• Eda Vrtačnik-Bokal Univerzitetni klinični center Ljubljana, Šlajmerjeva 3, 1000 Ljubljana
Keywords: in vitro fertilization, modified natural cycle, mild in-vitro fertilization, conventional in-vitro fertilization


Background: In-vitro fertilization (IVF) is performed with oocytes collected in natural and stimulated cycles. Different approaches to ovarian stimulation have been employed worldwide. Fol- lowing the introduction of gonadotrophin realising hormone (GnRH) antagonists and strategies to reduce multiple birth such as single embryo transfer, there is an interest in the revival of natural and mild approaches to ovarian stimulation in IVF. Particulary mild ovarian stimulation aims to achieve cost-effective, patient-friendly regimens which optimize the balance between outcomes and risks of treatment.

Methods: Pubmed was searched up to 2009 for papers on natural, modified natural, mild and con- ventional IVF cycles.

Results: Data discussed in this review do not allow any conclusions to be drawn regarding the most optimal mild ovarian stimulation protocol. However, it is absolutelly clear that introduction of GnRH antagonists into clinical practice has allowed for the introduction of milder stimulation approaches for IVF treatment because of preventing premature luteinising hor- mone (LH) rise by competitive blockade of the GnRH receptors. Studies also show that mild exogenous gonadotrophins interference with the decrease in follicle-stimulating hormone ((FSH) levels in the mid-folicular phase was sufficient to override the selection of a single dominant follicle and enhance the most mature follicles to growth due to their increased sensitivity for FSH and acquired responsiveness to LH.

Conclusions: The implementation of mild stimulation and modified natural cycle into standard clinical practise appears to be justified, although more prospective studies are needed to find the most appropriate mild stimulation approaches.


Download data is not yet available.


Steptoe PC, Edwards RG. Birth after the preimolantation of a human embryo. Lancet 1978; 2: 366.

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

Aboulghar MA, Mansour RT. Ovarian hyperstimulation syn- drome: classifications and critical analysis of preventive mea- sures. Hum Reprod Update 2003; 9: 275–89.

TarlatzisBC,FauserBC,KolibianakisEM,DiedrichK,Rombauts L, Devroey P. GnRH antagonists in ovarian stimulation for IVF. Hum Reprod Update 2006; 12: 333–40.

Nargund G, Fauser BC, Macklon NS, Ombelet W, Nygren K, Frydman R. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod 2007; 23: 2801–4.

Pelinck MJ, Hoek A, Simons AMH, Heineman MJ. Efficacy of natural cycle IVF: a review of the literature. Hum Reprod Update 2002; 8: 129–39.

Nargund G, Waterstone J, Bland J, Parson J, Camphell S. Cumula- tive conception and live birth rates in natural (unstimulated) IVF cycles. Hum Reprod 2001; 16: 259–62.

Feldman B, Seidman DS, Levron J, Bider D, Shulman A, Shine S, et al. In vitro fertilization following natural cycles in poor responders. Gynecol Endocrinol 2001; 15: 328–34.

ElizurSE,AslanD,ShulmanA,WiscB,BiderD,DorJ.Modified natural cycle using GnRH antagonist can be an optimal treatment in poor responders undrgoing IVF. J Assisted Reprod Genet 2005; 22: 75–9.

Papaleo E, De Santis L, Fusi F, Doldi N, Brigante C, Marelli G, et al. Natural cycle as first approach in aged patients with elevat- ed follicle-stimulating hormone undergoing intracytoplasmic sperm injection: A pilot study. Gyn Endocrin 2006; 22: 351–4.

Rongieres-Bertrand C, Olivennes F, Righini C, Fanchin R, Taieb J, Hamamah S, et al. Revival of the natural cycles in in-vitro fertiliza- tion with the use of a new gonadotrophin-releasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation. Hum Reprod 1999; 14: 683–8.

Tomaževič T, Geršak K, Meden Vrtovec H. Clinical parameters to predict the success of in vitro fertilization-embryo transfer in the natural cycle. Assist Reprod 1999; 9: 149–56.

TomazevicT,KorosecS,VirantKlunI,DrobnicS,VerdenikI.Age, oestradiol and blastocysts can predict success in natural cycle IVF-embryo transfer. Reprod Biomed Online 2007; 15: 220–6.

