GnRH-a and Pregnancy Rate in In Vitro Fertilization (IVF) Cycles.

This study has been completed.
Sponsor:
Collaborators:
University of Patras
Tottori University Hospital
Information provided by (Responsible Party):
Apostolos Kaponis, University of Patras
ClinicalTrials.gov Identifier:
NCT01269125
First received: January 3, 2011
Last updated: July 23, 2013
Last verified: July 2013
  Purpose

The investigators attempted to establish a rationale for the Gonadotropin Releasing Hormone-agonist (GnRH-a) administration, post-laparoscopically, in women with mild endometriosis (until stage II, according to AFS) who underwent IVF-ET procedure. Since GnRH-a reduces cytokine's concentration in serum (Iwabe et al., 1998; Iwabe et al., 2003) and peritoneal fluid of women with endometriosis (Taketani et al., 1992) the investigators hypothesized that GnRH-a can reduces also cytokine's concentration in the follicular fluid and this action may improve the oocyte quality and the fertility of these women.


Condition Intervention
Endometriosis
Infertility
Drug: Leuprolide
Procedure: IVF

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Ultralong Administration of GnRH-a Before in Vitro Fertilization Improves Fertilization Rate But Not Pregnancy Rate in Women With Endometriosis. A Prospective, Randomized, Controlled Trial.

Resource links provided by NLM:


Further study details as provided by University of Ioannina:

Primary Outcome Measures:
  • Clinical Pregnancy Rate [ Time Frame: June 2004-August 2010 ] [ Designated as safety issue: No ]
    Clinical pregnancy was confirmed by observing fetal cardiac activity on transvaginal ultrasound four weeks after a positive pregnancy test.

  • Embryo Quality (the Percentage of Grade 1 Embryos Per Participant). [ Time Frame: June 2004-August 2010 ] [ Designated as safety issue: No ]
    Embryo development was evaluated 2 days after oocyte pick-up. The number of blastomeres and the proportion of embryo volume occupied by fragments were used for the evaluation. Embryos with < 10%, < 10-20%, < 20-30% and >30% fragments were estimated as grade 1,2,3 and 4, respectively.

  • Fertilization Rate (Percentage of Fertilized Oocytes). [ Time Frame: June 2004-August 2010 ] [ Designated as safety issue: No ]
    The fertilization rate was estimated for every woman 24 hours after oocyte retrieval

  • Clinical Pregnancy Rate [ Time Frame: 4 weeks after a positive pregnancy test ] [ Designated as safety issue: No ]
    Clinical pregnancy rate was confirmed by observing fetal cardiac activity on transvaginal ultrasound four weeks after a positive pregnancy test.


Secondary Outcome Measures:
  • Follicular Fluid's TNF-a Concentration. [ Time Frame: June 2004-August 2010 ] [ Designated as safety issue: No ]
    TNF-a was measured in the FF of all women (secondary outcome measures). To prevent any cytokine alterations, only blood-free samples were used.


Enrollment: 180
Study Start Date: May 2004
Study Completion Date: September 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Endometriosis, leuprolide, IVF
Women with stage II endometriosis received GnRH-a (leuprolide) prior to an IVF attempt.
Drug: Leuprolide
single injection of 3.75 leuprolide every 28 days, 3 dosages
Other Name: Daronda depot 3.75, Abbott, Hellas
Procedure: IVF
Assisted Reproduction Technique.
Active Comparator: Endometriosis, IVF
Women with mild endometriosis who underwent an IVF attempt without prior administration of GnRH-a.
Drug: Leuprolide
single injection of 3.75 leuprolide every 28 days, 3 dosages
Other Name: Daronda depot 3.75, Abbott, Hellas
Procedure: IVF
Assisted Reproduction Technique.
Active Comparator: Tubal infertility, IVF
Women with tubal infertility underwent an IVF attempt.
Procedure: IVF
Assisted Reproduction Technique.

  Hide Detailed Description

Detailed Description:

This prospective, randomized study with control group was carried out at the Department of Obstetrics and Gynecology, Ioannina University School of Medicine (Ioannina, Greece). The study population consisted of 120 infertile women (more than a year of sexual attempts), aged 29-38 years, with laparoscopically documented endometriosis referred to the In Vitro Fertilization (IVF) Unit of the Department for infertility treatment during a 7-years period (May 2004 to September 2010). In addition, in the current study, we used 60 women with tubal infertility, documented by laparoscopy, without prior history of ovarian surgery, hydrosalpinx, and/or endometriosis as control group. This group was used to see if endometriosis affect the women's fertility. The participant's enrolment was made by three following authors A.K., K.Z., and M.P. During laparoscopy, the endoscopist documented the extension of the disease, the distribution of endometriotic lesions into the peritoneal cavity, and the presence/absence of active endometriotic lesions (red vascularized areas). All visible active endometriotic lesions were cauterized with bipolar diathermy. Women with sonographic evidence of ovarian endometrioma > 2 cm in mean diameter, with early follicular phase serum Follicular Stimulating Hormone (FSH) levels > 12 mIU/ml were excluded from the study. Cases of male factor infertility defined as a concentration of motile sperm less than 10 x 106 /ml and sperm with normal morphology less than 4% (Kruger, strict criteria) were also excluded from the study.

All women who decided to undergo an IVF-Embryo Transfer (ET) attempt were randomized into two groups according to administration or not of GnRH-a treatment, post-laparoscopy. The randomization is performed by accessing a central internet-based randomization program. The random allocation sequence and the assignment of the participants to interventions were made by the first author of the study (A.K.). The first group (Group A) was consisted of 60 women who received a depot preparation of a GnRH-a, 3.75 mg s.c, (leuprolide, Daronda depot, 3.75, Abbott, Hellas) every 28 days for three injections. The investigators preferred to pre-treat study patients with a long-acting GnRH-a for a period of 3 months because it has already reported that pregnancy rates after IVF-ET are similar in patients with endometriosis who are pre-treated with a GnRH-a for 10 to 90 days or greater than 90 days (Caruso 1997; Surrey et al., 2002). In this group, laparoscopies were performed 4 to 6 months prior of any cycle initiation for infertility. The second group (Group B) was consisted of 60 infertile women with endometriosis who did not receive the long-acting GnRH-a. All women were comparable regarding mean age, BMI, and duration of infertility.

All women of control and of group B, underwent controlled ovarian hyperstimulation (COH) after down-regulation with a GnRH-a (leuprolide, 20 IU/day, Daronda, 2.8, Abbott, Hellas) in a long protocol with a mid-luteal start. Administration of recombinant follicle stimulating hormone (rFSH, Gonal-F, Serono, Geneva, Switzeland) was started after at least 14 days of leuprolide therapy and when serum estradiol (E2) had been less than 100 pmol/l and when the thickness of the endometrium was less than 5mm. Down-regulation in women of group A was initiated 30 to 45 days after the third GnRH-a injection. A starting dose of 150 IU of follicle stimulating hormone (rFSH, Gonal-F, Serono, Geneva, Switzerland) was adjusted individually from day 6 of the cycle according to estradiol (E2) values and ultrasonographic follicular measurements. An ovulatory dose of human chorionic gonadotropin (HGG) (Pregnyl, Organon, Oss, The Netherlands) 5,000-10,000 IU was administered I.M. when mean diameter of an average of two to four follicles was larger than 16mm and the plasma estradiol concentration was higher than 1500 pmol/l.

All women were provided to luteal-phase support with natural micronized progesterone (Ultrogestan, Faran, Athens, Greece), 600 mgr daily vaginally in three divided dosages, starting the day after embryos transfer.

Follicular fluid sampling, oocyte collection and IVF Follicular fluid (FF) samples were collected during oocyte retrieval. From each patient, follicular fluid was sampled from the first one to three mature follicles, having a diameter of 18-20mm. Tumor Necrosis Factor(TNF)-a, Interleukine (IL)-1β, IL-6, IL-8 and IL-1-ra were measured in the FF of all women (secondary outcome measures). To prevent any cytokine alterations, only blood-free samples were used. IVF was performed in all cases. The fertilization rates were estimated for every woman 24 hours after oocyte retrieval (primary outcome measure).

Embryo grading and transfer The embryo quality and the clinical pregnancy rate were also primary outcome measures. Embryo development was evaluated 2 days after oocyte pick-up. The number of blastomeres and the proportion of embryo volume occupied by fragments were used for the evaluation. Embryos with < 10%, < 10-20%, < 20-30% and >30% fragments were estimated as grade 1,2,3 and 4, respectively. Three embryos with the highest blastomere number and the best morphology were transferred in each cycle. The remaining high-grade embryos were cryopreserved the same day.

Pregnancy was diagnosed by quantitative β-hCG, two weeks after embryos transfer. Clinical pregnancy was confirmed by observing fetal cardiac activity on transvaginal ultrasound four weeks after a positive pregnancy test. The clinical pregnancy rate and the quality of embryos were estimated in all women. The pregnancy rate was defined as the presence of sonographically visualized cardiac activity per cycle initiated.

  Eligibility

Ages Eligible for Study:   29 Years to 38 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Infertility
  • Mild endometriosis (until stage II)

Exclusion Criteria:

  • ovarian endometrioma > 2 cm
  • FSH > 12 mIU/ml
  • Mail factor infertility
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01269125

Locations
Greece
Dept. of Obstetrics & Gynecology, University Hospital
Ioannina, Epirus, Greece, 45111
Sponsors and Collaborators
University of Ioannina
University of Patras
Tottori University Hospital
Investigators
Principal Investigator: Apostolos Kaponis, MD Ioannina University School of Medicine
  More Information

Publications:
Responsible Party: Apostolos Kaponis, Lecturer of Ob/Gyn, University of Patras
ClinicalTrials.gov Identifier: NCT01269125     History of Changes
Other Study ID Numbers: 2003/89 PGNI
Study First Received: January 3, 2011
Results First Received: June 29, 2012
Last Updated: July 23, 2013
Health Authority: Greece: National Organization of Medicines

Keywords provided by University of Ioannina:
cytokines
endometriosis
fertilization rate
follicular fluid
pregnancy rate

Additional relevant MeSH terms:
Infertility
Endometriosis
Genital Diseases, Male
Genital Diseases, Female
Leuprolide
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antineoplastic Agents, Hormonal
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 22, 2014