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Selection of developmentally competent oocytes enhances IVF efficiency. Usually, oocyte quality is determined based on its nuclear maturation and the presence of specific cytoplasmic and extracytoplasmic morphologic features. Gonadotropin-releasing hormone agonists (GnRH Agonists) and gonadotropin-releasing hormone antagonists (GnRH Antagonists) are used during controlled ovarian stimulation (COS) protocols in order to prevent premature luteinizing hormone (LH) surge and premature ovulation. However, GnRH receptors are also expressed in extra-pituitary tissues such as ovary, but it is still unknown whether the type of GnRH analogues used during COS could affect the oocyte morphology, especially with the limited and conflicted currently available data. Thus, we are conducting this prospective, non-randomised, open-label, clinical trial to compare the effects of two pituitary suppression regimens; GnRH Agonist-Long Protocol and GnRH Antagonist-Flexible Protocol on oocyte morphology during IVF/ICSI.
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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 |
|---|---|---|
| Prevalence of oocyte dysmorphisms among the studied groups: | Before being subjected to ICSI, the oocytes from both groups will be morphologically analyzed under an inverted microscope; Nikon Eclipse Ti2; in order to detect cytoplasmic and extra-cytoplasmic dysmorphisms. | Before oocytes microinjection |
| 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 |
|---|---|---|---|
| 19787210 | Background | Aguilar-Rojas A, Huerta-Reyes M. Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review). Oncol Rep. 2009 Nov;22(5):981-90. doi: 10.3892/or_00000525. | |
| 18959738 | Background | Cheung LW, Wong AS. Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues. FEBS J. 2008 Nov;275(22):5479-95. doi: 10.1111/j.1742-4658.2008.06677.x. |
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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 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 |
| Number of Metaphase I Oocytes (MI): | The oocyte maturity will be assessed using Nikon SMZ1500 stereoscope. | Within two hours after oocyte retrieval |
| Number of Germinal Vesicle Oocytes (GV): | The oocyte maturity will be assessed using Nikon SMZ1500 stereoscope. | Within two hours after oocyte retrieval |
| Number of Atretic Oocytes: | 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 |
| 27743693 | Background | Setti AS, Figueira RC, de Almeida Ferreira Braga DP, Azevedo MC, Iaconelli A Jr, Borges E Jr. Oocytes with smooth endoplasmic reticulum clusters originate blastocysts with impaired implantation potential. Fertil Steril. 2016 Dec;106(7):1718-1724. doi: 10.1016/j.fertnstert.2016.09.006. Epub 2016 Oct 12. |
| 29718716 | Background | Sfontouris IA, Lainas GT, Lainas TG, Faros E, Banti M, Kardara K, Anagnostopoulou K, Kontos H, Petsas GK, Kolibianakis EM. Complex chromosomal aberrations in a fetus originating from oocytes with smooth endoplasmic reticulum (SER) aggregates. Syst Biol Reprod Med. 2018 Aug;64(4):283-290. doi: 10.1080/19396368.2018.1466375. Epub 2018 May 2. |
| 29635518 | Background | Stigliani S, Moretti S, Casciano I, Canepa P, Remorgida V, Anserini P, Scaruffi P. Presence of aggregates of smooth endoplasmic reticulum in MII oocytes affects oocyte competence: molecular-based evidence. Mol Hum Reprod. 2018 Jun 1;24(6):310-317. doi: 10.1093/molehr/gay018. |
| 21824710 | Background | Setti AS, Figueira RC, Braga DP, Colturato SS, Iaconelli A Jr, Borges E Jr. Relationship between oocyte abnormal morphology and intracytoplasmic sperm injection outcomes: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2011 Dec;159(2):364-70. doi: 10.1016/j.ejogrb.2011.07.031. Epub 2011 Aug 6. |
| 26630267 | Background | Lazzaroni-Tealdi E, Barad DH, Albertini DF, Yu Y, Kushnir VA, Russell H, Wu YG, Gleicher N. Oocyte Scoring Enhances Embryo-Scoring in Predicting Pregnancy Chances with IVF Where It Counts Most. PLoS One. 2015 Dec 2;10(12):e0143632. doi: 10.1371/journal.pone.0143632. eCollection 2015. |
| 22540993 | Background | Cota AM, Oliveira JB, Petersen CG, Mauri AL, Massaro FC, Silva LF, Nicoletti A, Cavagna M, Baruffi RL, Franco JG Jr. GnRH agonist versus GnRH antagonist in assisted reproduction cycles: oocyte morphology. Reprod Biol Endocrinol. 2012 Apr 27;10:33. doi: 10.1186/1477-7827-10-33. |
| 31436072 | Background | Zanetti BF, Braga DPAF, Setti AS, Iaconelli A Jr, Borges E Jr. Effect of GnRH analogues for pituitary suppression on oocyte morphology in repeated ovarian stimulation cycles. JBRA Assist Reprod. 2020 Jan 30;24(1):24-29. doi: 10.5935/1518-0557.20190050. |
| 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. |
| 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 |
| 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 |
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