What medications are used to prepare the endometrium for embryo transfer in a freeze cycle?

Endometrial Preparation for Frozen Embryo Transfer

Primary Medication Regimens

Two main protocols are used to prepare the endometrium for frozen embryo transfer: hormone replacement therapy (artificial cycle) using exogenous estrogen and progesterone, or natural/modified natural cycles using endogenous ovarian hormones. 1, 2

Hormone Replacement (Artificial) Cycle Protocol

• Estrogen administration is initiated to stimulate endometrial proliferation, typically using oral estradiol (Progynova/estradiol valerate) or transdermal estrogen patches 1, 2
• Progesterone supplementation is added once adequate endometrial thickness is achieved (typically ≥7 mm), with timing adjusted to match embryo developmental stage 3, 1
• For day 5 blastocyst transfer, progesterone is started 5 days before transfer; for day 3 cleavage embryos, progesterone begins 3 days prior 4
• Progesterone dosing for endometrial protection is 200 mg daily at bedtime for 12 continuous days per 28-day cycle when used with estrogen 5
• Progesterone can be administered via multiple routes: vaginal (most common), intramuscular, oral, or subcutaneous 1, 2

Natural and Modified Natural Cycle Protocols

• Natural cycles utilize endogenous estrogen and progesterone from the developing follicle and corpus luteum, requiring ovulation monitoring 2, 6
• Modified natural cycles trigger ovulation exogenously (typically with hCG) to provide better control over transfer timing while maintaining corpus luteum presence 2, 7
• These approaches avoid the need for extensive luteal support but require more intensive monitoring 2

Critical Safety Considerations

Progesterone capsules contain peanut oil and are absolutely contraindicated in patients with peanut allergy. 5

Important Warnings for Progesterone Use

• Progesterone with estrogen should not be used to prevent cardiovascular disease, as it may increase risk of heart attacks, strokes, breast cancer, and blood clots 5
• Some women experience significant drowsiness, dizziness, blurred vision, or difficulty walking after taking progesterone—these patients should take medication at bedtime in a standing position with water 5
• Progesterone is contraindicated in patients with unusual vaginal bleeding, current or prior cancers (especially breast/uterine), history of stroke or blood clots, or liver problems 5

Luteal Support Duration

• Continue progesterone until 10 weeks of pregnancy if conception occurs 3
• Estrogen continuation (when used in artificial cycles) should be maintained for 3-4 weeks after positive pregnancy confirmation, then gradually tapered over 2 weeks 3
• Alternative recommendation suggests continuing luteal support for 1-3 weeks after ultrasound confirmation of viable intrauterine pregnancy 3

Emerging Evidence on Protocol Selection

Recent data suggest that natural cycle FET with corpus luteum presence is associated with better maternal and perinatal outcomes, particularly lower preeclampsia risk, compared to artificial cycles. 7

• This has led some experts to advocate a "back to nature" approach, recommending expanded use of natural cycle FET in ovulatory women 6, 7
• However, preeclampsia risk assessment should guide protocol selection rather than abandoning artificial cycles entirely, as not all patients carry the same risk profile 7
• Artificial cycles remain valuable for their convenience in coordinating timing with IVF lab operations and patient schedules 2, 6

Key Clinical Pitfalls to Avoid

• Do not base the decision to transfer multiple embryos on endometrial preparation method—single embryo transfer should be applied in vitrified-warmed blastocyst cycles regardless of preparation protocol or embryo quality 8, 9
• Timing of progesterone administration is critical—it must be synchronized precisely with embryo developmental stage for optimal implantation 1, 4
• No single regimen has proven superior in terms of pregnancy outcomes, though natural cycles may offer maternal safety advantages 1, 2, 7