Effect of GnRH Agonist vs GnRH Antagonist on Oocyte Morphology in Polycystic Ovary Syndrome Patients During IVF/ICSI

Study Overview
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Brief Summary
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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 in polycystic ovary syndrome (PCOS) patients. 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 oocyte morphology in PCOS patients during IVF/ICSI.

Official Title
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Effect of GnRH Agonist (Long Protocol) vs GnRH Antagonist (Flexible Protocol) on Oocyte Morphology in Polycystic Ovary Syndrome Patients During IVF/ICSI

Conditions
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In Vitro Fertilization, Infertility, Intracytoplasmic Sperm Injection, Polycystic Ovary Syndrome

Intervention / Treatment
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* Drug: Triptorelin acetate
* Drug: Cetrorelix
* Drug: recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin
* Drug: Human Chorionic Gonadotropin (hCG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PCOS women undergoing IVF/ICSI. Age: 18-39 years. Both ovaries present. Exclusion Criteria: Age ≥ 40 years. History of three or more previous IVF failures. Patients with hormonal disorders like hyperprolactinemia, thyroid disorders. Patients who previously undergo Unilateral Oophorectomy. Patients with chronic diseases: diabetes mellitus, cardiovascular diseases, liver diseases, kidney diseases. Patients with diseases may affect IVF outcomes: Endometriosis, uterine fibroids, Hydrosalpinx, Adenomyosis, autoimmune diseases, Cancer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Agonist Group (long protocol):<br>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). | Drug: Triptorelin acetate<br>* 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.<br>Drug: recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin<br>* Dosage adjustment according to the ovarian response.<br>Drug: Human Chorionic Gonadotropin (hCG)<br>* 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.<br>|
| Experimental: Antagonist Group (Flexible protocol):<br>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). | Drug: Cetrorelix<br>* 0.25 mg subcutaneously (SC) once daily starting from the day detecting a leading follicle diameter ≥ 14 mm until the day of ovulation triggering.<br>Drug: recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin<br>* Dosage adjustment according to the ovarian response.<br>Drug: Human Chorionic Gonadotropin (hCG)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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): | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GnRH Agonist, GnRH Antagonist, Oocyte morphology, Assisted reproduction technique, In Vitro Fertilization, Intracytoplasmic sperm injection, Polycystic Ovary Syndrome