132-7.
  43. Lorusso F, Depalo R, Tsadilas S, Caradonna F, Di Gilio A, Capotorto MT, et al. Is the occurrence of the empty follicle syndrome a predictor that a subsequent stimulated cycle will be an unfavourable one? Reprod Biomed Online. 2005;10(5):571-4.
  44. Coskun S, Madan S, Bukhari I, Al-Hassan S, Al-Rejjal R, Awartani K. Poor prognosis in cycles following "genuine" empty follicle syndrome. Eur J Obstet Gynecol Reprod Biol. 2010;150(2):157-9.