Dual Ovarian Stimulation in the Same IVF/ICSI Cycles for Treatment of Poor Ovarian Responders
Condition: Infertility
MeSH terms: Infertility
Study type: Interventional
Phase: Phase 3

Summary: 
      This study is a prospective before & after clinical trial to investigate the efficacy of
      double stimulations during both the follicular and luteal phases in patients with poor
      ovarian response undergoing IVF and intracytoplasmic sperm injection (ICSI) cycles.

      The study protocol is approved by the Ethics Committee (Institutional Review Board) of Royan
      institute. The study is conducted according to the Declaration of Helsinki for medical
      research. All participants provide informed consent after counseling for infertility
      treatments and routine IVF/ICSI programs.

      All the patients who diagnosed as poor ovarian responders (POR) based on the Bologna criteria
      are eligible for participation in this study. In order to define the poor response in IVF, at
      least two of the following three features must be present: (i) advanced maternal age or any
      other risk factor for POR; (ii) a previous POR; and (iii) an abnormal ovarian reserve test
      (ORT). Two episodes of POR after maximal stimulation are sufficient to define a patient as
      poor responder in the absence of advanced maternal age or abnormal ORT.

      Stage one of treatment protocol First stimulation performs by Clomiphene citrate (Ovumid®,
      Iran Hormones Company) 25 mg/day with co-treatment of Letrozole (Letrofem®, Iran Hormones
      Company) 2.5 mg/day are given from cycle day 3 onwards. Letrozole is only given for 4 days
      and clomiphene citrate is continuously used before the trigger day. Patients start to inject
      human menopausal gonadotrophin (HMG) (Menopur®, Ferring, Switzerland) 150 IU every other day
      beginning on cycle day 6. When one or two dominant follicles (18 mm in diameter) observed,
      the final stage of oocyte maturation will be induced with triptorelin 100 μg (Decapeptyl®;
      Ferring GmbH, Germany) follows by ibuprofen 600 mg (Ibuprofen-Najo® , Coated Tablets, Najo
      Company, Iran) is used on the day of oocyte maturation triggering and the day after. After
      the first oocyte retrieval, human menopausal gonadotrophin and letrozole are administrated to
      stimulate follicle development, and oocyte retrieval will be carried out a second time when
      dominant follicles have matured. All highest-quality embryos (including grade 1 and grade 2,
      eight-cell blastomere embryos) will be cryopreserved by vitrification method on the third day
      after oocyte retrieval.

      Stage two of treatment protocol:

      Transvaginal ultrasound evaluation performs after oocyte retrieval to determine whether to
      continue the second ovarian stimulation. The criterion for continued stimulation is the
      presence of at least two antral follicles 2-8 mm in diameter. A total of 225 IU HMG
      (Menopur®, Ferring, Switzerland) and letrozole 2.5 mg (Letrofem®, Iran Hormones Company) is
      administered daily from the day of, or the day after, oocyte retrieval. The initial second
      stage follicular monitoring is conducted 5-7 days later, and then for follow up every 2-4
      days, by using a transvaginal ultrasound evaluation, to record the number of developing
      follicles. Letrozole administration is discontinued when the dominant follicles reached
      diameters of 12 mm, given that large follicles have redundant LH and FSH receptors, and good
      response to exogenous hormone stimulations. Daily administration of medroxyprogesterone
      acetate 10 mg (Progestrone®, 5mg bid; Aboureihan, Iran) is added beginning on stimulation day
      12 for cases in which post-ovulation follicle size is smaller than 14 mm in diameter and
      stimulation needed to continue for several more days. This performs to postpone menstruation
      and avoid oocyte retrieval during menstruation, to prevent the risk of infection from the
      procedure. When three dominant follicles reached diameters of 18 mm or one mature dominant
      follicle exceeded 20 mm, the final stage of oocyte maturation is induced again with
      triptorelin 100 μg (Decapeptyl®; Ferring GmbH, Germany) by injection. Again, ibuprofen 600 mg
      (Ibuprofen-Najo® , Coated Tablets, Najo Company, Iran) is used on the day of oocyte
      maturation triggering and the day after. Transvaginal ultrasound-guided oocyte retrieval was
      conducted 32-36 h after GnRH agonist administration. All retrieved oocytes were treated same
      as in the study stage one.
    

Detailed description: 
      Data collection will be performed by using questionnaire to be filled as per the available
      records and laboratory results. The mean of total number of retrieved oocytes and embryos
      after the present protocol were compared with the mean of total number of retrieved oocytes
      and embryos at previous routine cycle.
    

Intervention name(s): Ovulation stimulation
Intervention type(s): Drug
Intervention description(s): Double stimulation in 2 phases:
Phase I: Clomiphene citrate (Ovumid®) 25 mg/day with co-treatment of Letrozole (Letrofem®) 2.5 mg/day are given from cycle day 3 onwards. Letrozole (Letrofem®) 2.5 mg/day are given from cycle day 3 onwards. human menopausal gonadotrophin (HMG) Menopur®150 IU every other day beginning on cycle day 6. triptorelin (Decapeptyl®) 100 μg follows by ibuprofen 600 mg.
Phase 2:A total of 225 IU HMG(Decapeptyl®) and letrozole (Letrofem®) 2.5 mg is administered daily .Daily administration of medroxyprogesterone acetate (Progestrone®)10 mg. . the final stage of oocyte maturation is induced again with triptorelin (Decapeptyl®)100 μg by injection.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Double stimulations; luteal-phase ovarian stimulation; poor ovarian response