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The aim of this prospective, non-randomised, open-label, clinical trial is to compare the effects of two pituitary suppression regimens; GnRH Agonist-Long Protocol and GnRH Antagonist-Flexible Protocol on clinical and embryological IVF/ICSI outcomes, and on the follicular fluid levels of Placental Growth Factor (PlGF); which is known for his pivotal role in the regulation of ovulation, embryo development, and implantation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Agonist Group (Long protocol): | Active Comparator | The pituitary down-regulation in this group will be carried out using 0.05-0.1 mg of Triptorelin acetate subcutaneously (SC) once daily from the mid-luteal phase (day 21) of the menstrual cycle until the ovulation triggering day. When the suppressive effect is obtained, ovarian stimulation will commence with recombinant Follicle-Stimulating Hormone (r-FSH) or r-FSH + human Menopausal Gonadotropin (hMG) and the dose will be adjusted according to the ovarian response. Ovulation will be triggered by the administration of 10,000 IU of human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm. After 35±2 hours of ovulation triggering, the oocytes will be retrieved by transvaginal ultrasound-guided follicle aspiration. Then they will be prepared to undergo an Intracytoplasmic Sperm Injection (ICSI). |
|
| Antagonist Group (Flexible protocol): | Experimental | The ovarian stimulation in this group will be started with recombinant Follicle-Stimulating Hormone (r-FSH) or r-FSH + human Menopausal Gonadotropin (hMG) on the third day of the menstrual cycle and the dose will be adjusted according to the ovarian response. Initiation of 0.25 mg of GnRH antagonist; Cetrorelix; will take place after detecting a leading follicle diameter ≥ 14 mm. GnRH antagonist administration will be continued till the day of ovulation triggering, which will be accomplished by given 10,000 IU of human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm. After 35±2 hours of ovulation triggering, the oocytes will be retrieved by transvaginal ultrasound-guided follicle aspiration. Then they will be prepared to undergo an Intracytoplasmic Sperm Injection (ICSI). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Triptorelin acetate | Drug | 0.05-0.1 mg subcutaneously (SC) once daily from the mid-luteal phase (day 21) of the cycle until the day of ovulation triggering. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Follicular fluid Placental Growth Factor (PlGF) Concentrations: | Follicular fluid samples will be obtained on the day of oocyte retrieval, then they will be centrifuged to eliminate cellular elements and debris. After that, the supernatants will be frozen at -80 until assayed using an Eliza kit. | Immediately after oocyte retrieval (35±2 hours after hCG administration) |
| Measure | Description | Time Frame |
|---|---|---|
| Number of oocytes retrieved: | The oocytes will be retrieved by transvaginal ultrasound-guided follicle aspiration 35±2 hours after hCG administration. | Immediately after oocyte retrieval (35±2 hours after hCG administration) |
| Number of Metaphase II Oocytes (MII): |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sally Kadoura, B Pharm, MD | Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria | Principal Investigator |
| Abdul Hakim Nattouf, MD, PhD | Professor at Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria | Study Director |
| Marwan Alhalabi, MD, PhD | Professor at Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syria. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Orient Hospital | Damascus | Syria |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24040457 | Background | Lai Q, Zhang H, Zhu G, Li Y, Jin L, He L, Zhang Z, Yang P, Yu Q, Zhang S, Xu JF, Wang CY. Comparison of the GnRH agonist and antagonist protocol on the same patients in assisted reproduction during controlled ovarian stimulation cycles. Int J Clin Exp Pathol. 2013 Aug 15;6(9):1903-10. eCollection 2013. | |
| 25288473 | Background |
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| ID | Term |
|---|---|
| D007246 | Infertility |
| ID | Term |
|---|---|
