Skip to main content

Advertisement

SpringerLink
Log in

Why more is less and less is more when it comes to ovarian stimulation

  • Commentary
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The purpose of the present study is to describe the possible mechanisms which may explain the apparent paradox of “less is more.” Mild ovarian stimulation for in vitro fertilization (IVF) minimizes ovarian hyperstimulation syndrome (OHSS) and multiple gestations without compromising the pregnancy rate (PR).

Methods

The pertinent English literature (PubMed) addressing mild stimulation for IVF/assisted reproductive technology (ART) and publications addressing “mild” or “soft” controlled ovarian stimulation (COS) vs conventional COS for IVF, OHSS, natural cycle IVF, and IVF outcome in association with COS was searched.

Results

Four possible mechanisms can be put forward to explain the apparent paradox of “less is more.” (1) In the natural or mild stimulation cycles, the healthiest follicles are selected by the principle of “quality for quantity”; (2) high estradiol (E2) in the late follicular phase significantly correlated with higher rates of small for gestational age (SGA) and low-birth-weight (LBW) neonates; (3) anti-Mullerian hormone (AMH), LH, testosterone, and E2 are significantly higher in natural cycle (NC)-IVF than in stimulated IVF follicles, suggesting an alteration of the follicular metabolism in stimulated cycles; and (4) supraphysiological E2 may increase the growth hormone-binding protein (GH-BP) bio-neutralizing GH and diminishing the resultant insulin-like growth factor (IGF) levels, necessary for optimal synergism with follicle-stimulating hormone (FSH).

Conclusions

It is suggested to aim at the retrieval of around eight to ten eggs. Mild stimulation should be the common practice for IVF. In cases where more than ten ova are retrieved or high E2 levels are reached, either intentionally or unintentionally, “freeze-all policy” should be considered and embryo transfer (ET) done in a subsequent natural cycle.

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

    Article  PubMed  Google Scholar 

  2. Verberg MF, Eijkemans MJ, Macklon NS, Heijnen EM, Baart EB, Hohmann FP, et al. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Hum Reprod Update. 2009;15:5–12.

    Article  CAS  PubMed  Google Scholar 

  3. Verberg MF, Macklon NS, Nargund G, Frydman R, Devroey P, Broekmans FJ, et al. Mild ovarian stimulation for IVF. Hum Reprod Update. 2009;15:13–29.

    Article  CAS  PubMed  Google Scholar 

  4. Gougeon A. Human ovarian follicular development: from activation of resting follicles to preovulatory maturation. Ann Endocrinol (Paris). 2010;71:132–43.

    Article  CAS  Google Scholar 

  5. Knight PG, Glister C. TGF-beta superfamily members and ovarian follicle development. Reproduction. 2006;132:191–206.

    Article  CAS  PubMed  Google Scholar 

  6. Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22:980–8.

    Article  PubMed  Google Scholar 

  7. Baart EB, Macklon NS, Fauser BJ. Ovarian stimulation and embryo quality. Reprod Biomed Online. 2009;18 Suppl 2:45–50. Review.

    Article  PubMed  Google Scholar 

  8. Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotrophin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab. 2003;88:166–73.

    Article  CAS  PubMed  Google Scholar 

  9. Fauser BC, Nargund G, Andersen AN, Norman R, Tarlatzis B, Boivin J, et al. Mild ovarian stimulation for IVF: 10 years later. Hum Reprod. 2010;25:2678–84.

    Article  PubMed  Google Scholar 

  10. Heijnen EM, Eijkemans MJ, De Klerk C, Polinder S, Beckers NG, Klinkert ER, et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet. 2007;369(9563):743–9.

    Article  PubMed  Google Scholar 

  11. Pennings G, Ombelet W. Coming soon to your clinic: patient-friendly ART. Hum Reprod. 2007;22:2075–9.

    Article  PubMed  Google Scholar 

  12. Aanesen A, Nygren KG, Nylund L. Modified natural cycle IVF and mild IVF: a 10 year Swedish experience. Reprod Biomed Online. 2010;20:156–62.

    Article  PubMed  Google Scholar 

  13. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400,135 treatment cycles. Hum Reprod. 2011;26:1768–74.

    Article  PubMed  Google Scholar 

  14. Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL, et al. Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reprod Biomed Online. 2012;24:614–20.

    Article  CAS  PubMed  Google Scholar 

  15. Simón C, Cano F, Valbuena D, Remohí J, Pellicer A. Clinical evidence for a detrimental effect on uterine receptivity of high serum oestradiol concentrations in high and normal responder patients. Hum Reprod. 1995;10:2432–7.

