Natural Cycle/Progesterone Fortified Protocol for Endometrial Preparation for Frozen/Thawed Embryo Transfer
Condition: Infertility
MeSH terms: Infertility
Study type: Interventional

Summary: 
      This is a pilot study of a novel protocol for preparation of the endometrium for
      frozen/thawed embryo transfer whereby estrogen is not administered during the proliferative
      phase and progesterone is administered through vaginal suppositories in accordance with
      endometrial thickness only, disregarding the day of ovulation. Progesterone supplementation
      commences once the endometrium is at least 7 mm, a follicle is demonstrated on TVS, and
      ovulation has not yet taken place. The day of ET is scheduled according to the unit's working
      days and progesterone suppositories are commenced 48 hours before the scheduled embryo
      transfer.
    

Detailed description: 
      Natural cycle/progesterone fortified protocol for endometrial preparation for frozen/thawed
      embryo transfer Study type: Descriptive pilot study of a novel protocol for endometrial
      preparation for frozen/thawed embryo transfer Introduction: In the process of in-vitro
      fertilization (IVF) cycles embryos are frequently cryopreserved for future attempts at
      conception. In order for these embryos to take root in the uterus, the endometrial lining
      must be made "receptive" to embryo implantation.

      During the natural reproductive cycle, this process takes place in two stages. During the
      endometrium's proliferative phase, which takes place during the first 14 days of a 28 day
      cycle, estradiol is produced by the growing follicle whereby the thin endometrium remaining
      after the menstrual cycle proliferates to a width of between 7 to 14 mm on average, attains a
      triphasic appearance on ultrasound and acquires receptors for progesterone. After ovulation,
      the ovarian follicle transforms to a corpus luteum which produces progesterone. At this
      stage, exposure to progesterone transforms the endometrium to one which is receptive to
      embryo implantation. There is a minimum level of progesterone and a minimum time of exposure
      which is necessary to transform the endometrium to a receptive one while prolonged
      progesterone exposure renders the endometrium hostile to implantation. The boundaries of this
      time zone are referred to as the window of implantation. The length of time of this window is
      unknown.

      There are two strategies for returning frozen/thawed embryos to the uterus in women with
      regular menstrual cycles.

        1. The natural cycle: In our facility embryos are cryopreserved 48-72 hours after
           fertilization. In the natural cycle protocol women are monitored for estradiol,
           progesterone and LH levels in the blood and endometrial thickness and follicle
           development. The thawed embryos are transferred to the uterus 48-72 hours after presumed
           ovulation and the rise of progesterone

        2. Hormone replacement protocol: The patient is given beta estradiol 2mg three times a day
           (Estrofem - Novo Nordisk) from the first day of the menstrual cycle. This prevents
           indigenous follicle development on the one hand, but is sufficient to prepare the
           endometrium. When the endometrium is at least 7 mm thick vaginal suppositories of
           progesterone are administered 100 mg tid (Endometrin - Lapidot) for 48 hours after which
           the embryos are transferred. If the endometrium fails to reach 7 mm, additional estrogen
           is added. Since there is no corpus luteum in this protocol, estradiol and progesterone
           supplementation must be given until the placenta produces these hormones in sufficient
           quantities. We maintain hormonal support until 11.6 weeks of gestation in cycles where
           pregnancy is attained.

      The advantage of the natural cycle is that there is no need to take hormones. Nevertheless,
      it should be noted that even though progesterone supplementation is not necessary for the
      natural cycle protocol, many IVF units add progesterone support after embryo transfer. A
      recent study demonstrated that adding progesterone to the natural cycle increased the live
      birth rate (Bjuresten et al. 2011). Patients were monitored from day 10 to 14 for follicular
      development after which daily home urinary kits were provided to detect the LH surge. Three
      days after detection of the LH surge thawed embryos were transferred and patients in the
      study group commenced taking vaginal progesterone.

      The disadvantages of the natural cycle is that the IVF unit must be prepared to perform an
      embryo transfer on every day of the week including days on which the unit is closed, in
      accordance with the day of ovulation. Delaying embryo transfer to the unit's work schedule
      may cause the embryo transfer to take place outside of the endometrium's window of
      implantation.

      In the hormone replacement protocol the physician determines the day the patient begins
      progesterone supplementation, and therefore the day of embryo transfer can be scheduled
      according to the units work load. Furthermore there is no need for blood tests during patient
      monitoring. Ultrasound monitoring can usually be limited to two or three visits. The hormone
      replacement protocol is the protocol of choice in our unit.

      Rationale:

      Ovulation is not essential for embryo implantation in the endometrial lining as demonstrated
      in the hormone replacement protocol. In the proposed protocol the developing follicle
      stimulates endometrial growth and progesterone is commenced once endometrial growth reaches
      at least 7 mm and the dominant follicle has been established, regardless of when ovulation
      occurs. Embryo transfer is performed 48 hours after beginning progesterone. By dissociating
      the protocol from the day of ovulation greater leeway is achieved in choosing the day of
      embryo transfer.

      Objectives:

      This is a pilot study of a novel protocol for preparation of the endometrium for
      frozen/thawed embryo transfer whereby estrogen is not administered during the proliferative
      phase and progesterone is administered through vaginal suppositories in accordance with
      endometrial thickness only, disregarding the day of ovulation. The primary outcome is the
      biochemical pregnancy rate. Secondary outcomes include the clinical pregnancy rate and
      ongoing pregnancy rate.

