What is the recurrence risk of empty follicle syndrome after a progesterone‑primed ovarian stimulation (PPOS) cycle and what management should be recommended for the next cycle?

Empty Follicle Syndrome After PPOS: Recurrence Risk and Next Cycle Management

For a patient who experienced empty follicle syndrome (EFS) during a PPOS protocol, the recurrence risk is approximately 16%, and the next cycle should use a GnRH agonist trigger instead of hCG to induce final oocyte maturation, with consideration of switching to a GnRH antagonist protocol. 1, 2, 3

Understanding the Recurrence Risk

The recurrence rate of EFS in subsequent IVF cycles is 15.8% based on analysis of 163 EFS cases among 8,292 IVF cycles 3. This means that while EFS is typically a sporadic event, approximately 1 in 6 patients will experience it again 3.

Key risk factors that predict higher recurrence include:

• Advanced maternal age (mean 37.7 years in EFS cases versus 34.2 years in successful retrievals) 3
• Elevated baseline FSH levels (8.7 IU/L versus 6.7 IU/L in controls) 3
• Low estradiol levels before trigger (499.9 pg/mL versus 1516.3 pg/mL in successful cycles) 3
• Diminished ovarian reserve with AMH ≤0.5 ng/mL 4
• Fewer than 4 mature follicles after stimulation 4

The underlying mechanism likely represents dysfunctional folliculogenesis with early oocyte atresia despite apparently normal hormonal response, or may be a variant form of poor ovarian response 5, 3.

Specific Protocol Modifications for Next Cycle

Primary Recommendation: Change the Trigger Method

Switch from hCG trigger to GnRH agonist trigger for final oocyte maturation 1, 2. This is the most critical intervention based on successful case reports:

• Administer GnRH agonist (such as triptorelin 0.2 mg or leuprolide 1-2 mg) 40 hours before scheduled oocyte retrieval 1
• Consider adding hCG 6 hours after the GnRH agonist as a dual trigger approach 1
• This triggers an endogenous LH surge rather than relying on exogenous hCG, which may be the key to successful oocyte retrieval in recurrent EFS 2

Secondary Recommendation: Protocol Selection

Use a GnRH antagonist protocol rather than agonist down-regulation 2. The rationale is:

• EFS has been successfully treated by triggering endogenous gonadotrophin surge using GnRH agonist in an antagonist down-regulated cycle 2
• This allows flexibility to use GnRH agonist as the trigger while maintaining pituitary responsiveness 2
• One case report demonstrated successful retrieval of 9 oocytes from 10 follicles using this approach after multiple failed cycles 2

Avoid Common Pitfalls

Do not simply repeat the same protocol with different hCG batches 2. While some cases of "false EFS" respond to changing hCG batches, true recurrent EFS requires fundamental protocol changes 2, 5.

Do not delay oocyte retrieval beyond 36-40 hours after trigger 1, 2. The timing window is critical for successful retrieval with GnRH agonist trigger.

Counseling and Expectations

Patients with recurrent EFS should be counseled that:

• This may represent a variant of diminished ovarian reserve rather than a purely technical problem 4, 3
• Even with protocol modifications, success is not guaranteed, and some patients may require multiple attempts 1
• The condition cannot be predicted by ultrasound or hormonal monitoring alone, making diagnosis retrospective 5
• If EFS recurs despite protocol changes, consideration should be given to donor oocytes or alternative family-building options 3

Monitoring During Next Cycle

Specific parameters to track:

• Baseline AMH and FSH levels to assess ovarian reserve 4, 3
• Estradiol levels on trigger day (target >1000 pg/mL if possible) 3
• Number of follicles ≥14mm (aim for at least 4-5 mature follicles) 4
• Consider measuring LH levels after GnRH agonist trigger to confirm endogenous surge 2