Progestin Primed Double Stimulation Protocol Versus Flexible GnRH Antagonist Protocol in Poor Responders
Condition: Infertility, Female
MeSH terms: Infertility; Infertility, Female
Study type: Interventional
Phase: Phase 3

Summary: 
      The worldwide prevalence of primary and secondary infertility is estimated at ~2% and 10.5%,
      respectively, among women aged 20-44 years and attempting to conceive. Poor ovarian
      responders (PORs) involve 9-24% of patients undergoing in-vitro fertilization (IVF). proper
      tailoring of the ovarian stimulation protocol in order to maximize the number of oocytes
      collected represents a crucial step for them to eventually conceive.

      Recent evidence indicates that in the same menstrual cycle, there are multiple follicular
      recruitment waves. This coincides with the theory that folliculogenesis occurs in a wave-like
      fashion. Thus, within a single menstrual cycle, there can theoretically be multiple
      opportunities for a clinician to collect oocytes, as opposed to the conventional single
      cohort of antral follicles during the follicular phase.

      Utilizing this concept, clinicians have been attempting to retrieve oocytes from poor
      responders using both the follicular-phase stimulation (FPS) and the luteal-phase stimulation
      (LPS) protocols to increase the number of oocytes collected shorter within shorter period of
      time. By increasing the number of the retrieved oocytes collected, a better clinical can be
      assured since there is a clear relationship between the number of oocytes collected and live
      birth rates across all female age groups.

      which protocol is the most effective remains controversial and the efficacy of PPOS in POR
      compared with that of conventional protocols is unclear.
    

Detailed description: 
      The study will be conducted on 90 infertile women indicated for ICSI with criteria of poor
      ovarian response defined by Bologna criteria All participants will be informed about the
      nature of the study and informed consent will be taken from all of them.

      Group 1:45 patients will be given the progestin primed double stimulation protocol.

      Group 2: 45 patients will be given the flexible GnRh antagonist follicular controlled ovarian
      stimulations will be done in 2 cycles.

      Written informed consents will be obtained from all participants who accept to participate in
      the research protocol.

      Work up:

        1. Complete history taking and full assessment of different infertility factors.

        2. Hormonal investigations

             -  FSH, LH, E2, Prolactin

             -  AMH, TSH

        3. Basal transvaginal ultrasound

      Clinical and embryological procedures:

      Group 1:

      I. The follicular phase of the double stimulation protocol

        1. luteal phase priming using combined contraceptive pills from day 21 of the previous
           cycle for one week (0.03 mg ethinyl estradiol, gestodene 0.075 mg, Gynera tab, Bayer
           Pharma AG., Berlin, Germany).

        2. Controlled ovarian hyper-stimulation with 225-375 IU of gonadotropins will be started
           day 2-3 of menses after vaginal ultrasound confirming the absence of ovarian cysts.

        3. Dydrogesterone (Duphaston, Abbott company, Illinois, United states) at 20 mg/day will be
           started from the first day of the ovulation induction.

        4. Patient response will be monitored by:

             1. Transvaginal follicular scanning and the dose of the gonadotropins will be modified
                according to the response.

             2. Serum estradiol.

             3. Serum progesterone and LH on the day of triggering.

        5. GnRh agonist triggering (Decapeptyl, Ferring, SAINT-PREX Switzerland) in a dose of 2
           ampules of 0.2 mg will be administered when leading follicle >18 mm in diameter.

        6. Oocyte pickup will be done 36 hours after GnRh administration with precaution of leaving
           the follicles measuring 11 mm or less.

        7. After the pick-up, oocytes will be denuded. The denuded oocytes are then assessed for
           nuclear status. Mature oocytes will be used for ICSI.

      II. The luteal phase of the double stimulation protocol

      Controlled ovarian hyper-stimulation with 225-375 IU of gonadotropins will be started the
      next day after the previous oocyte pickup simultaneously with Dydrogesterone (Duphaston,
      Abbott company, Illinois, United states) at 20 mg/day.

      The rest will be as the follicular phase.

      III. Fertilization and embryo quality:

      The fertilization check, which will be performed 16 to 20 hours after ICSI. The resultant
      embryos will be scored, and they will be vitrified for subsequent transfer.

      IV. Embryo transfer

      - Starting from the next menstrual cycle Day 3, patients will receive oral estradiol valerate
      (Cyclo-Progynova (white tablets); Bayer, Germany) daily. From Day 10 onwards, endometrium
      growth will be monitored by transvaginal ultrasound. When endometrial thickness ≥ 7 mm.
      Progesterone administration (as 800 mg/day vaginal suppositories per day and 100 mg ampule IM
      every other day) will be initiated and Embryo transfer will be scheduled on Day 3, 4 or 5
      with maximum number of 3 class A embryos whether of cleavage or blastocyst stage.

