Empty Follicle Syndrome (EFS) is defined as the inability to aspirate oocytes from the follicles despite repeated washings despite normal follicle development after controlled ovarian stimulation.
Case 1
Couple with a 3-year history of infertility due to polycystic ovary syndrome (female 28 years old). When they could not get pregnant with other treatments, IVF treatment was recommended to the couple. First, suppression was applied with a long protocol. Then, the ovaries were stimulated using 150 units of recombinant gonadotropin per day for 12 days. On the day of hCG injection, there were nine follicles over 16 mm in diameter, and the largest was 20 mm. The patient was told to inject 10,000 units of intramuscular hCG, and 36 hours later, egg retrieval was performed by vaginal ultrasound. Despite repeated washings, no eggs were found in the aspiration.
Case 2
A couple (female 34 years old) with a 5-year history of infertility due to tubal factors. This couple had previously undergone 3 IVF cycles in different IVF centres. Still, no eggs could be collected despite the development of follicles.
Case 3
A couple with a 4-year history of infertility due to tubal factor (female 24 years old). Double IVF treatment was recommended. First, suppression was applied with the long protocol. Then the ovaries were stimulated using 150 units of recombinant gonadotropin per day for 11 days. On the day of the hCG injection, there were 13 follicles with a diameter of 16 mm (6 in the right ovary and 7 in the left ovary). The patient was told to inject 10.000 units of hCG intramuscularly, and egg retrieval was performed 36 hours later. All follicles in the right ovary were aspirated, but no oocytes were found despite repeated washings.
Basic Information
Empty Follicle Syndrome (EFS) is the inability to aspirate oocytes from the follicles despite repeated washings and normal follicle development after controlled ovarian stimulation. This situation occurs in 0.5-2% of all IVF cycles. Although EFS is usually an independent case, recurrent cases have also been reported. Human Chorionic Gonadotropin (hCG) is administered in IVF instead of LH secretion. This has two important effects on the process that develops inside the follicle before ovulation. hCG triggers the continuation of meiosis and maturation of the oocyte. An equally important function is facilitating the separation of the oocyte-cumulus complex from the follicle wall by softening the connective tissue. The oocyte-cumulus mass usually falls into the follicular fluid and is aspirated during egg retrieval. If hCG cannot fulfil this function for any reason, the oocyte-cumulus complex continues to adhere tightly to the follicle wall and is not found in the aspirated follicular fluid. In general, this is the underlying pathophysiology of EFS. In most cases, this is due to either the biological deficiency of hCG or the insufficient biological activity of the hCG present.
Incorrect timing of hCG or rapid hepatic excretion due to desialylation of administered hCG has also been shown as a possible cause. Dysfunctional folliculogenesis, especially in women with advanced ovarian ageing, biological anomalies in mature oocytes despite adequate hCG, and genetic factors have also been suggested as possible etiological causes.
Solution Alternatives
- Ensuring that the hCG to be administered is stored in the right conditions, administered in the right dose and at the right time: The first thing to do in Case 1 is to check the serial number of the hCG to determine whether it is stored correctly and whether it is administered at the right dose and time.
- Measurement of hCG in urine: HCG measurement can be done with a sensitive pregnancy test. In case of a negative result, this may be due to biological deficiencies, not administering the drug or an error in the storage conditions of the drug used. In Case 2, three cycles that resulted in EFS were performed in different IVF centres, so it is important to investigate what has happened in the past by looking at the clinical notes on these cycles and to determine if any other tests have been performed.