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D017329 | Triptorelin Pamoate |
| C062876 | cetrorelix |
| D008596 | Menotropins |
| D006063 | Chorionic Gonadotropin |
| ID | Term |
|---|---|
| D007987 | Gonadotropin-Releasing Hormone |
| D010906 | Pituitary Hormone-Releasing Hormones |
| D007028 | Hypothalamic Hormones |
| D036361 | Peptide Hormones |
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| Cetrorelix | Drug | 0.25 mg subcutaneously (SC) once daily starting from the day detecting a leading follicle diameter ≥ 14 mm until the day of ovulation triggering. |
|
| recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin | Drug | Dosage adjustment according to the ovarian response. |
|
| Human Chorionic Gonadotropin (hCG) | Drug | Ovulation will be triggered by the administration of 10,000 IU of Human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm. |
|
The oocyte maturity will be assessed using Nikon SMZ1500 stereoscope. |
| Within two hours after oocyte retrieval |
| Maturation Rate%: | Maturation Rate is calculated by dividing the number of mature (MII) oocytes by the number of retrieved oocytes. | Within two hours after oocyte retrieval |
| Fertilization Rate%: | Fertilization Rate is calculated by dividing the number of obtained zygote (2PN) by the number of injected oocytes. | 16-18 hours after microinjection |
| Cleavage Rate%: | Cleavage rate is calculated by dividing the number of cleavaged embryos by the number of zygotes (2PN). | Day 2 after microinjection |
| Embryo Quality: | Embryos are assessed using Nikon SMZ1500 stereoscope based on ESHRE criteria (2011). | Day of transfer (2 or 3 days after microinjection) |
| High Quality Embryos rate%: | High Quality Embryos rate is calculated by dividing the number of high quality embryos (Grade I) by the total number of cleavaged embryos. | Day of transfer (2 or 3 days after microinjection) |
| Biochemical Pregnancy Rate% (Per Embryo Transfer): | Biochemical pregnancy is defined as a positive serum beta-hCG pregnancy test after 2 weeks of embryo transfer. The biochemical pregnancy rate is calculated by dividing the number of women who are biochemically pregnant by the number of women who have at least 1 embryo transferred. | 2 weeks after embryo transfer |
| Clinical Pregnancy Rate% (Per Embryo Transfer): | Clinical pregnancy is defined as the presence of a gestational sac on ultrasound after 3-4 weeks of embryo transfer. The clinical pregnancy rate is calculated as by dividing the number of women who are clinically pregnant divided by the number of women who have at least 1 embryo transferred. | 3-4 weeks after embryo transfer |
| Hoseini FS, Noori Mugahi SM, Akbari-Asbagh F, Eftekhari-Yazdi P, Aflatoonian B, Aghaee-Bakhtiari SH, Aflatoonian R, Salsabili N. A randomized controlled trial of gonadotropin-releasing hormone agonist versus gonadotropin-releasing hormone antagonist in Iranian infertile couples: oocyte gene expression. Daru. 2014 Oct 7;22(1):67. doi: 10.1186/s40199-014-0067-4. |
| 27126581 | Background | Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2016 Apr 29;4(4):CD001750. doi: 10.1002/14651858.CD001750.pub4. |
| 27711226 | Background | Binder NK, Evans J, Salamonsen LA, Gardner DK, Kaitu'u-Lino TJ, Hannan NJ. Placental Growth Factor Is Secreted by the Human Endometrium and Has Potential Important Functions during Embryo Development and Implantation. PLoS One. 2016 Oct 6;11(10):e0163096. doi: 10.1371/journal.pone.0163096. eCollection 2016. |
| 29095972 | Background | Bender HR, Trau HA, Duffy DM. Placental Growth Factor Is Required for Ovulation, Luteinization, and Angiogenesis in Primate Ovulatory Follicles. Endocrinology. 2018 Feb 1;159(2):710-722. doi: 10.1210/en.2017-00739. |
| 21502182 | Background | Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011 Jun;26(6):1270-83. doi: 10.1093/humrep/der037. Epub 2011 Apr 18. |
| 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 |
| D006065 | Gonadotropins, Pituitary |
| D006062 | Gonadotropins |
| D010908 | Pituitary Hormones, Anterior |
| D010907 | Pituitary Hormones |
| D001688 | Biological Products |
| D045424 | Complex Mixtures |
| D010926 | Placental Hormones |
| D011257 | Pregnancy Proteins |