What are the different types of Frozen Embryo Transfer (FET) protocols?

Types of Frozen Embryo Transfer (FET) Protocols

There are three main FET protocols: natural cycle (with or without ovulation trigger), modified natural cycle (with HCG trigger), and artificial/hormone therapy cycle (with estrogen and progesterone supplementation, with or without GnRHa suppression). 1

Natural Cycle FET

True natural cycle FET involves monitoring the patient's spontaneous ovulation without any hormonal intervention 2:

• Requires daily blood or urine luteinizing hormone measurements to detect the natural LH surge 2
• No exogenous estrogen, progesterone, or HCG is administered 3
• Embryo transfer timing is based on natural ovulation detection 1
• Appropriate only for women with regular ovulatory menstrual cycles 2
• Live birth rate of approximately 37% per transfer 3

Key limitation: High cycle cancellation rate—99 out of 476 cycles (21%) were cancelled in one large randomized trial 3

Modified Natural Cycle FET

Modified natural cycle with HCG trigger uses minimal intervention to control timing 2:

• Follicular development is monitored via ultrasound 1
• HCG injection (typically 5,000-10,000 IU) is administered to trigger ovulation when the dominant follicle reaches appropriate size 2
• Progesterone luteal support is initiated after ovulation 4
• Live birth rate of approximately 33% per transfer 3
• Similar cancellation rate to true natural cycle (99/476 cycles cancelled) 3

Enhanced modified natural cycle protocol adds additional luteal support 4:

• One injection of recombinant HCG on day of transfer 4
• One injection of GnRH agonist 4 days after transfer 4
• This modification achieved significantly higher implantation (31% vs 17%), clinical pregnancy (51% vs 26%), and ongoing pregnancy rates (46% vs 20%) compared to standard natural cycle 4

Scheduled modified natural cycle allows flexible timing 5:

• Short-duration GnRH antagonist (1 ampule/day) with low-dose gonadotropins (75 IU/day) delays ovulation 5
• Enables scheduling of transfer day without compromising outcomes 5
• Live birth rate of 57.0% (not significantly different from traditional natural cycle at 49.4%) 5
• Eliminates cycle cancellations while maintaining natural cycle benefits 5

Artificial/Hormone Therapy (HT) Cycle FET

Standard HT protocol uses sequential hormone administration 2:

• Oral estradiol valerate 8 mg/day starting from day 2-4 of menstruation 3
• Endometrial thickness monitored via ultrasound 1
• Progesterone supplementation (typically vaginal 800 mg/day) begins when endometrial thickness reaches ≥7 mm 6, 7, 3
• Live birth rate of approximately 34% per transfer 3
• Zero cycle cancellations (0/476 cycles in large RCT) 3

Timing considerations for HT protocol 6, 7:

• Progesterone should only begin after achieving endometrial thickness ≥7 mm, regardless of days of estrogen administered 7
• After positive pregnancy test, continue estrogen and progesterone at original doses for 3-4 weeks 6
• Then gradually reduce dosage to complete discontinuation within 2 weeks 6

HT with GnRHa suppression adds pituitary downregulation 1:

• GnRH agonist administered before or concurrent with estrogen 1
• One small study (n=75) suggested higher live birth rates with GnRHa suppression compared to HT alone (OR 0.10,95% CI 0.04-0.30) 1
• However, this finding requires validation in larger trials 1

Comparative Effectiveness

No clear superiority exists between protocols based on current evidence 2, 1:

• A 2024 randomized trial of 1,428 women found no significant difference in live birth rates: natural cycle 37%, modified natural 33%, artificial cycle 34% 3
• The Cochrane review concluded insufficient evidence to recommend one regimen over another 1
• Maternal and neonatal outcomes did not differ significantly between groups 3

Critical practical differences 3:

• Natural and modified natural cycles have high cancellation rates (approximately 21%) 3
• Artificial cycles have zero cancellations, providing scheduling reliability 3
• Natural cycles require intensive monitoring with frequent ultrasounds and hormone measurements 2
• Artificial cycles are the only option for women with irregular or absent ovulation 2

Protocol Selection Algorithm

For women with regular ovulatory cycles 2, 3:

• Consider modified natural cycle with enhanced luteal support (HCG + GnRH agonist) if scheduling flexibility exists and patient accepts 21% cancellation risk 4
• Consider scheduled modified natural cycle protocol if scheduling control is needed while maintaining natural cycle approach 5
• Choose artificial cycle if scheduling certainty is essential or patient cannot tolerate multiple monitoring visits 3

For women with irregular cycles or anovulation 2:

• Artificial HT cycle is the only appropriate option 2

Common pitfall to avoid: Do not initiate progesterone in artificial cycles before endometrial thickness reaches ≥7 mm, as premature progesterone exposure may compromise implantation 6, 7