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The last decade has shown a progressive scientific interest for new strategies to improve the outcomes of controlled ovarian stimulation (COS).
Given the fact that interovulatory period has been described to have multiple waves of follicular recruitment, luteal phase ovarian stimulation (LPOS) has been proposed as new protocol for COS, with satisfactory ovarian response and pregnancy outcomes. On the other hand progestin-primed ovarian stimulation (PPOS) is today considered an innovative protocol aiming to achieve multi-follicle recruitment and block the luteinizing hormone (LH) surge through progesterone administration in place of the traditional down regulating or gonadotropin-releasing hormone (GnRH) antagonist. This protocol has been shown to be equally effective as LH suppression with GnRH antagonist reporting equivalent oocyte retrieval rates, endocrine profiles, viable embryo numbers, and pregnancy outcomes. Due to the feasibility and patients-friendly characteristics of PPOS in oocytes donors, the current study aims to investigate the impact on the number of cumulus-oocyte complexes (COCs) when a PPOS protocol is associated to both conventional follicular phase stimulation and LPOS for vitrification of oocytes in oocyte donors. Moreover, it aims to determine whether LPOS using PPOS protocol has comparable outcomes to conventional follicular phase stimulation with PPOS protocol, in oocyte donor patients.
The current study is a single centre randomized, crossover, open label, pilot trial.
The study will be conducted on 50 patients who wish to donate their oocytes. All participants will be informed about the nature of the study and informed consent will be taken from all of them.
Patients will randomly undergo two treatment sequences, treatment sequence 1 and treatment sequence 2. Treatment sequence 1 consists of treatment A followed by treatment B; treat-ment sequence 2 consists of treatment B followed by treatment A. The time-interval between the two treatments (washout period) will be minimum two months after trigger and maximum twelve months. All patients will undergo PPOS: one cycle with follicular phase ovarian stimulation and one cycle with LPOS.
Work up: Complete history, hormonal investigations (FSH, LH, E2, Progesterone, Prolactine, AMH, TSH), Basal transvaginal ultrasound
Treatment A: Ovarian stimulation is started on day 2 of the follicular phase with daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily from day 2 of the follicular phase onwards. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 6 until the day of trigger.
Patients response will be monitored by:
Serum E2, P, FSH, LH and human chorionic gonadotropin (HCG) levels on day 2 of the follicular phase. Patients will be reevaluated on stimulation day 8 every 2 days with ultrasound scan to assess follicular growth and endocrine monitoring with E2, P, FSH and LH levels until the criteria for oocyte trigger are achieved.
Treatment B: From day 20 of the menstrual cycle onwards, daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily will be administered.
Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 6 or when serum LH > 10 IU/L until day of trigger.
Patients response will be monitored by:
Serum estradiol E2, P, FSH, LH and HCG levels on day 20 of the follicular phase In case of absence of luteal phase values (progesterone > 1.5 ng/ml) at the blood sample of day 20, stimulation will not be started. In this case, hormonal serum assessment with evaluation of E2, P, FSH and LH levels will be repeated every 2 days until luteal phase values will be achieved, and the stimulation will be started. Patient will be reevaluated on stimulation day 8 every 2 days with ultrasound scan to assess follicular growth and endocrine monitoring with E2, P, FSH and LH levels until the criteria for oocyte trigger are achieved.
Both treatments: Oocyte maturation trigger will be planned when transvaginal ultrasound shows at least 3 follicles >20mm in diameter with a single subcutaneous injection of GnRH agonist (0.2 mg Gonapeptyl). Oocyte retrieval will be performed 36 hours after trigger. The retrieved cumulus oocyte complexes will be counted, denuded and the number of mature oocytes evaluated
Statistical Considerations and Sample size Justification
Fifty - patients (25 for each sequence) need to be included. Considering a dropout rate of about 15%, 66 patients will probably be required to reach an adequate sample size.This is a pilot study, and 50 subjects is considered both practically feasible and sufficient to get reliable results in order to guide further trials in this research area.