    Article  PubMed  Google Scholar 

  16. Valbuena D, Martin J, de Pablo JL, Remohí J, Pellicer A, Simón C. Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Fertil Steril. 2001;76:962–8.

    Article  CAS  PubMed  Google Scholar 

  17. Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Jenkins J, et al. Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum Reprod. 2010;25:2092–100.

    Article  CAS  PubMed  Google Scholar 

  18. Labarta E, Martínez-Conejero JA, Alamá P, Horcajadas JA, Pellicer A, Simón C, et al. Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011;26:1813–25.

    Article  CAS  PubMed  Google Scholar 

  19. Van Vaerenbergh I, Fatemi HM, Blockeel C, Van Lommel L, In’t Veld P, Schuit F, et al. Progesterone rise on HCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression. Reprod Biomed Online. 2011;22:263–71.

    Article  PubMed  Google Scholar 

  20. Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Hum Reprod Update. 2013;19:433–57.

    Article  CAS  PubMed  Google Scholar 

  21. Fatemi HM, Popovic-Todorovic B. Implantation in assisted reproduction: a look at endometrial receptivity. Reprod Biomed Online. 2013;27:530–8.

    Article  CAS  PubMed  Google Scholar 

  22. Labarta E, Bosch E, Alamá P, Rubio C, Rodrigo L, Pellicer A. Moderate ovarian stimulation does not increase the incidence of human embryo chromosomal abnormalities in in vitro fertilization cycles. J Clin Endocrinol Metab. 2012;97:E1987–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Morin S, Melzer-Ross K, McCulloh D, Grifo J, Munné S. A greater number of euploid blastocysts in a given cohort predicts excellent outcomes in single embryo transfer cycles. J Assist Reprod Genet. 2014;31:667–73.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Youssef MA, Van der Veen F, Al-Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev. 2014;10:CD008046.

    PubMed  Google Scholar 

  25. Arce JC, Andersen AN, Fernández-Sánchez M, Visnova H, Bosch E, García-Velasco JA, et al. Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone-stratified, dose–response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril. 2014;102:1633–40.

    Article  CAS  PubMed  Google Scholar 

  26. Evans J, Hannan NJ, Edgell TA, Vollenhoven BJ, Lutjen PJ, Osianlis T, et al. Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence. Hum Reprod Update. 2014;20:808–21.

    Article  PubMed  Google Scholar 

  27. Barker DJ, Lampl M, Roseboom T, Winder N. Resource allocation in utero and health in later life. Placenta. 2012;33 Suppl 2:e30–4.

    Article  PubMed  Google Scholar 

  28. Dong MY, Wang FF, Pan JX. Adverse intrauterine environment and gamete/embryo-fetal origins of diseases. In: Huang HF, Sheng JZ, editors. Gamete and embryo-fetal origins of adult diseases. New York: Springer; 2013. p. 61–78.

    Google Scholar 

  29. Bonagura TW, Pepe GJ, Enders AC, Albrecht ED. Suppression of extravillous trophoblast vascular endothelial growth factor expression and uterine spiral artery invasion by estrogen during early baboon pregnancy. Endocrinology. 2008;149:5078–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Hu XL, Feng C, Lin XH, Zhong ZX, Zhu YM, Lv PP, et al. High maternal serum estradiol environment in the first trimester is associated with the increased risk of small-for-gestational-age birth. J Clin Endocrinol Metab. 2014;99:2217–24.

    Article  CAS  PubMed  Google Scholar 

  31. Albrecht ED, Bonagura TW, Burleigh DW, Enders AC, Aberdeen GW, Pepe GJ. Suppression of extravillous trophoblast invasion of uterine spiral arteries by estrogen during early baboon pregnancy. Placenta. 2006;27:483–90.

    Article  CAS  PubMed  Google Scholar 

  32. Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell. 2000;103:843–52.

    Article  CAS  PubMed  Google Scholar 

  33. Smits LJ, Elzenga HM, Gemke RJ, Hornstra G, van Eijsden M. The association between interpregnancy interval and birth weight: what is the role of maternal polyunsaturated fatty acid status? BMC Pregnancy Childbirth. 2013;13:23.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Xu GF, Zhang JY, Pan HT, Tian S, Liu ME, Yu TT, et al. Cardiovascular dysfunction in offspring of ovarian-hyperstimulated women and effects of estradiol and progesterone: a retrospective cohort study and proteomics analysis. J Clin Endocrinol Metab. 2014;99:E2494–503.

