Skip to main content

Advertisement

SpringerLink
Log in

Mild/minimal stimulation protocol for ovarian stimulation of patients at high risk of developing ovarian hyperstimulation syndrome

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background

Recently, an increased scientific interest was focused on mild approaches for ovarian stimulation in clinical practice. Milder stimulation aims to develop safer and more patient-friendly protocols which are more physiological, less drug use, less expensive and the risks of treatment are highly minimized.

Aim

To investigate the efficacy and safety of a mild ovarian stimulation protocol in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS), compared to conventional long down-regulation protocol.

Subjects and methods

This a prospective, open, randomized study, included 349 infertile patients considered at high risk of developing OHSS, undergoing in vitro fertilization treatment in two private assisted reproduction centers. The patients were randomized into two groups: group A (n = 148) had a mild/minimal stimulation protocol of recombinant FSH (rFSH) combined with GnRH antagonist. Group B (n = 201) (control group) had a standard long protocol of rFSH combined with GnRH agonist.

Results

There was no significant difference observed between the two groups regarding the mean number of oocytes retrieved per patient, mature metaphase II oocytes, fertilization rate, and embryo cleavage rate. Significantly higher implantation rate (21.5 vs 14.5 %) (p < 0.05), pregnancy rate (37.7 vs 23.4 %) (p < 0.05), and delivery rate (32.8 vs 20.1 %) (p < 0.05) were observed in favor of groups A compared to group B. Lower proportion of patients (4.7 %), though not statistically significant, has developed OHSS in group A compared to group B (8.4 %).

Conclusion

Our study shows that mild stimulation regimen is highly effective for ovarian stimulation of patients who have experienced OHSS complication without increasing the risk of OHSS.

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

Abbreviations

OHSS:

Ovarian hyperstimulation syndrome

rFSH:

Recombinant follicle-stimulating hormone

IVF:

In vitro fertilization

PCOS:

Polycystic ovarian syndrome

References

  1. Templeton A, Morris JK (1998) Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 339:573–577

    Article  CAS  PubMed  Google Scholar 

  2. Macklon NS, Stouffer RL, Giudice LC, Fauser BC (2006) The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev 27:170–207

    Article  PubMed  Google Scholar 

  3. Fauser BC, Devroey P (2005) Why is the clinical acceptance of gonadotropin-releasing hormone antagonist cotreatment during ovarian hyperstimulation for in vitro fertilization so slow? Fertil Steril 83:1607–1611

    Article  PubMed  Google Scholar 

  4. Wang YA, Sullivan EA, Black D, Dean J, Bryant J, Chapman M (2005) Preterm birth and low birth weight after assisted reproductive technology-related pregnancy in Australia between 1996 and 2000. Fertil Steril 83:1650–1658

    Article  PubMed  Google Scholar 

  5. Navot D, Bergh PA, Laufer N (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 58:249–261

    CAS  PubMed  Google Scholar 

  6. Golan A, Ron-El R, Soffer Y, Weinraub Z, Caspi E (1989) Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 44:430–440

    Article  CAS  PubMed  Google Scholar 

  7. Smitz J, Camus M, Devroey P, Erard P, Wisanto A, Van Steirteghem AC (1990) Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in vitro fertilization. Hum Reprod 5:993–997

    Google Scholar 

  8. Schenker JG, Weinstein D (1978) Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 30:255–268

    CAS  PubMed  Google Scholar 

  9. Aboulghar MA, Mansour RT, Serour GI et al (1992) Follicular aspiration does not protect against the development of ovarian hyperstimulation syndrome. J Assist Reprod Genet 9:238–243

    Article  CAS  PubMed  Google Scholar 

  10. Delvigne A, Dubois M, Battheu B et al (1993) The ovarian hyperstimulation syndrome in in vitro fertilization: a Belgian multicentric study. II. Multiple discriminant analysis for risk prediction. Hum Reprod 8:1361–1366

    CAS  PubMed  Google Scholar 

  11. Ragni G, Vegetti W, Riccaboni A, Engl B, Brigante C, Crosignani PG (2005) Comparison of GnRH agonists and antagonists in assisted reproduction cycles of patients at high risk of ovarian hyperstimulation syndrome. Hum Reprod 20:2421–2425

    Article  CAS  PubMed  Google Scholar 

  12. Ferraretti AP, Gianaroli L, Magli C, Fortini D, Selman HA, Feliciani E (1999) Elective cryopreservation of all pronucleate embryos in women at risk of ovarian hyperstimulation syndrome: efficiency and safety. Hum Reprod 14:1457–1460

    Article  CAS  PubMed  Google Scholar 

  13. Gianaroli L, Ferraretti AP, Fiorentino A (1996) The ovarian hyperstimulation syndrome. Reprod Med Rev 5:169–184

    Article  Google Scholar 

  14. Gonen Y, Balakier H, Powel W, Casper RF (1990) Use of gonadotrophin releasing hormone agonist to trigger follicular maturation for in vitro fertilization. J Clin Endocrinol Metab 71:918–922

    Article  CAS  PubMed  Google Scholar 

  15. Tomazevic T, Meden-Vrtovec H (1996) Early timed follicular aspiration prevents severe ovarian hyperstimulation syndrome. J Assist Reprod Genet 13:282–286

    Article  CAS  PubMed  Google Scholar 

  16. Koenig E, Bussen S, Suetterlin M, Stteck T (1998) Prophylactic intravenous hydroxylethyl starch solution prevents moderate-severe ovarian hyperstimulation in in vitro fertilization patients: a prospective randomized, doubleblind and placebo-controlled study. Hum Reprod 13:2421–2424

    Article  Google Scholar 

  17. Edwards RG, Lobo R, Bouchard P (1996) Time to revolutionize ovarian stimulation. Hum Reprod 11:917–919

    Article  CAS  PubMed  Google Scholar 

  18. Edwards B (2007) IVF, IVM, natural cycle IVF, minimal stimulation IVF—time for a rethink. RBM online 15:106–119

    CAS  PubMed  Google Scholar 

  19. Nargund G, Fauser BCJM, Macklon NS, Ombelet W, Nygren K, Frydman R (2007) For the Rotterdam ISMAAR consensus group on terminology for ovarian stimulation for IVF: the ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod 22:2801–2804

    Article  CAS  PubMed  Google Scholar 

  20. Tozer AJ, Iles RK, Iammarrone E, Gillott CM, Al-Shawaf T, Grudzinskas JG (2004) The effects of ‘coasting’ on follicular fluid concentrations of vascular endothelial growth factor in women at risk of developing ovarian hyperstimulation syndrome. Hum Reprod 19:522–528

    Article  CAS  PubMed  Google Scholar 

  21. Chen C-D, Chao KH, Yang J-H (2003) Comparison of coasting and intravenous albumin in the prevention of ovarian hyperstimulation syndrome. Fertil Steril 80:86–90

    Article  PubMed  Google Scholar 

  22. Youssef MA, Van der Veen F, Al-Inany HG, Griesinger G, Mochtar MH, van Wely M (2011) Gonadotropin-releasing hormone agonist versus hCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev 1:CD008046

    PubMed  Google Scholar 

  23. Kol S, Itskovitz-Eldor J (2010) Gonadotropin-releasing hormone agonist trigger: the way to eliminate ovarian hyperstimulation syndrome—a 20-year experience. Semin Reprod Med 28:500–505

    Article  CAS  PubMed  Google Scholar 

  24. Kol S, Humaidan P (2013) GnRH agonist triggering: recent developments. Reprod Biomed Online 26:226–230

    Article  CAS  PubMed  Google Scholar 

  25. Youssef MA, van Wely M, Hassan MA et al (2010) Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? a systematic review and meta-analysis. Hum Reprod Update 16:459–466

