Addition of Gonadotropin Releasing Hormone Agonist to Luteal Phase Support

Study Overview
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Brief Summary
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Hormonal milieu during implantation is crucial to embryo-endometrium interaction and to the viability of the conceptus. Alterations in the peri-implantation environment are considered to impair perinatal outcomes in intracytoplasmic sperm injection (ICSI) therapy. GnRH-a is a new and promising modality for LPS. Regimens for using GnRH-a in LPS, including single mid-luteal bolus or the addition of a GnRH-a to progesterone supplementation, have been recently suggested. The aim of this study is to evaluate the impact of addition of mid-luteal single-dose or multiple-dose GnRH agonist to the routine luteal phase support in patients undergoing ICSI cycles using GnRH antagonist protocol.

Detailed Description
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Hormonal milieu during implantation is crucial to embryo-endometrium interaction and to the viability of the conceptus. There are many protocols of luteal phase support (LPS) in assisted reproductive technology (ART) cycles. GnRH-agonist (GnRH-a) is a new and promising modality for LPS. Regimens for using GnRH-a in LPS, including single mid-luteal bolus or the addition of a GnRH-a to progesterone supplementation, have been recently suggested. If the GnRH-a is administered in the mid-luteal phase, an initial flare-up with increased levels of LH takes 3-4 days before receptor down-regulation kicks in. The increased luteinizing hormone (LH) results in increased support for the corpus luteum (CL), leading to higher output of P4 and providing stronger LPS. In earlier studies, the inadvertent administration of GnRH-a in the mid-luteal phase, did not compromise pregnancy outcomes but rather enhanced implantation rates. Therefore, the use of GnRH-a in LPS was investigated and found to enhance clinical outcomes after GnRH-a and GnRH antagonist- treated ovarian stimulation cycles, as well as, in recipients of donated oocytes. Several studies since then investigated the role of GnRHa for LPS, found that luteal support with GnRH-a could be used as the first choice in patients at high risk for ovarian hyperstimulation syndrome (OHSS), or even as the sole source of LPS in a GnRH-a-triggered antagonist ovarian stimulation cycle. Although many trials have showed substantial efficacy of GnRH-a addition for luteal support on pregnancy outcomes in women undergoing IVF/ICSI, others, found no benefit of its addition to the standard LPS. A meta-analysis concluded that there is benefit, however, this evidence is of very low quality. The aim of this study is to evaluate the impact of addition of mid-luteal single-dose or multiple-dose GnRH agonist to the routine luteal phase support in patients undergoing ICSI cycles using GnRH antagonist protocol.

Official Title
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Impact of Addition of Gonadotropin Releasing Hormone Agonist to Luteal Phase Support on Antagonist ICSI Cycles

Conditions
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Female Infertility

Intervention / Treatment
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* Drug: gonadotropin releasing hormone-agonist
* Drug: Progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient age ≤ 38 years. BMI ≤ 30. Basal follicle stimulating hormone (FSH) level ≤ 10 IU/L. Anti-Müllerian hormone (AMH): ≤ 5 ng/ml. Exclusion Criteria: Endometriosis. Polycystic ovarian syndrome (PCOS). Uterine pathology or anomaly. Evidence of hydrosalpinx by hysterosalpingography or ultrasound. Comorbidities: Diabetes mellitus, hypertension, immune diseases.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 38 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Will receive routine LPS and additional single GnRH-a bolus, triptorelin 0.1 mg subcutaneous injection on the 6th day after oocyte retrieval. | Drug: gonadotropin releasing hormone-agonist<br>* subcutaneous injection<br>* Other names: triptorelin 0.1 mg;Drug: Progesterone<br>* vaginal suppositories (400 mg twice daily) starting on the day after oocyte retrieval and will be continued till pregnancy assessed by serum β-HCG 15 days after ICSI, and if pregnant, for 10 weeks of gestation.<br>* Other names: cyclogest;|
| Experimental: Group 2<br>Will receive routine LPS and additional multiple mid-luteal GnRH-a, triptorelin 0.1 mg subcutaneous injection on the 5th, 7th and 9th days after oocyte retrieval. | Drug: gonadotropin releasing hormone-agonist<br>* subcutaneous injection<br>* Other names: triptorelin 0.1 mg;Drug: Progesterone<br>* vaginal suppositories (400 mg twice daily) starting on the day after oocyte retrieval and will be continued till pregnancy assessed by serum β-HCG 15 days after ICSI, and if pregnant, for 10 weeks of gestation.<br>* Other names: cyclogest;|
| Active Comparator: Group 3 (Control)<br>Will receive the routine LPS without GnRH-a | Drug: Progesterone<br>* vaginal suppositories (400 mg twice daily) starting on the day after oocyte retrieval and will be continued till pregnancy assessed by serum β-HCG 15 days after ICSI, and if pregnant, for 10 weeks of gestation.<br>* Other names: cyclogest;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate | Calculated as the number of clinical pregnancies (Presence of an intrauterine gestational sac with embryonic cardiac activity observed by vaginal ultrasound) divided by the number of embryo transfer procedures. | 2 weeks after positive pregnancy test | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Implantation rate | the ratio of the number of gestational sacs detected by sonography to the total number of embryos transferred. | 2 weeks after positive pregnancy test | 
| Multiple pregnancy rate | The percentage of pregnancies with more than one fetus | 8 weeks of gestation | 
| Serum β-human chorionic gonadotropin (β-HCG) concentration | In milli-International unit/ml on day 15 after ICSI | 15 days after ICSI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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luteal phase support, ICSI, gonadotropin releasing hormone agonist