Effect of GnRH Agonist vs GnRH Antagonist on IVF/ICSI Outcomes in Polycystic Ovary Syndrome Patients.

Study Overview
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Brief Summary
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This prospective, non-randomised, open-label, clinical trial is conducting on polycystic ovary syndrome (PCOS) subjects 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

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

Conditions
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In Vitro Fertilization, Intracytoplasmic Sperm Injection, Infertility, 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 diagnosed according to the Rotterdam criteria 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 (hCG) 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 (hCG) 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 |
| --- | --- | --- |
| 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 Elisa kit. | Immediately after oocyte retrieval (35±2 hours after hCG administration) | 

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 | 
| 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, Assisted reproduction technique, In Vitro Fertilization, Intracytoplasmic sperm injection, Polycystic Ovary Syndrome, Placental growth factor