Comparative Study Between Minidose Long Protocol and Microdose Flare Protocol in Controlled Ovarian Hyperstimulation
Condition: Infertility
MeSH terms: Infertility
Study type: Interventional
Phase: Phase 3

Summary: 
      Objective: To compare two stimulation protocols, the minidose long protocol and the microdose
      flare protocol designed for low responders undergoing ICSI.

      Design: Randomized prospective study. Setting: University hospital IVF unit. Patients: 60
      poor responder patients coming for IVF center for ICSI. Interventions: Minidose long protocol
      in which half the dose of agonist was administered from the mid luteal phase until the day of
      HCG administration was compared with microdose flare protocol in which half the dose of GnRH
      was administered from the second day of the cycle until the day of HCG administration. Both
      groups received Gn stimulation from the second day of the cycle (300-450 IU).

      Main outcome measures: Number of oocytes retrieved.
    

Detailed description: 
      Patients and methods:

      60 patients expected to have poor response for ovarian stimulation attending kasr EL-Aini
      hospital IVF center planning for ICSI during the year 2011 were randomized to receive
      ovulation induction for controlled ovarian hyperstimulation by either one of two protocols:
      Minidose long protocol and microdose flare protocol.

      Inclusion criteria:

      All patients included were classified as poor responders when one of the following criteria
      was present:

        -  Age > 35 years.

        -  Day 3 serum FSH level > 10m IU/ml.

        -  Number of antral follicles measuring 4-8mm during the early phase < 6.

        -  Small ovarian volume.

        -  AMH < 1.

        -  Prior poor ovarian response to COH (oocytes < 5).

      Exclusion criteria:

        -  Polycystic ovarian syndrome patients.

        -  Patients with Endometriosis.

        -  Normal responders to ovulation induction.

        -  Patients having ovarian cyst.

        -  Patients receiving ovulation induction in the preceding cycle. The study was approved by
           Kasr El-Aini IVF center research committee. Each patient had given informed consent
           after full explanation of the procedure. Randomization was performed according to a
           computer generated list. The patients were randomized to two groups.

      The Minidose long protocol:

      Decapeptyl 50µg/ day was administered SC from cycle day 21 until menstruation. On the second
      day of the cycle, patients were assessed for downregulation; E2 level < 50 pg/ml, endometrial
      thickness less than 5 mm, no follicles > 15mm. Once patient downregulation was confirmed, Gn
      dose was commenced at an initial dose of 300-450 IU/day for the first 5 days followed by
      individual adjustment in Gn dose according to ovarian response and the dose of Decapeptyl
      50µg/day was continued until day of HCG administration.

      The microdose flare protocol:

      Administration of OCP's at the prior menses followed by Decapeptyl 50µg/day SC started on the
      second day of the cycle and continued until the day of HCG administration. Gn was started
      concomitantly on the second day of the cycle as described above.

      Cycle monitoring:

      Monitoring consisted of several ultrasound examination and serum E2 level in both protocols.
      The starting Gn dosage was determined by a combination of factors including patient age,
      ovarian reserve testing, prior stimulation response and was adjusted according to individual
      response. Serum LH levels were measured from day 6 of stimulation to exclude premature
      luteinization (LH > 15 IU/L).

      10,000 IU HCG was administered intramuscular when at least two leading follicles were 18mm in
      diameter. Oocyte retrieval was performed 35 hours after HCG administration by ultrasound
      guided transvaginal aspiration.

      Laboratory procedures:

      The ICSI procedure was performed 4 hours after oocyte aspiration for all the mature oocytes.
      Fertilization was assessed 16-18 hours after ICSI and was considered normal only when two
      distinct pronuclei were present. The embryos obtained were categorized on day 2-3 into 3
      grades depending on their morphological appearance, zonal thickness, cytoplasmic
      fragmentation and blastomere size.

      Transfer procedure and luteal support:

      Depending on patient age, embryo quality and the number of embryos available, 1-4 embryos
      were transferred 2-3 days after oocyte collection under transabdominal ultrasound guidance
      using a cook catheter.

      The luteal phase was supported with micronized progesterone 400 mg twice daily administered
      vaginally until a pregnancy test was performed.

      Outcome measures:

      To assess a difference in pregnancy rates between the two protocols, a sample size of 100's
      of patients should be considered but considering the size of our work, it would be many years
      before such large samples could be recruited. We therefore chose to focus on oocyte number as
      a main outcome measure.

      The data recorded for analysis included: age, infertility history and etiology, day 3 FSH,
      duration of stimulation, number of gonadotrophin ampoules required, E2 level on the day of
      HCG administration, number of oocytes retrieved and fertilized and number of embryos
      transferred.

      The primary outcome measure was the number of oocytes retrieved. The secondary outcome
      measures were implantation and clinical pregnancy rates. A clinical pregnancy was defined as
      a normal gestational sac measured with transvaginal ultrasound after 5 weeks.
    

Intervention name(s): Decapeptyl
Intervention type(s): Drug
Intervention description(s): half the dose of Gn agonist
Other intervention name(s): GnRH agonist
Intervention MeSH terms: Triptorelin Pamoate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Low responders; Minidose long protocol; Microdose flare protocol; Oocyte yield