The primary endpoint, the total number of cumulus-oocyte complexes, will be compared between the two treatments using an analysis of variance model with subject, period, and treatment as factors. The mean difference between the two treatments and its 95% confidence interval will be estimated from the model.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Follitropin delta and dydrogesterone (treatment A followed by treatment B) | Other | Treatment A: Ovarian stimulation is started with daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily from day 2 of the follicular phase onwards. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 until the criteria for oocyte trigger are achieved. Treatment B: From day 20 of the menstrual cycle onwards, daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily will be administered. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 or when serum LH > 10 IU/L until day of trigger. For both treatment (A and B) oocyte maturation trigger will be planned when transvaginal ultrasound shows at least 3 follicles >20mm in diameter with a single subcutaneous injection of GnRH agonist (Gonapeptyl 0.2 mg). Oocyte retrieval will be performed 36 hours after trigger. The retrieved cumulus oocyte complexes will be counted, denuded and the number of mature oocytes evaluated. |
|
| Follitropin delta and dydrogesterone (treatment B followed by treatment A) | Other | Treatment B: From day 20 of the menstrual cycle onwards, daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily will be administered. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 or when serum LH > 10 IU/L until day of trigger. Treatment A: Ovarian stimulation is started with daily subcutaneous injections of Follitropin delta12 mcg/daily (Rekovelle) from day 2 of the follicular phase onwards. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 until the criteria for oocyte trigger are achieved. For both treatment (B and A) oocyte maturation trigger will be planned when transvaginal ultrasound shows at least 3 follicles >20mm in diameter with a single subcutaneous injection of GnRH agonist (Gonapeptyl 0.2 mg). Oocyte retrieval will be performed 36 hours after trigger. The retrieved cumulus oocyte complexes will be counted, denuded and the number of mature oocytes evaluated. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Follitropin delta (Rekovelle) | Drug | 12 mcg/day will be used for ovarian stimulation in both arms |
|
| Measure | Description | Time Frame |
|---|---|---|
| number of retrieved COCs in both treatment groups | number of retrieved cumulus-oocyte complexes | 10-20 minutes after oocyte retrieval |
| Measure | Description | Time Frame |
|---|---|---|
| Endocrine profile in both treatment groups | evaluation of serum E2, FSH, LH, Progesterone | through study completion, an average of 1 year |
| Consumption of gonadotrophins in both treatment groups |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Christophe Blockeel, Prof, MD | Contact | + 32 2 4776699 | Christophe.Blockeel@uzbrussel.be | |
| Elsie Nulens | Contact | Elsie.Nulens@uzbrussel.be |
| Name | Affiliation | Role |
|---|---|---|
| Christophe Blockeel, Prof, MD | Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Belgium | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brussels Ivf | Recruiting | Brussels | 1090 | Belgium |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22068695 | Background | Baerwald AR, Adams GP, Pierson RA. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update. 2012 Jan-Feb;18(1):73-91. doi: 10.1093/humupd/dmr039. Epub 2011 Nov 8. | |
| 12849812 | Background | Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003 Jul;80(1):116-22. doi: 10.1016/s0015-0282(03)00544-2. |
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| ID | Term |
|---|---|
| C000620228 | follitropin delta |
| D004394 | Dydrogesterone |
| D007987 | Gonadotropin-Releasing Hormone |
| ID | Term |
|---|---|
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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| Duphaston | Drug | 20 mg/day will be used for pituitary suppression in both arms |
|
| GnRH agonist (Gonapeptyl) | Drug | (2 ampules:0.2 mg) will be used for ovulation triggering in both arms |
|
(mcg) of gonadotrophins used during ovarian stimulation
| through study completion, an average of 1 year |
| Duration of ovarian stimulation in both treatment groups | days of ovarian stimulation | through study completion, an average of 1 year |
| Days of progestin use in both treatment groups | days of progestin use during ovarian stimulation | through study completion, an average of 1 year |
| Total number of MII oocytes in both treatment groups | the number of MII oocytes retrieved that will be assessed after denudation | 1-2 hours after oocyte retrieval |