- Recovering during egg collection: At this stage, it is important that EFS is known to both the IVF specialist and the embryologist and that these two specialists communicate during the procedure and make sure that at least one oocyte is collected from the ovary where the procedure was performed before proceeding to the second ovary. An inconclusive manifestation of EFS is very sparse granulous cells in the aspirated follicular fluid. Suppose all follicles in one ovary have been aspirated, but no oocyte has been collected (as in Case 3). In that case, a solution should be to apply a sensitive urine pregnancy test without aspiration from the other ovary. While the patient is still under sedation or general anaesthesia, a urine sample can be taken from the bladder with the aid of a catheter, and measurement can be made in just two minutes with a standard pregnancy test. Suppose the result of the pregnancy test is negative. In that case, egg collection should be stopped as a precaution, and it should be planned to repeat the egg collection after 36 hours by administering 10,000 units of hCG from a different batch. Most urine pregnancy tests are sensitive enough to measure even the hCG level in the amount of 25-50 mIU/ml. The level formed after the subcutaneous injection of 10,000 units of hCG is 348.6+-98 mIU/ml in both blood and urine. The same amount is compared with sub-muscular injection. Then 259.0+-115 mIU/ml was reported.
Consultancy
Counselling to be given to the patient in the case of EFS is also important. It should be explained to the patient that EFS does not imply a low probability of pregnancy for subsequent IVF cycles. In particular, the possibility of recurrence of the double situation in Case 1 should be mentioned. It should be explained that there are some methods to prevent recurrent cases and what these methods are. The couple in Case 2 should be told that oocyte donation may be the best solution if EFS continues to recur.
In case 3, giving the couple proper counselling before repeating the hCG injection and oocyte retrieval is very important. Cases of pregnancy have been reported from both fresh and frozen embryos after inhibition of EFS during oocyte retrieval, as described above. However, none of the seven salvaged EFS cycles performed in a series of case studies in 2010 resulted in pregnancy. Therefore, it should be explained to the patient that this chance is very low, although there is a chance of success in such cases.
Prevention
A recommended method is to measure the hCG level in the blood 12 hours after injection. A level above 50 mIU/ml will suffice. However, if it is below this level or does not appear in the blood, the dose, timing and storage conditions should be checked. If necessary, another dose of hCG injection from a new batch should be administered. The oocyte retrieval time should be re-determined accordingly. Whether this practice will be done regularly in each IVF cycle or only in cases with a history of EFS is a decision for IVF centres.
In the case of EFS, if the hCG in the blood is below ten mIU/ml at the time of oocyte retrieval and the dose, timing and storage conditions of hCG are found to be suitable, then hCG from another batch should be administered in the next IVF cycle.
Suppose the hCG in the blood is normal. In that case, the bioactivity of the administered hCG is a more likely problem, as there will be no biological deficiency. Successful switching from urine-derived hCG to recombinant hCG has also been reported in cases of EFS where other methods have failed. It is conceivable that there are some slight isometric differences between the two.
Another method is to use the GnRH antagonists protocol and trigger endogenous LH secretion with a GnRH agonist. In some cases, endogenous LH secretion may be more effective than hCG in triggering the last pre-ovulation process.
Summary
Problem
Inability to aspirate oocyte despite repeated washings from ‘mature’ follicles after hCG injection, although it was determined that there was sufficient response to controlled ovarian stimulation in IVF, according to ultrasound and hormone results.
Basic Knowledge
- Occurs in 0.5-2% of IVF cycles,
- Retrospective diagnosis,
- Mainly independent cases, but recurrent cases have also been reported.
Solution Alternatives
- Be aware that EFS is a recoverable state.
- If oocyte cannot be collected from one ovary, hCG should be checked in the urine, and if it is not found in the urine, oocyte collection should be planned after re-administration of hCG, and eggs should be collected from the other ovary.
- If there is a biological deficiency of hCG, hCG from a different series should be administered, or a different type of hCG should be used.
- If the hCG level in the blood is normal, a different type of hCG should be used, or a GnRH agonist should be used to trigger endogenous LH secretion by switching to an antagonist protocol.
Prevention
- hCG must be stored in the right conditions,
- Make sure that the correct dose and timing are made,
- 12 hours after hCG administration, hCG should be checked in the blood.
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REFERENCES:
https://pubmed.ncbi.nlm.nih.gov/25769434/
https://pubmed.ncbi.nlm.nih.gov/23768623/
https://pubmed.ncbi.nlm.nih.gov/26986742/
