Genuine Empty Follicle Syndrome: Role of Double Trigger and Delayed Oocyte Retrieval (DTDO)
Empty follicle syndrome (EFS) can be classified as either genuine EFS (GEFS) or false EFS (FEFS), occurring in 33% and 67% of EFS cases respectively.
Genuine EFS is defined as the failure to retrieve any oocytes following ovarian stimulation with an ideal post-trigger increase in beta-hCG (human chorionic gonadotrophin) or LH (luteinizing hormone) levels. Conversely false EFS is defined as the failure to retrieve any oocytes following ovarian stimulation and low post-trigger beta-hCG or LH levels.
Genuine EFS can happen as a result of dysfunctional folliculogenesis, failure of cumulus cell complex to detach from the follicular wall or faulty aspiration technique. On the other hand false EFS is likely a result of incorrect drug administration, drug manufacturer defect or low bioavailability of trigger shot.
A number of different strategies have been proposed previously to overcome EFS including the administration of GnRHa (gonadotropin-releasing hormone agonist) and hCG trigger shot, at 40 and 34 hours respectively, prior to oocyte retrieval however there is no further evidence supporting this strategy.
The idea behind this strategy is that the addition of a GnRHa trigger causes a FSH surge, followed by the hCG triggered LH surge, which better mimics the natural cycle and therefore may be a viable treatment option for genuine EFS.
To evaluate if in vivo exposure of oocytes to trigger agents GnRHa and hCG at 40 hours and 36 hours, respectively, could correct GEFS, retrieve more mature oocytes and improve pregnancy outcomes in patients with a history of GEFS.
A retrospective observational study was conducted of anonymized treatment records from a tertiary fertility center.
In total 7238 cycles were analysed to identify patients < 40 years old for GEFS in previous IVF cycles, followed by a double trigger and delayed oocyte retrieval (DTDO) ICSI cycle using GnRHa and hCG. Only cycles within 12 months of each other were included in the study while FEFS was ruled out by post-trigger beta-hCG or LH levels.
Ovarian stimulation was carried out using the flexible antagonist protocol starting on day 2 or 3 of the menstrual cycle. Initial gonadotrophin dose was set according to age, antral follicle count, AMH, BMI and previous response which was then adjusted follicular growth and estradiol levels. GnRH antagonist was started once the leading follicle reached 14µm in size (or estradiol ≥ 600pg/ml). Finally, once 2 or more follicles were ≥ 18µm in size, both trigger shots were administered in hospital at the correct time by a trained nurse to minimise potential errors.
Oocyte retrieval was then carried out 36 hours post hCG trigger as per standard procedure on all patients. Similarly, ICSI technique, embryo culture and transfer technique were all standardized to minimize potential bias in the results. A freeze all strategy for day 3 embryos was employed in all cycles.
Hormone replacement therapy was then used for endometrial preparation beginning on day 2 or 3 of the menstrual cycle until endometrial thickness reached 8mm at which time luteal phase support (progesterone plus estradiol) was started. Embryo transfer was then performed on day 4 on luteal phase support with the transfer of two day 3 embryos. Luteal phase support was finally ceased in week 10 following a positive beta-hCG.
Clinical pregnancy was confirmed by transvaginal ultrasound in week 4 or 5, while a live birth after 24 weeks gestation defined the live birth rate. Similarly, miscarriage was defined as the loss of a viable foetus before week 21.
Statistical analysis was restricted to only the first frozen embryo transfer (FET) cycle in each patient to minimise further bias.
In total 13 women were identified with GEFS who met the inclusion exclusion criteria. Mean age was 31 with a BMI of 25kg/m2, AMH = 3.1ng/ml and 5.41 years mean duration of infertility. Baseline characteristics of the group did not differ between the non-DTDO and DTDO cycles, with no significant differences seen in their response to stimulation.
Interestingly unlike the non-DTDO cycle where no oocytes were retrieved, 12 out of 13 (92.3%) women successfully retrieved oocytes following their first DTDO cycle. The mean number of mature (metaphase II) oocytes retrieved was 11.4, of which 9.9 were successfully fertilised. By the end of day 3 culturing 11 out of 13 women had good quality embryos available for transfer, with a mean of 9.3 embryos per patient.
Of these 11 women, 9 continued with embryo transfer resulting in 55.6% (5/9) positive beta-hCG, 44.4% (4/9) clinical pregnancy rate, 44.4% (4/9) live birth rate and 11.1% (1/9) biochemical pregnancy (miscarriage) in their first FET cycle.
Finally, there was no reports of premature ovulation, ovarian hyperstimulation syndrome or other complications using this treatment strategy.
SUMMARY: Empty follicle syndrome treatment
In women with genuine empty follicle syndrome (EFS), the use of a double trigger & delayed oocyte retrieval (DTDO) protocol successfully treated EFS in 92.3% of cases, with a mean of 11.4 ±5.0 mature oocytes retrieved per patient and 9.3 ±2.6 good quality embryos available for transfer after day 3.
- Observational study design.
- Small study size.
- No unique control group with participating women being their historical control.
No external funding was declared for this study.
The action of drawing.
Cluster of cells surrounding the oocyte during folliculogenesis.
A drug or substance that has an effect on the immune system.
A medical test or experiment that is done on a whole living organism.
Second half of the menstrual cycle, from ovulation to the start of menstruation.
Unfertilised immature / mature egg.
Song J and Sun Z, (2019). A borderline form of empty follicle syndrome treated with a double-trigger of gonadotropin-releasing hormone agonist and human chorionic gonadotropin: A case report. https://doi.org/10.1097/md.0000000000016213
Punhani R, et al. (2016). Empty follicle syndrome: Case series and review of literature. https://doi.org/10.4103/2348-2907.192287
Deepika K, et al. (2015). Empty follicle syndrome: Successful pregnancy following dual trigger. https://doi.org/10.4103/0974-1208.165152
Beck-Fruchter R, et al. (2012). Empty follicle syndrome: successful treatment in a recurrent case and review of the literature. https://doi.org/10.1093/humrep/des037
Peñarrubia J, et al. (1999). Recurrent empty follicle syndrome successfully treated with recombinant human chorionic gonadotrophin. https://doi.org/10.1093/humrep/14.7.1703
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