FET is a procedure where a previously cryopreserved embryo is thawed and transferred into the uterus. Success relies almost entirely on the endometrium, the uterine lining, being perfectly prepared to receive the embryo. This preparation is achieved by controlling the hormonal environment, specifically using Estrogen (E) and Progesterone (P). These steroid hormones must be administered in a precise sequence and reach specific concentrations to create a receptive environment for implantation.
Essential Role of Estrogen and Progesterone in Implantation
The uterine lining requires a two-step hormonal process to become receptive, mirroring the natural menstrual cycle. Estrogen is introduced first, initiating the proliferative phase by stimulating the growth and thickening of the endometrium. This builds a robust, nutrient-rich cushion where the embryo can implant.
Once the lining reaches a satisfactory thickness, Progesterone is introduced to trigger the secretory phase. Progesterone transforms the estrogen-primed lining, making it highly receptive to the embryo. This transformation involves structural changes, creating the temporary “implantation window” that is open for only a short period.
This sequential action is necessary because the endometrium must be synchronized with the developmental stage of the transferred embryo. Without adequate levels and correct timing of both hormones, the uterus remains non-receptive, leading to implantation failure.
Hormonal Protocols for Uterine Lining Preparation
Fertility specialists use different strategies to achieve the necessary hormonal state for FET, primarily the Medicated (or Programmed) Cycle and the Modified Natural Cycle. The Medicated Cycle offers maximum control by suppressing the patient’s natural hormone production. This allows the medical team to supply all required Estrogen and Progesterone externally, typically via oral pills, patches, or injections.
The primary advantage of the Medicated Cycle is its predictability, allowing the transfer date to be scheduled weeks in advance. Estrogen is administered first until the lining reaches the target thickness, followed by Progesterone to time the transfer precisely.
In contrast, the Modified Natural Cycle utilizes the patient’s own menstrual cycle and relies on natural Estrogen production from a growing follicle. Monitoring is more intensive, using frequent blood tests and ultrasounds to detect natural ovulation and the subsequent Progesterone rise.
While a true natural cycle uses no external hormones, the modified version often adds Progesterone supplementation after ovulation to support the luteal phase. The choice between protocols is based on the patient’s cycle regularity and medical history, though both have comparable success rates.
Critical Target Levels and Timing Window Before Transfer
Achieving the ideal physical state for the uterine lining is prioritized over focusing on a specific Estrogen level. During the Estrogen-priming phase, the goal is for the endometrial thickness to reach a minimum of 7 to 8 millimeters. This lining should often display a trilaminar (three-layered) appearance on ultrasound.
Estrogen levels (Estradiol or E2) are monitored to confirm sufficient exposure, with typical ranges before Progesterone initiation falling between 100 and 500 pg/mL. Optimal outcomes are often suggested when E2 levels are within the 200–600 pg/mL range, though a wider range is acceptable if the lining is structurally ready.
The timing of Progesterone initiation is the most sensitive factor, defining a narrow “Progesterone window” for successful implantation. For a blastocyst (a five-day-old embryo), the transfer must occur after five full days of Progesterone exposure, making the transfer day the sixth day.
Synchronization is paramount because Progesterone quickly opens and closes the implantation window. A transfer performed even one day too early or too late can significantly reduce success rates. On the day of transfer, the circulating Progesterone level is closely monitored to ensure it adequately sustains the lining. Optimal Progesterone levels (P4) are targeted to be above 10 ng/mL, with many clinics aiming for levels greater than 15 ng/mL (or 50 nmol/L).
Managing Variations in Hormone Levels
The strict nature of the implantation window requires constant monitoring, and intervention is necessary when hormone levels are suboptimal. If Estrogen levels are too low, or the endometrial lining plateaus without reaching the minimum 7-8 mm thickness, the dosage is increased.
A cycle may be delayed or cancelled if the lining does not respond to increased Estrogen doses, as a thin lining significantly lowers the chance of implantation. Conversely, if blood tests reveal a Progesterone level above a low threshold (e.g., 1.5 ng/mL) before the planned start date, the cycle is often cancelled.
This premature elevation indicates the implantation window has opened early, making it asynchronous with the planned transfer. If Progesterone is initiated but a blood test before transfer shows the level is below the target threshold (e.g., <10 ng/mL), the dosage is immediately increased. Managing these variations avoids an unsynchronized transfer, ensuring the highest probability of success.