Empty Follicle Syndrome

The Empty Follicle Syndrome (EFS) is a frustrating condition in which no oocytes (eggs) are retrieved at IVF, even though ultrasound and estradiol measurements showed the presence of many potential follicles. The mechanism responsible for EFS remains obscure. Many hypotheses have been put forward, but none truly explain this syndrome. The most likely cause of EFS is ovarian ageing, as many patients who suffer from EFS are also poor responders. If an EFS cycle does occur during your treatment, please make sure you discuss it thoroughly with your fertility physician. EFS is an infrequent event and has been estimated to occur in between 2 - 7% of IVF cycles. However, the overall risk of recurrence in later IVF cycles is 20% and the risk of recurrence is higher as the age of the patient increases.

To date, Empty Follicle Syndrome (EFS) has only been reported in GnRH agonist down-regulated IVF cycles. Some cases have been successfully treated by changing the batch, or by repeating the dose of hCG. A case of EFS was reported recently on PubMed in both GnRH antagonist and GnRH agonist down-regulated IVF cycles when final oocyte maturation was triggered using urinary hCG (u-hCG). Failure to retrieve oocytes occurred, despite administration of a further dose of u-hCG from a different batch and a delayed repeated oocyte recovery performed in the second GnRH agonist down-regulated cycle. A successful oocyte recovery cycle was achieved after triggering of an endogenous gonadotrophin surge using GnRH agonist in an antagonist down-regulated cycle. Nine oocytes were readily retrieved from 10 follicles, at 36 h after GnRH agonist administration, and eight of these fertilized normally. Two good quality embryos were used for fresh transfer and four were cryopreserved for future use. The authors concluded that EFS can occur in GnRH antagonist down-regulated IVF cycles, and can be successfully treated by triggering a natural gonadotrophin surge using GnRH agonist in the absence of any response to previous treatment methods. This represents a novel therapeutic modality for this uncommon but frustrating condition.

Another paper reports experience with three IVF cycles in which no oocytes were collected. In all cases, an additional IVF cycle was performed. The ovarian stimulation protocol, ultrasound and hormonal surveillance methods, human chorionic gonadotrophin timing and oocyte retrieval technique were similar in all patients. The assessment of additional cycles demonstrated a poor response in terms of oocyte quality, since the number of mature oocytes was low despite the high number of oocytes collected. Thus, the data suggest that in these patients, EFS should be considered as a borderline form of poor response to ovarian stimulation. If this is confirmed, EFS should be a recurrent event and an empty cycle could be a good predictor that a subsequent stimulated cycle will be an unfavourable.

A group from UK recently reported five cases in which no oocytes were retrieved after standard ovarian stimulation for in-vitro fertilization (IVF), and in which it was found that mistakes had been made at the time of human chorionic gonadotrophin (HCG) administration. In all five cases, oocyte retrieval was achieved after injecting HCG, when necessary, and reprogramming aspiration 24–36 h later. A mean of 7 ± 3.2 MII oocytes were recovered per patient and 3.2 ± 0.8 embryos were transferred. Three clinical pregnancies were obtained, and four healthy infants were born. In their program, these were the only cases of empty follicle syndrome (EFS) that appeared over a total of 1118 cycles, and were all explained by human error in the administration of HCG. Our experience too shows that human error could be considered a significant factor in the aetiology of empty follicle syndrome, and that EFS may be in part avoided by taking simple preventive measures.

A novel method of rescuing empty follicle syndrome (EFS) was recently published and provides evidence that it is a drug-related problem rather than a clinical dysfunction. In a preliminary study the authors from UK established that in EFS the serum beta-human chorionic gonadotrophin (beta-HCG) concentrations 36 h after HCG administration never exceeded 10 mIU/ ml. beta-HCG concentrations were thus used to confirm EFS when oocytes were not retrieved from one ovary after controlled ovarian hyperstimulation. The procedure was suspended leaving intact all follicles in the second, ovary. After confirmation of EFS, a second HCG from a different batch was administered and 36 h later mature oocytes were retrieved from the intact ovary, suggesting a fault with the HCG previously administered. Three patients have been treated in this way. In the first case, four out of five mature eggs were fertilized after intracytoplasmic sperm injection (ICSI) resulting in the transfer of three top grade (grade 1) embryos. In the second case all seven mature oocytes fertilized after in-vitro fertilization (IVF) and three grade 1 embryos were transferred resulting in a twin pregnancy, now delivered. In the third case, five out of nine oocytes were fertilized after ICSI and one out of the three treated with high insemination concentration IVF fertilized, resulting in the transfer of three ICSI embryos.

We suspected hCG batch-to-batch consistency a couple of times with our own cases, but could never confirm the above. Would love other clinics to post their experiences here.