    Article  CAS  PubMed  Google Scholar 

  35. Pinborg A, Henningsen AA, Loft A, Malchau SS, Forman J, Andersen AN. Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique? Hum Reprod. 2014;29:618–27.

    Article  CAS  PubMed  Google Scholar 

  36. Imudia AN, Awonuga AO, Doyle JO, Kaimal AJ, Wright DL, Toth TL, et al. Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Fertil Steril. 2012;97:1374–9.

    Article  CAS  PubMed  Google Scholar 

  37. Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ. 2004;328:261–5.

    Article  PubMed Central  PubMed  Google Scholar 

  38. von Wolff M, Kollmann Z, Flück CE, Stute P, Marti U, Weiss B, et al. Gonadotrophin stimulation for in vitro fertilization significantly alters the hormone milieu in follicular fluid: a comparative study between natural cycle IVF and conventional IVF. Hum Reprod. 2014;29:1049–57.

    Article  Google Scholar 

  39. Fanchin R, Mendez Lozano DH, Frydman N, Gougeon A, di Clemente N, Frydman R, et al. Anti-Mullerian hormone concentrations in the follicular fluid of the preovulatory follicle are predictive of the implantation potential of the ensuing embryo obtained by in vitro fertilization. J Clin Endocrinol Metab. 2007;92:1796–802.

    Article  CAS  PubMed  Google Scholar 

  40. Takahashi C, Fujito A, Kazuka M, Sugiyama R, Ito H, Isaka K. Anti-Mullerian hormone substance from follicular fluid is positively associated with success in oocyte fertilization during in vitro fertilization. Fertil Steril. 2008;89:586–91.

    Article  CAS  PubMed  Google Scholar 

  41. Pabuccu R, Kaya C, Cağlar GS, Oztas E, Satiroglu H. Follicular-fluid anti-Mullerian hormone concentrations are predictive of assisted reproduction outcome in PCOS patients. Reprod Biomed Online. 2009;19:631–7.

    Article  CAS  PubMed  Google Scholar 

  42. Sirotkin AV, Makarevich AV, Corkins MR, Kotwica J, Kwon HB, Bulla J, et al. Secretory activity of bovine ovarian granulosa cells transfected with sense and antisense insulin-like growth factor (IGF) binding protein-3 and the response to IGF-I, GH, LH, oxytocin and oestradiol. J Mol Endocrinol. 2001;27:329–38.

    Article  CAS  PubMed  Google Scholar 

  43. Sirotkin AV, Makarevich AV, Kwon HB, Kotwica J, Bulla J, Hetényi L, et al. IGF-I and oxytocin interact by regulating the secretory activity of porcine ovarian cells? J Endocrinol. 2001;171:475–80.

    Article  CAS  PubMed  Google Scholar 

  44. Sirotkin AV. Control of reproductive processes by growth hormone: extra- and intracellular mechanisms. Vet J. 2005;170:307–17. Review.

    Article  CAS  PubMed  Google Scholar 

  45. Silva JR, Figueiredo JR, van den Hurk R. Involvement of growth hormone (GH) and insulin-like growth factor (IGF) system in ovarian folliculogenesis. Theriogenology. 2009;71:1193–208. Review.

    Article  CAS  PubMed  Google Scholar 

  46. Webb R, Campbell BK. Development of the dominant follicle: mechanisms of selection and maintenance of oocyte quality. Soc Reprod Fertil Suppl. 2007;64:141–63. Review.

    CAS  PubMed  Google Scholar 

  47. Mihm M, Evans AC. Mechanisms for dominant follicle selection in monovulatory species: a comparison of morphological, endocrine and intraovarian events in cows, mares and women. Reprod Domest Anim. 2008;43 Suppl 2:48–56. Review.

    Article  PubMed  Google Scholar 

  48. Giudice LC. Insulin-like growth factors and ovarian follicular development. Endocr Rev. 1992;13:641–69. Review.

    CAS  PubMed  Google Scholar 

  49. Giudice LC. Insulin-like growth factor family in Graafian follicle development and function. J Soc Gynecol Investig. 2001;8(1 Suppl Proceedings):S 26–9. Review.

    Article  CAS  Google Scholar 

  50. Patiño R, Yoshizaki G, Thomas P, Kagawa H. Gonadotropic control of ovarian follicle maturation: the two-stage concept and its mechanisms. Comp Biochem Physiol B Biochem Mol Biol. 2001;129:427–39. Review.