    Article  CAS  PubMed  Google Scholar 

  26. Whelan JG, Vlahos NF (2000) The ovarian hyperstimulation syndrome. Fertil Steril 73(883–89):6

    Google Scholar 

  27. Ulug U, Bahceci M, Erden HF, Shalev E, Ben-Shlomo I (2002) The significance of coasting duration during ovarian stimulation for conception in assisted fertilization cycles. Hum Reprod 17:310–313

    Article  PubMed  Google Scholar 

  28. Blondin P, Guilbault LA, Sirard MA (1997) The time interval between FSH-P administration and slaughter can influence the developmental competence of beef heifer oocytes. Theriogenology 48:803–813

    Article  CAS  PubMed  Google Scholar 

  29. Krasnow JS, Berga SL, Guzick DS, Zeleznik AJ, Yeo KT (1996) Vascular permeability factor and vascular endothelial growth factor in ovarian hyperstimulation: a preliminary report. Fert Steril 65:552–555

    CAS  Google Scholar 

  30. Fluker MR, Copeland JE, Yuzpe AA (2000) An ounce of prevention: outpatient management of the ovarian hyperstimulation syndrome. Fertil Steril 73:821–824

    Article  CAS  PubMed  Google Scholar 

  31. Carizza C, Abdelmassih V, Abdelmassih S et al (2008) Cabergoline reduces the early onset of ovarian hyperstimulation syndrome: a prospective randomized study. Reprod Biomed Online 17:751–755

    Article  CAS  PubMed  Google Scholar 

  32. Tehraninejad ES, Hafezi M, Arabipoor A, Aziminekoo E, Chehrazi M, Bahmanabadi A (2010) Comparison of cabergoline and intravenous albumin in the prevention of ovarian hyperstimulation syndrome: a randomized clinical trial. J Assist Reprod Genet 29:259–264

    Article  Google Scholar 

  33. Gómez R, Soares SR, Busso C, Garcia-Velasco JA, Simón C, Pellicer A (2010) Physiology andpathology of ovarian hyperstimulation syndrome. Semin Reprod Med 28:448–457

    Article  PubMed  Google Scholar 

  34. Aboulghar M, Evers JH, Al-Inany H (2002) Intravenous albumin for preventing severe ovarian hyperstimulation syndrome: a Cochrane review. Hum Reprod 17:3027–3032

    Article  CAS  PubMed  Google Scholar 

  35. Jee BC, Suh CS, Kim YB, Kim SH, Choi YM, Kim JG, Moon SY (2010) Administration of intravenous albumin around the time of oocyte retrieval reduces pregnancy rate without preventing ovarian hyperstimulation syndrome: a systematic review and meta-analysis. Gynecol Obstet Invest 70:47–54

    Article  CAS  PubMed  Google Scholar 

  36. Youssef MA, Al-Inany HG, Evers JL, Aboulghar M (2011) Intravenous fluids for the prevention of severe ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2:CD001302

    PubMed  Google Scholar 

  37. Devroey P, Bourgain C, Macklon NS, Fauser BC (2004) Reproductive biology and IVF: ovarian stimulation and endometrial receptivity. Trends Endocrinol Metab 15:84–90

    Article  CAS  PubMed  Google Scholar 

  38. Beckers NG, Platteau P, Eijkemans MJ et al (2006) The early luteal phase administration of oestrogen and progesterone does not induce premature luteolysis in normo-ovulatory women. Eur J Endocrinol 155:355–363

    Article  CAS  PubMed  Google Scholar 

  39. Baart EB, Martini E, Eijkemans MJ et al (2007) Milder ovarian stimulation for in vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod 22:980–988

    Article  PubMed  Google Scholar 

  40. Westergaard LG, Erb K, Laursen S, Rasmussen PE, Rex S (1996) The effect of human menopausal gonadotropin and highly purified, urine-derived follicle stimulating hormone on the outcome of in vitro fertilisation in down regulated normogonadotropic women. Hum Reprod 11:1209–1213

    Article  CAS  PubMed  Google Scholar 

  41. Westergaard LG, Laurse SB, Anderson CY (2000) Increased risk of early pregnancy loss by profound suppression on luteinizing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction. Hum Reprod 15:1003–1008