Vlaisavljević V, Kovačič B, Reljič M, Gavrič Lovrec V. Three pro- tocols for monitoring follicle development in 587 unstimulated cycles of in vitro fertilization and intracytoplasmic sperm injec- tion. J Reprod Med 2001; 892–8.

Jancar N, Kopitar AN, Ihan A, Virant Klun I, Bokal EV. Effect of apoptosis and reactive oxygen species production in human granulosa cells on oocyte fertilization and blastocyst develop- ment. J Assist Reprod Genet. 2007; 24: 91–7.

JancarN,Virant-KlunI,OsredkarJ,VrtacnikBokalE.Apoptosis, reactive oxygen species and follicular anti-Müllerian hormone in natural versus stimulated cycles. Reprod Biomed Online. 2008; 16: 640–8.

Vrtačnik Bokal E, Jančar N, Virant Klun I. Follicular and serum anti-mullerian hormone in natural and stimulated cycles. Hum Reprod 2008; 23: i27–i28.

Heijnen E, Marinus JC, De Klerk C, Polinder S, Beckers NGM, Klinkert ER, et al. A mild treatment strategy for in-vitro fer- tilisation: a randomised non-inferiority trial. Lancet 2007; 369: 743–9.

Pache TD, Wladimiroff JW, de Jong FH, Hop WC, Fauser BC. Growth patterns of nondominant ovarian follicles during the normal menstrual cycle. Fertil Steril 1990; 54: 638–42.

Schipper I, Hop WC, Fauser BC. The follicle-stimulating hor- mone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development. J Clin Endocrinol Metab 1998; 83: 1292–8.

McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev 2000; 21: 200–14.

FauserBC,DonderwinkelP,SchootDC.Thestep-downpriciple in gonadotrophin treatment and the role of GnRH analogues. Bailliers Clin Obstet Gynaecol 1993; 7: 309–30.

Oehninger S, Hodgen GD. Induction of ovulation for assisted reproduction programmes. Bailliers Clin Obstet Gynaecol 1990; 4: 541–73.

Zeleznik AJ, Hutchison JS, Schuler HM. Interfrence with the gonadotropin-suppressing actions of estradiol in macaques overrides the selection of a single preovulatory follicle. Endo- crinology 1985; 117: 991–9.

Hohmann FP, Laven JS, de Jong FH, Ejkemans MJ, Fauser BC. Low-dose exogenous FSH initiated during the early, mid or late follicular phase can induce multiple dominant follicle develop- ment. Hum Reprod 2001; 16: 846–54.

Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, et al. Milder ovarian stimulation for in-vitro fertiliza- tion reduces aneuploidy in the human preimplatation embryo: a randomized controlled trial. Hum Reprod 2007; 22: 980–88.

Spremembe in dopolnitve pravil obveznega zdravstvenega zavarovanja. Ur l RS 33/08.

SilbersteinT,TimarchiJR,GonzalesLetal.Pregnancyoutcome in in vitro fertilization decreases to plateau with repeated cycles. Fertil Steril 2005; 84: 1043–5.

WangJG,DouglasNC,DickenE,NakhudaGS,GuarnacciaMM, Sauer MV. Cryopersevation of supernumerary high quality embryos predicts favorable outcomes for patients undergoing repeated embryos predicts favorable outcomes for patients undergoing repeated cycles of in vitro fertilization. Fertil Steril 2008; 89: 368–74.

Bangsboll S, Pinborg A, Yding Andersen C, Nyboe Andersen A. Patients’ attitudes towards donation of surplus crypreserved embryos for treatment or research. Hum Reprod 2004; 19: 2415–9.

Zakon o zdravljenju neplodnosti in postopkih oploditve z bio- medicinsko pomočjo (ZZNPOB). Ur l RS 70/00.

Jones HW, Cohen J, Cooke I. Kempers R. IFFS Surveillance 07. Fertil Steril 2007; 87 Suppl 1: S1–S61.

How to Cite
Vrtačnik-BokalE. FROM THE CONVENTIONAL TO THE MILDER APPROACHES TO OVARIAN STIMULATION FOR IN VITRO FERTILIZATION. ZdravVestn [Internet]. 14Feb.2018 [cited 21Jul.2019];78. Available from: