New trial of progestin-primed ovarian stimulation using dydrogesterone versus a typical GnRH antagonist regimen in assisted reproductive technology
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To compare the clinical and ongoing pregnancy rates between a protocol using oral dydrogesterone with human menopausal gonadotropin (HMG) for progestin-primed ovarian stimulation (PPOS) and the typical gonadotropin-releasing hormone (GnRH) antagonist regimen in women undergoing controlled ovarian hyperstimulation (COH).
This was a prospective, controlled study of 251 women who underwent COH for in vitro fertilization between October 2016 and July 2017. The patients were allocated alternately into two groups: a dydrogesterone protocol (study group) and a GnRH antagonist protocol (control group). In study group, dydrogesterone (20 mg/day) plus HMG (150 or 225 IU) were administered simultaneously beginning on days 2 or 3 of the menstrual cycle. In both groups, all high-quality embryos were cryopreserved for later transfer. The primary outcome was the ongoing pregnancy rate at 12 weeks per frozen–thawed embryo transfer (FET) and the secondary outcome was the clinical pregnancy rate.
None of the patients experienced a premature luteinizing hormone surge. During the follow-up period, 397 FET cycles were completed. The ongoing pregnancy rates at 12 weeks were 40.0% in study group versus 38.1% in control group (absolute difference 1.9%; 95% CI − 6.83 to 17.2%). The clinical pregnancy rate in study group (52.8%) was also not inferior to that in control group (49.5%; absolute difference 3.3%; 95% CI − 4.02 to 20.2%).
The clinical and ongoing pregnancy rates in study group were comparable to those in control group. Therefore, PPOS with dydrogesterone is a reasonable option to provide COH.
KeywordsDydrogesterone Progestin-primed ovarian stimulation Premature LH surge GnRH antagonist Controlled ovarian stimulation
Assisted reproductive technology
Body mass index
Controlled ovarian hyperstimulation
Frozen embryo transfer
Human chorionic gonadotropin
Human menopausal gonadotropin
Hormone replacement therapy
In vitro fertilization
Intra-cytoplasmic sperm injection
Ovarian hyperstimulation syndrome
Progestin-primed ovarian stimulation
United States dollar
The authors wish to thank Ms. Mika Matsuoka for data collection, and Ms. Nami Hirayama and Ms. Yumiko Kobayashi for statistical analysis (clinical staff in the Kamiya Ladies Clinic). We also thank Dr. Shigeo Araki (Chief Director of the International Institute of Medical Technology IMT College) and Dr. Daiki Iwami (staff member of the Department of Renal and Genitourinary Surgery, Hokkaido University, Graduate School of Medicine) for proofreading the manuscript, and Dr. Kota Ono (staff member of the Department of Biostatistics, Hokkaido University, Graduate School of Medicine) as a statistical adviser. We thank Ellen Knapp, PhD, and James Cummins, PhD, from Edanz Group (http://www.edanzediting.com/ac) for editing drafts of this manuscript.
NI: Protocol development, data analysis, data collection, manuscript writing. MK: Data collection. NO: Data collection. TY: Data collection. EW: Data collection. OM: Data collection. HK: Data collection, protocol development.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in this study were in accordance with the ethical standards of the Kamiya Ladies Clinic and with the 1964 Helsinki declaration and its later amendments or similar ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 4.Reichman DE, Zakarin L, Chao K, Meyer L, Davis OK, Rosenwaks Z (2014) Diminished ovarian reserve is the predominant risk factor for gonadotropin-releasing hormone antagonist failure resulting in breakthrough luteinizing hormone surges in in vitro fertilization cycles. Fertility Steril 102(1):99–102. https://doi.org/10.1016/j.fertnstert.2014.04.010 CrossRefGoogle Scholar
- 5.Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, Ai A, Shoham Z (2015) Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertility Steril 104(1):62–70.e63. https://doi.org/10.1016/j.fertnstert.2015.03.022 CrossRefGoogle Scholar
- 7.Wang Y, Chen Q, Wang N, Chen H, Lyu Q, Kuang Y (2016) Controlled ovarian stimulation using medroxyprogesterone acetate and hMG in patients with polycystic ovary syndrome treated for IVF: a double-blind randomized crossover clinical trial. Medicine (Baltimore) 95(9):e2939. https://doi.org/10.1097/MD.0000000000002939 CrossRefGoogle Scholar
