DPOS Versus GnRH Antagonist Protocol for Oocyte Accumulation in Low Ovarian Reserve Patients: An RCT

Screening for eligibility and randomization

• This trial will be conducted at Tam Anh TP. Ho Chi Minh General hospital, Ho Chi Minh City, Vietnam and Tam Anh General hospital, Ha Noi, Vietnam
• Women who are potentially eligible will be provided information about the trial when IVF treatment is indicated
• Patients will be provided information related to the study together with the informed consent documents. Signed informed consent forms will be obtained by the investigators from all women before the enrolment.
• Women will be randomized (1:1) to either DPOS or GnRH antagonist protocol

Ovarian stimulation

• The patients will be stimulated with the same protocol in all OS cycles after randomization.
• For DPOS arm (Group I): Patients will be co-administered with oral DYG (Duphaston) 30mg/d and Human Menopausal Gonadotrophin (hMG) 225 IU/day (IU/d) via intramuscular injection from menstrual cycle day 2 - 4 (CD2 - CD4) to the day of final oocyte maturation.
• For GnRH antagonist arm (Group II): In the fixed GnRH antagonist protocol, hMG 225 IU will be administered daily from menstrual cycle day 2 - 4 (CD2 - CD4). Daily administration of GnRH antagonist (Ganirelix 0.25 mg) will be initiated on the 5th day of stimulation. Treatment with hMG and GnRH antagonist will be continued daily until the day of final oocyte maturation triggering.

Oocytes retrieval and cryopreservation

• After 36 hours of final maturation injection, all follicles greater than 12mm in diameter will be aspirated.
• Oocyte cryopreservation will be applied to collect at least 7 ± 1 oocytes
• Matured oocytes will be frozen by vitrification (CRYOTEC® Method)

Oocyte thawing and ICSI

• For the last ovarian stimulation cycle, based on the aim to collect at least 7 ± 1 oocytes, the clinician will determine the last ovarian stimulation cycle on the day of final oocyte maturation.
• The frozen oocytes of the previous OS cycle will be thawed; all fresh and frozen oocytes will be fertilized by ICSI.
• The thawing process will follow the CRYOTEC® Method
• ICSI will be used for the fertilization of mature oocytes.

Embryo cryopreservation

• Both the fresh and frozen fertilized oocytes continue to culture in the CXCM medium (Irvine Scientific., USA) to blastocyst.
• Freeze-all strategy is applied in both arms, then the frozen embryo will be transferred in the next cycle.

Endometrium preparation and embryo transfer

• Endometrial preparation with hormonal replacement therapy will be performed. In the following cycle, the endometrium will be prepared using oral estradiol valerate (Valiera®; Laboratories Recalcine) 6 mg/day starting from the second or third day of the menstrual cycle. The endometrial thickness will be monitored from day six onwards, and vaginal progesterone (Cyclogest®; Actavis) 800 mg/day plus dydrogesterone (Duphaston 10mg) at the dose of 10mg twice daily will be started when endometrial thickness reaches 8 mm or more. Elective single blastocyst transfer will be performed.
• Embryos will be thawed on the day of embryo transfer, five or six days after the start of progesterone depending on the day-5 or day-6 embryo, respectively. Embryos will be transferred into the uterine cavity under ultrasound guidance.

Pregnancy test and ultrasound to confirm fetal viability

• A pregnancy test will be performed by measuring the blood beta-hCG level 10 - 11 days after embryo transfer. If the pregnancy test is positive (≥25mIU/mL), the patient is indicated to use exogenous estrogen and progesterone until at least 12 weeks of gestation.
• A pregnancy ultrasound will be performed three weeks after the positive pregnancy test equal to 7 weeks of gestational age.
• The primary endpoint is ongoing pregnancy (11 - 12 weeks of gestation) after the first embryo transfer

Inclusion criteria

• Woman aged between 18 and 37 years
• AFC ≤ 5 and/or AMH ≤ 1.2 ng/ml
• Agree to perform freeze-all strategy and single frozen blastocyst embryo transfer

Exclusion criteria

• Oocyte recipient
• Indication of preimplantation genetic testing
• Known allergic reactions to medications in the Study (progesterone products, GnRH antagonist….)
• Basal FSH above 15mIU/mL.
• Have contraindications of ART treatment (e.g. critical or acute diseases)
• Retrieved sperm
• Repeated Implantation failure ( ≥ 3 failed embryo transfers with good-quality embryos)
• Inability to comply with the study procedures.
• Patients with a history of thyroid cancer who are on hormone replacement therapy or those diagnosed with thyroid diseases at the time of eligibility assessment