Frozen Embryo Transfer (FET) involves thawing and transferring a cryopreserved embryo. This process requires precise preparation of the uterine lining, or endometrium, to ensure it is receptive. Progesterone prepares the uterus for implantation and supports the early stages of pregnancy. The timing of when progesterone is started is controlled to synchronize the uterine environment with the embryo’s developmental stage, maximizing the chances of a successful pregnancy.
The Role of Progesterone in Uterine Preparation
Progesterone is the main hormone responsible for transforming the endometrium from a proliferative state to a secretory state, making it receptive to an embryo. After estrogen thickens the lining, progesterone signals uterine cells to mature, increase blood flow, and secrete nutrients to support implantation. This hormonal shift creates the “Window of Implantation” (WOI), the short period when the endometrium allows the embryo to attach.
The WOI is biologically narrow, often lasting only 2 to 3 days. Starting progesterone too early or too late results in endometrial asynchrony, where the embryo and uterine lining are out of sync. Because the frozen embryo’s developmental stage is known precisely, progesterone timing must be carefully calculated to ensure the embryo arrives at a prepared uterus. This coordinated timing is essential, as a mismatch can lead to implantation failure.
Timing Progesterone Initiation in Programmed Cycles
Programmed, or Hormone Replacement Therapy (HRT), cycles are highly controlled and do not rely on the patient’s natural ovulation. In these cycles, the clinic determines the timing of progesterone to artificially synchronize the endometrium with the embryo’s age. The patient first receives estrogen to thicken the uterine lining, typically until it reaches 7 millimeters or greater. Once the lining is ready, progesterone is initiated, marking the start of the countdown to the transfer day.
The precise timing is calculated backward from the transfer date based on the embryo’s age. For a Day 5 blastocyst, the transfer is planned for the sixth day after starting progesterone supplementation. This ensures the embryo has been exposed to the correct hormonal environment for a duration equivalent to its age. For example, if a Day 5 blastocyst is transferred on a Monday, the patient starts progesterone five full days prior, on the Wednesday before.
For a Day 3 cleavage-stage embryo, the transfer is scheduled for the fourth day of progesterone exposure. The goal is to mimic the natural five-day journey an embryo takes from fertilization to implantation in the uterus. Since the ovaries are suppressed, the patient relies completely on the administered medication to create the receptive environment.
Timing Progesterone Initiation in Natural Cycles
In a natural cycle FET, the patient’s body produces the hormones necessary to prepare the endometrium, and timing is determined by the cycle’s natural biological events. This protocol is used for patients with regular menstrual cycles who ovulate predictably. Monitoring involves tracking the growth of a dominant follicle and checking hormone levels, including Luteinizing Hormone (LH).
The LH surge signals impending ovulation and determines the start of the countdown. In a true natural cycle, without a trigger shot, progesterone supplementation often starts 24 hours after detecting the LH surge. For a Day 5 blastocyst transfer, the embryo is typically transferred seven days after the LH surge (LH+7), aligning with five days of progesterone exposure.
A modified natural cycle uses a trigger shot, such as Human Chorionic Gonadotropin (hCG), to induce ovulation once the follicle is mature. Progesterone is usually started 36 hours after the hCG trigger administration. The transfer of a Day 5 blastocyst then takes place six days after the trigger shot (hCG+6 or hCG+7), ensuring five days of necessary progesterone exposure.
Methods of Delivery and Monitoring Progesterone Levels
Progesterone supplementation is delivered through several methods based on the specific FET protocol and physician preference. The most common forms are vaginal suppositories or gels, which allow for direct absorption by the uterine tissue. Intramuscular injections, where progesterone is suspended in oil (PIO), are also used, particularly in programmed cycles where the body produces no natural progesterone.
Injectable progesterone is often used in programmed cycles because it can achieve more consistent and higher serum progesterone levels compared to vaginal administration. Progesterone levels in the blood are monitored after the hormone has started to ensure the dosage is adequate to support the uterine lining. If blood levels are insufficient, the dose or method of delivery may be adjusted before the scheduled embryo transfer.