- 8.Zhu X, Ye H, Fu Y (2017) Duphaston and human menopausal gonadotropin protocol in normally ovulatory women undergoing controlled ovarian hyperstimulation during in vitro fertilization/intracytoplasmic sperm injection treatments in combination with embryo cryopreservation. Fertility Steril 108(3):505–512. https://doi.org/10.1016/j.fertnstert.2017.06.017 (e502) CrossRefGoogle Scholar
- 9.Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, Shoham Z (2014) Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen–thawed embryo transfer cycles. Fertility Steril 101(1):105–111. https://doi.org/10.1016/j.fertnstert.2013.09.007 CrossRefGoogle Scholar
- 10.Wang N, Wang Y, Chen Q, Dong J, Tian H, Fu Y, Ai A, Lyu Q, Kuang Y (2016) Luteal-phase ovarian stimulation vs conventional ovarian stimulation in patients with normal ovarian reserve treated for IVF: a large retrospective cohort study. Clin Endocrinol (Oxf) 84(5):720–728. https://doi.org/10.1111/cen.12983 CrossRefGoogle Scholar
- 13.Yu S, Long H, Chang HY, Liu Y, Gao H, Zhu J, Quan X, Lyu Q, Kuang Y, Ai A (2018) New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles. Hum Reprod 33(2):229–237. https://doi.org/10.1093/humrep/dex367 CrossRefPubMedGoogle Scholar
- 17.Cummins JM, Breen TM, Harrison KL, Shaw JM, Wilson LM, Hennessey JF (1986) A formula for scoring human embryo growth rates in in vitro fertilization: its value in predicting pregnancy and in comparison with visual estimates of embryo quality. J In Vitro Fertilization Embryo Transf 3(5):284–295CrossRefGoogle Scholar
- 18.Toftager M, Bogstad J, Bryndorf T, Lossl K, Roskaer J, Holland T, Praetorius L, Zedeler A, Nilas L, Pinborg A (2016) Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles. Hum Reprod 31(6):1253–1264. https://doi.org/10.1093/humrep/dew051 CrossRefPubMedGoogle Scholar
- 19.Robert J (2009) Guidance for industry non-inferiority clinical trials. Food and Drug Administration, US Department of Health and Human Services Publishing online. https://www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm187447.pdf. Accessed 31 July 2018
- 22.Zhu X, Zhang X, Fu Y (2015) Utrogestan as an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Medicine (Baltimore) 94(21):e909. https://doi.org/10.1097/MD.0000000000000909 CrossRefGoogle Scholar
- 25.Harris TG, Dye S, Robinson JE, Skinner DC, Evans NP (1999) Progesterone can block transmission of the estradiol-induced signal for luteinizing hormone surge generation during a specific period of time immediately after activation of the gonadotropin-releasing hormone surge-generating system. Endocrinology 140(2):827–834. https://doi.org/10.1210/endo.140.2.6490 CrossRefPubMedGoogle Scholar
- 27.Richter TA, Robinson JE, Lozano JM, Evans NP (2005) Progesterone can block the preovulatory gonadotropin-releasing hormone/luteinising hormone surge in the ewe by a direct inhibitory action on oestradiol-responsive cells within the hypothalamus. J Neuroendocrinol 17(3):161–169. https://doi.org/10.1111/j.1365-2826.2005.01287.x CrossRefPubMedGoogle Scholar
- 32.Tournaye H, Sukhikh GT, Kahler E, Griesinger G (2017) A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod 32(5):1019–1027. https://doi.org/10.1093/humrep/dex023 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Zhu X, Ye H, Fu Y (2017) Use of utrogestan during controlled ovarian hyperstimulation in normally ovulating women undergoing in vitro fertilization or intracytoplasmic sperm injection treatments in combination with a “freeze all” strategy: a randomized controlled dose-finding study of 100 mg versus 200 mg. Fertility Steril 107(2):379–386. https://doi.org/10.1016/j.fertnstert.2016.10.030 (e374) CrossRefGoogle Scholar
- 34.Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, Trabucco E, Venturella R, Vajta G, Rienzi L (2016) Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertility Steril 105(6):1488–1495.e1481. https://doi.org/10.1016/j.fertnstert.2016.03.002 CrossRefGoogle Scholar
- 35.Griffin D, Benadiva C, Kummer N, Budinetz T, Nulsen J, Engmann L (2012) Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders. Fertility Steril 97(6):1316–1320. https://doi.org/10.1016/j.fertnstert.2012.03.015 CrossRefGoogle Scholar
- 38.Humaidan P, Bredkjaer HE, Bungum L, Bungum M, Grondahl ML, Westergaard L, Andersen CY (2005) GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod 20(5):1213–1220. https://doi.org/10.1093/humrep/deh765 CrossRefPubMedGoogle Scholar