The Effect of Pre-treatment With GnRH Analogues Prior in Vitro Fertilization in Patients With Endometriosis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the administration of an analogue of gonadotropin-releasing hormone (GnRH) during the three months prior to the performing of an IVF may improve the response to ovarian stimulation, implantation rate and clinical pregnancy rate in patients with endometriosis/ endometriomas.

Detailed Description
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Endometriosis is defined as the presence of ectopic endometrial tissue which induces a local inflammatory reaction. Usually, this tissue is located at any level in the pelvic region, but extrapelvic locations have been described. It is a chronic disease whose cause is unknown, although a genetic predisposition has been proven. It is estimated that endometriosis affects 7-15% of women of fertile age, and up to 30-40% of women with endometriosis have infertility. Assisted reproduction techniques (ART) are the treatment of many causes of infertility, including endometriosis. The results of assisted reproduction in women with endometriosis appear to be somewhat worse than those obtained from women without endometriosis. Some authors have proven a significant reduction in implantation and pregnancy rates in these patients. The worst pregnancy rate and implantation is believed to be originated in a poor oocyte quality, which can lead to a lower rate of fertilization. This poor oocyte quality produce poorer quality embryos with a reduced capacity to implant, particularly in severe endometriosis. On the other hand, endometrial receptivity does not appear to contribute to the reduction of results of ART in these women. In an attempt to improve ART outcomes in women with endometriosis, different strategies have been proposed prior to the cycle realization, with different results. Surgical resection of endometriomas (endometriosis cysts) before the cycle of IVF/ICSI may adversely affect the results. On the other hand, careful laparoscopic cystectomy appears not to affect the ovarian response to stimulation. In addition to surgical approaches, have been tried different medical treatments to improve the results of IVF / intracytoplasmatic sperm injection (ICSI) in women with endometriosis. It has been suggested that treatment with Danazol prior to IVF may improve results. Similarly, prolonged treatment with GnRH analogues few months before IVF could improve the implantation and pregnancy rates. Unfortunately, many of these studies were not randomized and / or controlled so that the true value of therapy with GnRH analogues before IVF in women with endometriosis still needs to be valued. A recent meta-analysis showed that a 3-6 month treatment with GnRH analogues before IVF increased 4 times the odds of clinical pregnancy in women with endometriosis. Nevertheless, these results were concluded from 165 patients and 78 pregnancies, included in 3 clinical trials, which was not specifically to patients with endometriomas. The lack of studies with proper design, suggests that there is insufficient evidence at present to establish firm recommendations in this regard. This study will contribute to increasing scientific evidence to recommend or not pretreatment with GnRH agonists before IVF en patients with endometriosis.

Official Title
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A Comparative Study, Randomized, Blinded, About the Effect of Pre-treatment With GnRH Analogues Versus Placebo in Infertile Patients With Endometriosis Undergoing in Vitro Fertilization Treatment

Conditions
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Endometriosis, Infertility

Intervention / Treatment
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* Drug: Triptorelin acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infertile women with endometriosis diagnosed by surgery in the previous year to their inclusion in the study with signs of residual disease and/or by the existence of ovarian endometrioma in vaginal ecography who are susceptible to IVF treatment. BMI < 28 Kg/m2 Age < 40 years old Signed informed consent to perform IVF and participation in this study Exclusion Criteria: Follicle stimulating hormone (FSH) 2nd-5th cycle day > 12 IU/L Liver disease (sALAT> 80 IU/L) Kidney disease (creatinine > 130 nmol/L) Other relevant disease that contraindicates a pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GnRHa<br>Triptorelin acetate 3,75 mg subcutaneous injection administered on days 1, 28 and 56 after menstrual cycle. | Drug: Triptorelin acetate<br>* Triptorelin acetate Dosing regimen: 1 subcutaneous injection of 3,75 mg/28 days, total of 3 doses Placebo Dosing regimen: subcutaneous injection of the same volume of physiological serum/28 days, total of 3 doses<br>* Other names: Gonapeptyl Depot 3,75;|
| Placebo Comparator: Physiological serum<br>physiological serum subcutaneous injection with same delivery device and same volume that active comparator ) administered on days 1, 28 and 56 after menstrual cycle. | Drug: Triptorelin acetate<br>* Triptorelin acetate Dosing regimen: 1 subcutaneous injection of 3,75 mg/28 days, total of 3 doses Placebo Dosing regimen: subcutaneous injection of the same volume of physiological serum/28 days, total of 3 doses<br>* Other names: Gonapeptyl Depot 3,75;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate by started cycle | Number of pregnancies with fetal hearth beat on ultrasound exam divided by total number of started cycle | 2 weeks after biochemical diagnosis of pregnancy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of oocytes retrieved, total and metaphase II |  | In the moment of oocyte retrieval | 
| Embryo quality | A Class: high quality; 4 equal cells, <11% fragmentation, display no irregularities (vacuoles and multinucleation) and normal zona pellucida. B Class: good quality; 2 or 5 cells and <26% fragmentation or 4 cells and 12-25% fragmentation, same or similar size (cells even number), display no irregularities and normal zona pellucida. C Class: intermediate quality; no multinucleation , 3 or 6 cells with <36% fragmentation or 2, 4 and 5 cells with 25-35% fragmentation or inequal size blastomeres or absence/low vacuoles cells or anormal zona pellucida. | Two-three days after oocyte recovery and IVF | 
| Number and size of endometrioma(s) | Total number in each ovary, uni or bilateral cysts and maximum diameter (mm) of the biggest endometrioma | Day of the Basal ultrasound | 
| Rate of pregnancy to term in patients with endometriosis / endometriomas | Number of deliveries at 37th to 41st weeks of pregnancy divided by total number of pregnancies | 37 weeks after cycle | 
| Miscarriage rate | Number of pregnancy losses divided by total number clinical pregnancies | 22nd week of pregnancy | 
| Rate of healthy and live births | Number of healthy and live births divided by total number of started cycle | 37th to 41st weeks of pregnancy | 
| Fertilization rate | Number of cleavage embryos divided by total number of metaphase II oocytes | Two days after oocyte recovery and IVF | 
| Total dose of gonadotropins and days of treatment | Total dose of gonadotropins in IU, and total days on treatment | Day of the administration of human chorionic gonadotropin (hCG) | 
| Cancellation rate and causes | Number of cancelled cycles divided by total number or started cycles | Last day of gonadotropin treatment | 
| Ovarian Hyperstimulation Syndrome (OHSS) incidence | Number of patients diagnosed of OHSS divided by ended cycles. Classification in mild, moderate and severe | One month after hCG | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endometriosis, GnRH treatment, Infertility, IVF