Natural Cycle/Progesterone Fortified Protocol for Endometrial Preparation for Frozen/Thawed Embryo Transfer

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.