    Article  PubMed  Google Scholar 

  51. Blumenfeld Z, Amit T, Barkey RJ, Lunenfeld B, Brandes JM. Synergistic effect of growth hormone and gonadotropins in achieving conception in “clonidine-negative” patients with unexplained infertility. Ann N Y Acad Sci. 1991;626:250–65. Review.

    Article  CAS  PubMed  Google Scholar 

  52. Blumenfeld Z, Barkey RJ, Youdim MB, Brandes JM, Amit T. Growth hormone (GH)-binding protein regulation by estrogen, progesterone, and gonadotropins in human: the effect of ovulation induction with menopausal gonadotropins, GH, and gestation. J Clin Endocrinol Metab. 1992;75:1242–9.

    CAS  PubMed  Google Scholar 

  53. Amit T, Dirnfeld M, Barkey RJ, Peleg I, Hacham H, Abramovici H, et al. Growth hormone-binding protein (GH-BP) levels in follicular fluid from human preovulatory follicles: correlation with serum GH-BP levels. J Clin Endocrinol Metab. 1993;77:33–9.

    CAS  PubMed  Google Scholar 

  54. Blumenfeld Z, Amit T. The role of growth hormone in ovulation induction. Ann Med. 1994;26:249–54.

    Article  CAS  PubMed  Google Scholar 

  55. Blumenfeld Z, Amit T. The role of growth hormone (GH), GH-receptor and GH-binding protein in reproduction and ovulation induction. J Pediatr Endocrinol Metab. 1996;9:145–62. Review.

    CAS  PubMed  Google Scholar 

  56. Revelli A, Chiadò A, Dalmasso P, Stabile V, Evangelista F, Basso G, et al. “Mild” vs. “long” protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial. J Assist Reprod Genet. 2014;31:809–15.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Thomsen L, Humaidan P. Ovarian hyperstimulation syndrome in the 21st century: the role of gonadotropin-releasing hormone agonist trigger and kisspeptin. Curr Opin Obstet Gynecol. 2015;27:210–4.

  58. Banker M, Garcia-Velasco JA. Revisiting ovarian hyper stimulation syndrome: towards OHSS free clinic. J Hum Reprod Sci. 2015;8:13–7.

    Article  PubMed Central  PubMed  Google Scholar 

  59. Seyhan A, Ata B, Polat M, Son WY, Yarali H, Dahan MH. Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG. Hum Reprod. 2013;28:2522–8.

    Article  CAS  PubMed  Google Scholar 

  60. Fatemi HM, Popovic-Todorovic B, Humaidan P, Kol S, Banker M, Devroey P, et al. Severe ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and “freeze-all” approach in GnRH antagonist protocol. Fertil Steril. 2014;101:1008–11.

    Article  CAS  PubMed  Google Scholar 

  61. Ling LP, Phoon JW, Lau MS, Chan JK, Viardot-Foucault V, Tan TY, et al. GnRH agonist trigger and ovarian hyperstimulation syndrome: relook at ‘freeze-all strategy’. Reprod Biomed Online. 2014;29:392–4.

    Article  CAS  PubMed  Google Scholar 

  62. Gurbuz AS, Gode F, Ozcimen N, Isik AZ. Gonadotrophin-releasing hormone agonist trigger and freeze-all strategy does not prevent severe ovarian hyperstimulation syndrome: a report of three cases. Reprod Biomed Online. 2014;29:541–4.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Reproductive Endocrinology, Department OB/GYN, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 8 Haaliyah St, 31096, Haifa, Israel

    Zeev Blumenfeld

Authors
  1. Zeev Blumenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zeev Blumenfeld.

Ethics declarations

Conflict of interest

The author has nothing to disclose.

Additional information

Capsule

Four possible mechanisms are discussed that shed light on the question of why less gonadotropin during COH may in fact be better than more:

1. In the natural or mild stimulation cycles, the healthiest follicles are selected by the principle of quality for quantity.

2. High E2 significantly correlated with SGA and LBW neonates.

3. Better intrafollicular hormonal milieu in minimal stimulation.

4. Supraphysiological E2 may increase the GH-BP bio-neutralizing GH and diminishing the resultant IGF levels, necessary for optimal synergism with FSH.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blumenfeld, Z. Why more is less and less is more when it comes to ovarian stimulation. J Assist Reprod Genet 32, 1713–1719 (2015). https://doi.org/10.1007/s10815-015-0599-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-015-0599-7

Keywords

Search

Navigation