| 30594482 | Background | Bosch E, Havelock J, Martin FS, Rasmussen BB, Klein BM, Mannaerts B, Arce JC; ESTHER-2 Study Group. Follitropin delta in repeated ovarian stimulation for IVF: a controlled, assessor-blind Phase 3 safety trial. Reprod Biomed Online. 2019 Feb;38(2):195-205. doi: 10.1016/j.rbmo.2018.10.012. Epub 2018 Dec 14. |
| 24636401 | Background | Cakmak H, Tran ND, Zamah AM, Cedars MI, Rosen MP. A novel "delayed start" protocol with gonadotropin-releasing hormone antagonist improves outcomes in poor responders. Fertil Steril. 2014 May;101(5):1308-14. doi: 10.1016/j.fertnstert.2014.01.050. Epub 2014 Mar 14. |
| 12470574 | Background | Chian RC, Chung JT, Downey BR, Tan SL. Maturational and developmental competence of immature oocytes retrieved from bovine ovaries at different phases of folliculogenesis. Reprod Biomed Online. 2002 Mar-Apr;4(2):127-32. doi: 10.1016/s1472-6483(10)61929-3. |
| 3783014 | Background | Cummins JM, Breen TM, Harrison KL, Shaw JM, Wilson LM, Hennessey JF. 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 Fert Embryo Transf. 1986 Oct;3(5):284-95. doi: 10.1007/BF01133388. |
| 18854106 | Background | Demirtas E, Elizur SE, Holzer H, Gidoni Y, Son WY, Chian RC, Tan SL. Immature oocyte retrieval in the luteal phase to preserve fertility in cancer patients. Reprod Biomed Online. 2008 Oct;17(4):520-3. doi: 10.1016/s1472-6483(10)60239-8. |
| 30713022 | Background | Fernandez-Sanchez M, Visnova H, Yuzpe A, Klein BM, Mannaerts B, Arce JC; ESTHER-1 and ESTHER-2 Study Group. Individualization of the starting dose of follitropin delta reduces the overall OHSS risk and/or the need for additional preventive interventions: cumulative data over three stimulation cycles. Reprod Biomed Online. 2019 Apr;38(4):528-537. doi: 10.1016/j.rbmo.2018.12.032. Epub 2018 Dec 23. |
| 33814126 | Background | Giles J, Alama P, Gamiz P, Vidal C, Badia P, Pellicer A, Bosch E. Medroxyprogesterone acetate is a useful alternative to a gonadotropin-releasing hormone antagonist in oocyte donation: a randomized, controlled trial. Fertil Steril. 2021 Aug;116(2):404-412. doi: 10.1016/j.fertnstert.2021.02.036. Epub 2021 Apr 2. |
| 34531825 | Background | Guan S, Feng Y, Huang Y, Huang J. Progestin-Primed Ovarian Stimulation Protocol for Patients in Assisted Reproductive Technology: A Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne). 2021 Aug 31;12:702558. doi: 10.3389/fendo.2021.702558. eCollection 2021. |
| 33483281 | Background | Ioannidou PG, Bosdou JK, Lainas GT, Lainas TG, Grimbizis GF, Kolibianakis EM. How frequent is severe ovarian hyperstimulation syndrome after GnRH agonist triggering in high-risk women? A systematic review and meta-analysis. Reprod Biomed Online. 2021 Mar;42(3):635-650. doi: 10.1016/j.rbmo.2020.11.008. Epub 2020 Nov 28. |
| 25444501 | Background | Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014 Dec;29(6):684-91. doi: 10.1016/j.rbmo.2014.08.009. Epub 2014 Sep 6. |
| 24161646 | Background | Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, Shoham Z. 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. Fertil Steril. 2014 Jan;101(1):105-11. doi: 10.1016/j.fertnstert.2013.09.007. Epub 2013 Oct 23. |
| 20688325 | Background | Maman E, Meirow D, Brengauz M, Raanani H, Dor J, Hourvitz A. Luteal phase oocyte retrieval and in vitro maturation is an optional procedure for urgent fertility preservation. Fertil Steril. 2011 Jan;95(1):64-7. doi: 10.1016/j.fertnstert.2010.06.064. Epub 2010 Aug 5. |
| 6403567 | Background | McNatty KP, Hillier SG, van den Boogaard AM, Trimbos-Kemper TC, Reichert LE Jr, van Hall EV. Follicular development during the luteal phase of the human menstrual cycle. J Clin Endocrinol Metab. 1983 May;56(5):1022-31. doi: 10.1210/jcem-56-5-1022. |
| 27912901 | Background | Nyboe Andersen A, Nelson SM, Fauser BC, Garcia-Velasco JA, Klein BM, Arce JC; ESTHER-1 study group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertil Steril. 2017 Feb;107(2):387-396.e4. doi: 10.1016/j.fertnstert.2016.10.033. Epub 2016 Nov 29. |
| 34179971 | Background | Qiao J, Zhang Y, Liang X, Ho T, Huang HY, Kim SH, Goethberg M, Mannaerts B, Arce JC. A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients. Hum Reprod. 2021 Aug 18;36(9):2452-2462. doi: 10.1093/humrep/deab155. |
| 31371053 | Background | Yildiz S, Turkgeldi E, Angun B, Eraslan A, Urman B, Ata B. Comparison of a novel flexible progestin primed ovarian stimulation protocol and the flexible gonadotropin-releasing hormone antagonist protocol for assisted reproductive technology. Fertil Steril. 2019 Oct;112(4):677-683. doi: 10.1016/j.fertnstert.2019.06.009. Epub 2019 Jul 29. |
| 29300975 | Background | Yu S, Long H, Chang HY, Liu Y, Gao H, Zhu J, Quan X, Lyu Q, Kuang Y, Ai A. 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. 2018 Feb 1;33(2):229-237. doi: 10.1093/humrep/dex367. |
| D011083 |
| Polycyclic Compounds |
| D010906 | Pituitary Hormone-Releasing Hormones |
| D007028 | Hypothalamic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |