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

Infertility Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01269125
• Other study ID #: 2003/89 PGNI
• Status: Completed
• Phase: N/A
• First received: January 3, 2011
• Last updated: July 23, 2013
• Start date: May 2004
• Est. completion date: September 2010

Study information

• Verified date: July 2013
• Source: University of Ioannina
• Contact: n/a
• Is FDA regulated: No
• Health authority: Greece: National Organization of Medicines
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 180
• Est. completion date: September 2010
• Est. primary completion date: August 2010
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 29 Years to 38 Years

Eligibility

Inclusion Criteria:

• Infertility

• Mild endometriosis (until stage II)

Exclusion Criteria:

• ovarian endometrioma > 2 cm

• FSH > 12 mIU/ml

• Mail factor infertility

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Endometriosis
• Infertility

Intervention

Drug:
• Leuprolide
single injection of 3.75 leuprolide every 28 days, 3 dosages

Procedure:
• IVF
Assisted Reproduction Technique.

Locations

Country	Name	City	State
Greece	Dept. of Obstetrics & Gynecology, University Hospital	Ioannina	Epirus

Sponsors (3)

Lead Sponsor	Collaborator
University of Ioannina	Tottori University Hospital, University of Patras

Country where clinical trial is conducted

Greece, 

References & Publications (4)

Fedele L, Parazzini F, Radici E, Bocciolone L, Bianchi S, Bianchi C, Candiani GB. Buserelin acetate versus expectant management in the treatment of infertility associated with minimal or mild endometriosis: a randomized clinical trial. Am J Obstet Gynecol. 1992 May;166(5):1345-50. — View Citation

Rickes D, Nickel I, Kropf S, Kleinstein J. Increased pregnancy rates after ultralong postoperative therapy with gonadotropin-releasing hormone analogs in patients with endometriosis. Fertil Steril. 2002 Oct;78(4):757-62. — View Citation

Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004635. Review. — View Citation

Vercellini P, Crosignani PG, Fadini R, Radici E, Belloni C, Sismondi P. A gonadotrophin-releasing hormone agonist compared with expectant management after conservative surgery for symptomatic endometriosis. Br J Obstet Gynaecol. 1999 Jul;106(7):672-7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical Pregnancy Rate	Clinical pregnancy was confirmed by observing fetal cardiac activity on transvaginal ultrasound four weeks after a positive pregnancy test.	June 2004-August 2010	No
Primary	Embryo Quality (the Percentage of Grade 1 Embryos Per Participant).	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.	June 2004-August 2010	No
Primary	Fertilization Rate (Percentage of Fertilized Oocytes).	The fertilization rate was estimated for every woman 24 hours after oocyte retrieval	June 2004-August 2010	No
Primary	Clinical Pregnancy Rate	Clinical pregnancy rate was confirmed by observing fetal cardiac activity on transvaginal ultrasound four weeks after a positive pregnancy test.	4 weeks after a positive pregnancy test	No
Secondary	Follicular Fluid's TNF-a Concentration.	TNF-a was measured in the FF of all women (secondary outcome measures). To prevent any cytokine alterations, only blood-free samples were used.	June 2004-August 2010	No