empty follicle syndrome

Empty Follicle Syndrome: Types, Causes, Diagnosis & Treatment

A rare condition in which no eggs are retrieved during an IVF procedure. The condition of Empty Follicle Syndrome (EFS) can  be emotionally devastating. This blog aims to provide readers with deeper insights into the intriguing nature of EFS by shedding light on its potential causes through an exploration of various studies conducted thus far.

What Is Empty Follicle Syndrome? 

Empty Follicle Syndrome (EFS) is a rare but significant setback encountered in IVF cycles, characterized by the absence of retrieved eggs despite ovarian stimulation and the trigger injectio for oocyte maturation. 

During follicular development, the oocyte becomes surrounded by cumulus cells that are connected to mural granulosa cells through cell-to-cell junctions, securing the egg within the follicle. The natural LH surge in the middle of the menstrual cycle, which can be replicated by administering HCG or GnRH agonists, triggers the breakdown of these intercellular connections. This allows the cumulus-oocyte complex (COC) to move freely in the follicular fluid, facilitating its retrieval during aspiration. The final step of ovarian stimulation, known as HCG triggering (sometimes replaced by a GRH-analogue to stimulate the endogenous LH peak), is crucial. Without this trigger, the COC cannot detach from the follicle wall and may not be retrieved during aspiration from the follicular fluid.

Types Of Empty Follicle Syndrome

EFS can be categorized into two primary types based on Human Chorionic Gonadotropin (HCG) levels:

  • Genuine Empty Follicle Syndrome: G-EFS occurs when no oocytes are retrieved despite the presence of appropriate levels of serum β-hCG at the time of retrieval. This type suggests a problem other than hCG administration, such as errors in folliculogenesis, premature apoptosis of oocytes, or abnormalities in oocyte maturation. G-EFS cases tend to recur,  and in some cases may have a genetic basis.
  • False Empty Follicle Syndrome: F-EFS occurs when no oocytes are retrieved, and there are undetectable levels of serum β-hCG (human chorionic gonadotropin) on the day of retrieval. It can result from errors in pharmaceutical preparation or administration, provider or patient errors in administering hCG, or other technical issues during the ART procedure. It can also occur after the administrato ofthe gnRH agonist trigger which gives a very small peak in the LH surge or shows no LH surge.

Significance of Empty Follicle Syndrome

Managing patients with EFS is complex due to the unknown cause. With our limited understanding of the underlying mechanisms, it is difficult to predict recurrence or offer definitive treatment options. This lack of clarity can lead to emotional distress for patients and requires supportive counseling.

Despite its rarity, studying and understanding EFS is crucial for improving IVF success rates and for patients to know the possible risks involved. For experts, knowing the causes behind oocyte-follicle wall detachment failure can help them in developing more targeted strategies to optimize oocyte retrieval and minimize the risk of EFS occurrence. This can significantly benefit patients undergoing IVF cycles and their chances of achieving a successful pregnancy.

Read more: IVF Procedure process step by step

How Common Is EFS?

As mentioned earlier, incidents of EFS are quite rare. However, it still is a significant issue. A study conducted from May 2012 to September 2013 found that out of 3,356 cycles, 58 women had EFS, with a prevalence of 1.7%. The findings of this study also suggested that factors associated with EFS included diminished ovarian reserve, low anti-Müllerian hormone (AMH) levels, and fewer than four mature follicles.

Another study conducted by Youssef et al. (2004), analyzing the prevalence of EFS and potential risk factors, examined data from 202 IVF oocyte retrieval procedures performed on 35 patients. They found that EFS occurred in a relatively low percentage of cycles (1.8%). However, the risk of EFS increased significantly with advancing maternal age. Patients over 40 years old had the highest recurrence rate (57%), highlighting age as a potential contributing factor to EFS. This study also acknowledged that the underlying causes of EFS are unclear. However, the findings suggest a possible link between ovarian aging and an increased risk of EFS.

A 2017 study also identified EFS in 0.9% of cycles, highlighting its uncommon occurrence. 

These studies indicate that the prevalence of EFS falls between 0.9% and 1.8% across studies. Age and diminished ovarian reserve appear as potential risk factors based on these findings. 

Potential Causes Of EFS (Empty Follicle Syndrome).

While more research is needed to fully understand the causes of EFS, studies have investigated the prevalence and potential risk factors associated with it in IVF cycles:

  • