What is the role of Gonadotropin-releasing hormone (GnRH) agonist in luteal support during Frozen Embryo Transfer (FET) cycles?

GnRH Agonist in Luteal Support for FET Cycles

GnRH agonist administration during luteal support in hormone replacement therapy (HRT)-FET cycles significantly improves clinical pregnancy and live birth rates, but its benefit in natural cycle FET remains unproven.

Evidence-Based Recommendations by FET Protocol Type

HRT-FET Cycles (Strongest Evidence)

• Administer GnRH agonist (triptorelin 0.1 mg) as adjunctive luteal support in HRT-FET cycles 1, 2
• The most effective protocol involves triptorelin administration on days 0,3, and 6 after embryo transfer, combined with standard progesterone supplementation 2
• This approach increases clinical pregnancy rates by 47% (58.0% vs 48.4%, p=0.003) and live birth rates by 33% (52.7% vs 45.6%, p=0.001) compared to progesterone alone 1
• Clinical pregnancy rates improve from 42% to 65.5% (p=0.013) when GnRH agonist is added to standard luteal support 3

Natural Cycle FET

• Do not routinely add GnRH agonist to luteal support in natural cycle FET 1, 4
• No significant improvement in clinical pregnancy rates (58.2% vs 52.9%, p=0.364) or live birth rates (54.4% vs 47.0%, p=0.211) has been demonstrated 1
• A single dose of triptorelin 0.1 mg at implantation time showed no benefit (clinical pregnancy 26% vs 21%, p=0.40) 4

Stimulated FET Cycles

• Evidence is insufficient to recommend routine GnRH agonist use in stimulated FET cycles 1
• No statistically significant differences in pregnancy outcomes have been demonstrated 1

Practical Implementation Protocol

For HRT-FET Cycles (Recommended Approach)

Timing and Dosing:

• Begin standard HRT protocol with estradiol valerate 6 mg daily from cycle day 2 5
• Add vaginal progesterone 400 mg twice daily when endometrium reaches adequate thickness 5, 2
• Administer triptorelin 0.1 mg subcutaneously on the day of transfer (day 0), then repeat on days 3 and 6 post-transfer 2

Alternative Protocol (Also Effective):

• Administer triptorelin 3-4 times during the early luteal phase, starting at the initial stage of luteal support 1
• This provides flexibility in timing while maintaining efficacy 1

Luteal Support Duration

• Continue progesterone and estrogen at original doses for 3-4 weeks after pregnancy confirmation 5
• Gradually reduce dosage over 2 weeks before complete discontinuation 5
• In natural or stimulated cycles, continue luteal support for 1-3 weeks after ultrasound confirmation of viable intrauterine pregnancy 5

Mechanism and Rationale

Why GnRH Agonist Works in HRT-FET:

• HRT-FET cycles lack endogenous LH support for corpus luteum function 1
• GnRH agonist triggers endogenous LH surge, supporting early luteal phase and implantation 6
• Improves implantation rates (44.1% vs 21.1%, p=0.002) through enhanced endometrial receptivity 3

Why It Fails in Natural Cycles:

• Natural cycles already have adequate endogenous LH and corpus luteum function 4
• Additional GnRH agonist provides no incremental benefit when physiologic luteal support exists 1, 4

Critical Caveats and Pitfalls

Common Errors to Avoid

• Do not use GnRH agonist as sole luteal support - it must be combined with progesterone supplementation 2
• Do not apply HRT-FET protocols to natural cycle FET - the evidence does not support this extrapolation 1, 4
• Do not administer single-dose GnRH agonist - multiple doses (days 0,3,6) are required for efficacy 2

Safety Considerations

• GnRH agonist use in luteal support does not increase OHSS risk when used post-transfer 6
• No significant increase in spontaneous abortion rates has been reported 2
• The protocol is well-tolerated with minimal side effects 2

When to Avoid

• Natural cycle FET with confirmed ovulation and adequate progesterone levels 1, 4
• Patients with contraindications to GnRH agonist therapy 5
• When cost-effectiveness is a primary concern in natural cycle FET where benefit is unproven 4

Quality of Evidence Assessment

The recommendation for HRT-FET is based on recent (2024) retrospective analysis of 3,515 cycles 1 and supported by randomized controlled trials 2. The evidence against use in natural cycles comes from prospective RCTs showing no benefit 4. This creates a clear algorithmic approach: use GnRH agonist in HRT-FET, avoid in natural cycle FET 1, 4, 2.