      Intervention: We propose a protocol for endometrial preparation for frozen/thawed embryo
      transfer which combines the advantages of both protocols. Patients do not receive estradiol
      and therefore ovarian follicle production is not suppressed. Progesterone supplementation
      commences once the endometrium is at least 7 mm, a follicle is demonstrated on TVS, and
      ovulation has not yet taken place. The day of ET is scheduled according to the unit's working
      days and progesterone suppositories are commenced 48 hours before the scheduled embryo
      transfer. In order to ensure synchronization between the endometrium and the embryos, embryo
      transfer of 48 hour embryos will be transferred 48 hours after progesterone therapy. This is
      not different from our current practice.

      Like the natural cycle protocol, we allow ovulation to take place but we are not dependent on
      the day of ovulation to dictate to us the day of embryo transfer, as long as we begin
      progesterone supplementation before or at the same time as the natural rise of progesterone
      which accompanies ovulation. The progesterone supplementation dose is identical to the
      standard protocol so that even if ovulation is suppressed the luteal support is adequate.

      In this protocol there is no need for daily blood and ultrasound studies. For most patients,
      one visit around day 10-13 will probably suffice to schedule the embryo transfer.
      Progesterone supplementation can be less intensive and estrogen supplementation unnecessary.

      Recruitment:

      Recruitment for the study will be done by the investigators who are all senior ob/gyn
      specialists at the IVF unit. Patients to be recruited are those women who have cryopreserved
      embryos in our unit and who request a frozen thawed embryo replacement cycle. No recruitment
      outside of the unit will take place, no transfer of frozen embryos from other units will be
      included and therefore no advertising is necessary.

      Inclusion criteria:

        1. Women younger than 39 at the time of cryopreservation

        2. Regular menstrual cycles of at least 26 days and at most 32 days.

        3. Women with no more than 3 failed prior embryo transfers

        4. Patients with embryos cryopreserved 48 hours after ovum pick up Exclusion and withdrawal
           criteria

      1. Women with known uterine malformations or significant myomas 2. Women with elevated
      Progesterone of at least 1.5 ng/mL for the duration of more than 72 hours before embryo
      transfer can be performed 3. Women suspected of having endometrial pathology based on
      previous treatment cycles i.e. "thin endometrium", polyps, adhesions 4. Women whose embryos
      did not survive the thawing process, i.e. no embryos available for transfer after thawing 5.
      Women without follicular development

      Protocol:

      A blood sample for estradiol, progesterone and LH will be taken on days 10 - 14 of a 28 day
      cycle as well as a TVS study of the endometrial thickness and ovarian follicles. The day of
      the first visit can be adjusted according to the length of the cycle.

      Based on these tests the physician will determine if there is active follicle formation prior
      to ovulation. Evidence of active follicle formation includes a clear follicle of at least 12
      mm and estradiol of at least 80 pg/ml. If the endometrium is at least 7 mm, ET will be
      scheduled. If the endometrium is less than 7 mm the patient will be invited for a second
      visit 1-3 days later.

      Should there be evidence of ovulation having already taken place, such as a progesterone
      level over 1.5 ng/ml and sonographic evidence of a corpus luteum, then the cycle will be
      cancelled.

      If there is no evidence of follicular activity at the first visit after menstruation; i.e.
      estradiol under 80 pg/ml and no follicle demonstrated on ultrasound, the patient will be
      withdrawn from the study.

      Progesterone suppositories (Endometrin), 100 mg 3 times a day will commence 48 hours before
      scheduled embryo transfer until the day of the pregnancy test 14 days later. All embryo
      transfers will be done under abdominal ultrasound guidance. At the time of embryo we will
      record the size of the leading follicle and whether it has attributes of a corpus luteum.

      Once pregnancy is confirmed progesterone support will be continued until 11.6 weeks three
      times a day. Blood samples and sonographic studies will be done as needed until embryo
      transfer. HCG, progesterone and estradiol will be measured 14 days after embryo transfer and
      16-17 days after should a pregnancy be detected. An ultrasound will be performed at 5-6 weeks
      to confirm the presence of a gestational sac and at 6-7 weeks to confirm a heartbeat. Data
      will be collected until pregnancy termination or delivery.

      Sample size:

      The biochemical pregnancy rate for FET in our unit for patients of this age group is 24%.

      A sample size of 40 patients will provide 13% accuracy for pregnancy rate. Recruitment will
      end after 40 patients have completed the protocol up to the stage of embryo transfer. Up to
      75 women will be recruited in order to assure that 40 patients complete the protocol. The
      primary endpoint is the biochemical pregnancy rate. Secondary endpoints include implantation
      rate and clinical pregnancy rate. For the purposes of comparison a cohort of patients not in
      the study undergoing the traditional hormone replacement preparation will be analyzed.

      All patient data will be kept confidential by all researchers. Patient research files will be
      kept in a locked closet in the IVF unit. Patients names and ID numbers will be replaced by
      patient codes in the database before submitting for statistical analysis.
    

Intervention name(s): FET after endometrial preparation
Intervention type(s): Other
Intervention description(s): Patients included in the protocol will begin progesterone supplementation 48 hours before scheduled embryo transfer once it has been established that the endometrium is at least 7 mm and there is a leading follicle.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Frozen Embryo Transfer, Progesterone, Endometrium