    Article  CAS  PubMed  Google Scholar 

  42. Fleming R, Lloyd F, Herbert M, Fenwick J, Griffiths T, Murdoch A (1998) Effects of profound suppression of luteinizing hormone during ovarian stimulation on follicular activity, oocyte and embryo function in cycles stimulated with purified follicle stimulating hormone. Hum Reprod 13:1788–1792

    Article  CAS  PubMed  Google Scholar 

  43. Janssens RMJ, Lambalk CB, Vermiden JPW et al (2000) Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomised, double-blind placebo-controlled study. Hum Reprod 15:2333–2340

    Article  CAS  PubMed  Google Scholar 

  44. Cedrin-Durnerin I (2004) Antagonist protocols: residual LH levels and the value of exogenous LH supplementation. J Gynecol Obstet Biol Reprod (Paris) 33:3S29–3S31

    CAS  Google Scholar 

  45. Urman B, Fluker MR, Yuen BH, Fleige-Zahradka BG, Zouves CG, Moon YS (1992) The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins. Fertil Steril 57:1269–1273

    CAS  PubMed  Google Scholar 

  46. Homburg R, Berkowitz D, Levy T, Feldberg D, Ashkenazi J, Ben-Rafael Z (1993) In vitro fertilization and embryo transfer for the treatment of infertility associated with polycystic ovary syndrome. Fertil Steril 60:858–863

    CAS  PubMed  Google Scholar 

  47. Doldi N, Marsiglio E, Destefani A, Gessi A, Merati G, Ferrari A (1999) Elevated serum progesterone on the day of hCG administration in IVF is associated with a higher pregnancy rate in polycystic ovary syndrome. Hum Reprod 14:601–605

    Article  CAS  PubMed  Google Scholar 

  48. Kodama H, Fukuda J, Karube H, Matsui T, Shimizu Y, Tanaka T (1995) High incidence of embryo transfer cancellations in patients with polycystic ovarian syndrome. Hum Reprod 10:1962–1967

    CAS  PubMed  Google Scholar 

  49. Marci R, Senn A, Dessole S, Chanson A, Loumaye E, Grandi P, Germond M (2001) A low-dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins. Fertil Steril 75:1131–1135

    Article  CAS  PubMed  Google Scholar 

  50. Sundstrom P, Nilsson BO (1988) Meiotic and cytoplasmic maturation of oocytes collected in stimulated cycles is asynchronous. Hum Reprod 3:613–619

    CAS  PubMed  Google Scholar 

  51. Moor RM, Osborn JC, Crosby IM (1985) Gonadotrophin-induced abnormalities in sheep oocytes after superovulation. J Reprod Fertil 74:167–172

    Article  CAS  PubMed  Google Scholar 

  52. Tesarik J, Mendoza C (1995) Nongenomic effects of 17b-estradiol on maturing human oocytes: relationship to oocyte developmental potential. J Clin. Endocrino Metab 80:1438–1443

    CAS  Google Scholar 

  53. Tesarik J, Mendoza C (1997) Direct non-genomic effects of follicular steroids on maturing human oocytes: oestrogen versus androgen antagonism. Hum Reprod Update 3:95–100

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors L. Rinaldi, F. Lisi, and H. Selman declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. RISEL-One Day Medical Center, Via Attilio Ambrosini 114, 00147, Rome, Italy

    L. Rinaldi & H. Selman

  2. CERMER Clinica Villa Mafalda, Rome, Italy

    F. Lisi

Authors
  1. L. Rinaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Lisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Selman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. Rinaldi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rinaldi, L., Lisi, F. & Selman, H. Mild/minimal stimulation protocol for ovarian stimulation of patients at high risk of developing ovarian hyperstimulation syndrome. J Endocrinol Invest 37, 65–70 (2014). https://doi.org/10.1007/s40618-013-0021-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-013-0021-1

Keywords

Search

Navigation