      V. Luteal support - Progesterone administration (as 800 mg/day vaginal suppositories per day
      and 100 mg ampule IM every other day) will be continued until pregnancy testing 18 days after
      embryo transfer. The pregnant cases will continue the luteal support till the 12 weeks of
      gestation.

      Group 2:

      VI. The flexible GnRH antagonist protocol controlled ovarian stimulation This controlled
      ovarian stimulation will be done twice in two different cycles

      In each cycle:

        1. luteal phase priming using combined contraceptive pills from day 21 of the previous
           cycle for one week (0.03 mg ethinyl estradiol, gestodene 0.075 mg , Gynera tab, Bayer
           Pharma AG., Berlin, Germany).

        2. Controlled ovarian hyper-stimulation using antagonist protocol will be used. Stimulation
           with 225-375 IU of gonadotropins will be started day 2-3 of menses after vaginal
           ultrasound confirming the absence of ovarian cysts.

        3. GnRH antagonist ( Cetrotide , Merck Serono, Darmstadt, Germany) will be given daily as
           the biggest oocyte reaches size 14 mm.

        4. Patient response will be monitored by:

             1. Transvaginal follicular scanning and the dose of the gonadotropins will be modified
                according to the response.

             2. Serum estradiol.

             3. Serum progesterone on the day of triggering.

        5. GnRh agonist triggering (Decapeptyl, Ferring, Saint-Prex Switzerland) in a dose of 2
           ampules 0.2 mg will be administered when leading follicle >18 mm in diameter. While in
           the second cycle HCG triggering (Choriomon, IBSA, Lugano, Switzerland) in a dose of
           10,000 IU will be administered when the leading follicle >18 mm in diameter.

        6. Oocyte pickup will be done 36 hours after GnRh administration.

        7. After the pick-up, oocytes will be denuded. The denuded oocytes are then assessed for
           nuclear status. Mature oocytes will be used for ICSI.

      VII. Fertilization and embryo quality:

      The fertilization check, which will be performed 16 to 20 hours after ICSI. The resultant
      embryos will be scored.

      Embryos of the first cycle will be vitrified while embryos of the second cycle will be
      freshly transferred unless there is excess for vitrification for subsequent trials of
      transfer.

      VIII. Embryo transfer

      - Progesterone administration (as 800 mg/day vaginal suppositories per day and 100 mg ampule
      IM every other day) will be initiated on the day of the oocyte pick up of the second cycle.
      Embryo transfer will be scheduled on Day 3, 4 or 5 with maximum number of 3 class A embryos
      whether of cleavage or blastocyst stage that will be a mixture of the thawed embryos of the
      first cycle and fresh embryos of the second cycle.

      IX. Luteal support Progesterone administration (as 800 mg/day vaginal suppositories per day
      and 100 mg ampule IM every other day) will be continued until pregnancy testing 18 days after
      embryo transfer. The pregnant cases will continue the luteal support till the 12 weeks of
      gestation.
    

Intervention name(s): Duphaston; Gonadotropin; Cetrotide Injectable Product; Decapeptyl; Chorionic Gonadotropin; Combined Oral Contraceptive; Cyclo-Progynova; progesterone
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): will be used for pituitary suppression in the first arm:20 mg/day will be started from the first day of the ovulation induction in the follicular phase and in the luteal phase will be started the next day after oocyte pickup at 20 mg/day.; will be used for controlled ovarian hyperstimulation in both arms; will used in the second arm for pituitary suppression in the second group daily when the biggest oocyte reaches size 14 mm till ovulation triggering; will be used for ovulation triggering.in the first arm:in a dose of 2 ampules of 0.2 mg will be administered when leading follicle >18 mm in diameter. in the second arm:in a dose of 2 ampules 0.2 mg will be administered when leading follicle >18 mm in diameter in the first cycle only.; will be used in the second cycle of the second arm for ovulation triggering in a dose of 10,000 IU when the leading follicle >18 mm in diameter.; luteal phase priming from day 21 of the cycle before controlled ovarian stimulation for one week .; Starting from cycle Day 3 of the intented cycle for thawed embryo transfer, patients will receive the white tablets of Cyclo-Progynova daily. From Day 10 onwards, endometrium growth will be monitored by transvaginal ultrasound.; in the intended cycle of embryo transfer when endometrial thickness ≥ 7 mm. Progesterone administration (as 800 mg/day vaginal suppositories per day and 100 mg ampule IM every other day) will be continued until pregnancy testing 18 days after embryo transfer and in pregnant cases will continued till the 12 weeks of gestation.
Other intervention name(s): Fostimon; Menopure; Menogon; Gonapure; choriomon; Gynera; prontogest
Intervention MeSH terms: Triptorelin Pamoate; Contraceptive Agents; Contraceptives, Oral; Chorionic Gonadotropin; Cetrorelix; Contraceptives, Oral, Combined; Progesterone; Dydrogesterone; Estradiol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment