Mild Stimulation Protocol Versus Microdose Gonadotropin-releasing Hormone Agonist Flare up Protocol in Poor Responders
Condition: Pregnancy
Study type: Interventional
Phase: Phase 4

Summary: 
      Despite the progression in assisted reproductive technology (ART), the preferred protocol for
      poor responders is still controversial. The management of poor responders consists of 10% of
      ART cycles .

      The response to controlled ovarian hyperstimulation (COH) is lower regarding estradiol level
      , number of obtained oocytes , and fertilization , implantation and pregnancy rates in
      patients with low ovarian reserve . Furthermore , bad quality embryos are observed in these
      women more than normoresponders and the increase of cancellation rate and doses of
      gonadotropin administration are remarkable results in poor responders . Several criteria have
      introduced for poor responders , the main defect in the management of them is lack of
      specific definition .Several strategies are available to improve ART cycles outcome in poor
      responders. These modalities include using : high FSH dose , stop GnRH-agonist protocol ,
      addition of growth hormone , transdermal testosterone , aromatase inhibitor , GnRH-antagonist
      and recombinant FSH ( r-FSH) ; while the improvement of pregnancy rate has been quite low.

      The most common used protocol for ovarian stimulation is microdose GnRH-agonist flare in poor
      responders .Some investigators concluded that the use of GnRH-agonist " even in lower doses ,
      led to prolonged stimulation and increased the cost without improving IVF outcome.
      Furthermore this method increased LH , progesterone and androgen of serum in follicular phase
      , which caused deleterious effect on follicular growth and oocyte quality .

      Clomiphene citrate co-treatment with gonadotropin and antagonist are one of the recommended
      protocol in poor responders . Clomiphene citrate increases endogenous FSH versus agonist in
      microdose protocol. Decreasing the doses of used gonadotropin and duration of stimulation are
      its beneficial effects in COH cycle .

      The aim of this study was comparing CC/gonadotropin/antagonist and GnRH agonist flare
      protocols on IVF outcome in poor responders .
    

Detailed description: 
      Despite the progression in assisted reproductive technology (ART) , the preferred protocol
      for poor responders is still controversial. The management of poor responders consists of 10%
      of ART cycles .

      The response to controlled ovarian hyperstimulation (COH) is lower regarding estradiol (E₂)
      level , number of obtained oocytes , and fertilization , implantation and pregnancy rates in
      patients with low ovarian reserve . Furthermore , bad quality embryos are observed in these
      women more than normoresponders and the increase of cancellation rate and doses of
      gonadotropin administration are remarkable results in poor responders Several criteria have
      introduced for poor responders , the main defect in the management of them is lack of
      specific definition .Several strategies are available to improve ART cycles outcome in poor
      responders. These modalities include using : high FSH dose , stop GnRH-agonist protocol ,
      addition of growth hormone , transdermal testosterone , aromatase inhibitor , GnRH-antagonist
      and recombinant FSH ( r-FSH) ; while the improvement of pregnancy rate has been quite low.

      The most common used protocol for ovarian stimulation is microdose GnRH-agonist flare in poor
      responders .Some investigators concluded that the use of GnRH-agonist " even in lower doses "
      led to prolonged stimulation and increased the cost without improving IVF outcome.
      Furthermore this method increased LH , progesterone and androgen of serum in follicular phase
      , which caused deleterious effect on follicular growth and oocyte quality .

      Clomiphene citrate co-treatment with gonadotropin and antagonist are one of the recommended
      protocol in poor responders . Clomiphene citrate increases endogenous FSH versus agonist in
      microdose protocol. Decreasing the doses of used gonadotropin and duration of stimulation are
      its beneficial effects in COH cycle .

      The aim of this study was comparing CC/gonadotropin/antagonist and GnRH agonist flare
      protocols on IVF outcome in poor responders .

      Materials and Methods Study design This study was a prospective randomized controlled trial
      including 159 poor responder patients who were candidate for IVF . Women with ≥38 years old
      who had one or more previous failed IVF cycles in which three or fewer oocyte were been
      retrieved and/or serum E2 level on the day of hCG administration was ≤500 pg/ml were enrolled
      in this study . Patients with BMI > 30 , endocrine or metabolic disorders , history of
      ovarian surgery , sever endometriosis and sever male factor ( azospermia ) were excluded from
      the study . Patients were divided into two groups , 79 women in group I received
      CC/gonadotropin/antagonist (mild protocol) and 80 women in group II received microdose
      GnRH-agonist flare (microdose protocol) . A method of computer-generated randomization was
      used .

      Treatment Protocols All women received oral contraceptive for 21 days which started on the
      first day of previous cycle . In group I , stimulation were performed by administration of
      clomiphene citrate (Iran hormone, Tehran, Iran) 100 mg from day 3 of withdrawal bleeding
      until day 7 of cycle and gonadotropin stimulation with 225-300 IU daily , recombinant FSH
      (r-FSH) SC or hMG IM , were started from day 5 of cycle . In group II ovarian stimulation was
      initiated with GnRH-agonist , buserelin (Suprefact, Aventis Pharma, Frankfurt, Germany) 50 µg
      SC twice a day from cycle day 2 of withdrawal bleeding . After two days , 225-300 IU/day
      recombinant FSH (r-FSH) SC or hMG IM were administered.

      Ovarian response was monitored by serial ultrasound examinations and evaluation of serum E₂
      levels , then doses of gonadotropin were adjusted as required in both groups.

      In group I , when at least one follicle ≥ 14 mm in mean diameter was observed , 0.25 mg GnRH
      antagonist (ganirelix , Organon, netherlands) SC daily was started and continued until hCG
      injection . Urinary Human chorionic gonadotropin 10000 IU was administered intramuscular when
      at least two follicles reached a mean diameter of 18 mm in both groups . Also , endometrial
      thickness and serum E₂ level were measured on the day of hCG injection .Oocyte retrieval was
      performed 34-36 hours after hCG injection and conventional IVF or intracytoplasmic sperm
      injection (ICSI) was done as appropriately . All embryos were scored by the number , size ,
      shape , symmetry and cytoplasmic appearance of blastomers , and the presence of anucleate
      cytoplasmic fragmentation .

      Based on the number and quality of available embryos and patient's age , one to five embryos
      were transferred on the day 2 or 3 after oocyte retrieval under ultrasound guidance with a
      CCD embryo transfer catheter (Laboratory C.C.D., Paris, France). Luteal support with
      progesterone 100 mg daily IM was started on the day of oocyte retrieval and was continued
      until the documentation of fetal heart activity on ultrasound.

      Cycle cancellation was defined as three groups : [1] poor ovarian response : fewer than two
      growing follicles on transvaginal ultrasound, and an E₂ level < 200 pg/ml on the day 7 of
      stimulation ; [2] failed oocyte retrieval : no obtained oocyte on the day of ovarian puncture
      ; [3] failed fertilization : no fertilized oocyte after IVF/ICSI.
    

Intervention name(s): clomiphene citrate; buserelin
Intervention type(s): Drug; Drug
Intervention description(s): 100 mg per day oral for 7 days; 50 µg Subcutaneous twice a day from cycle day 2 of menstrual cycle
Intervention MeSH terms: Clomiphene; Enclomiphene; Zuclomiphene; Buserelin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Pregnancy; Clomiphene Citrate; Fertilization; Buserelin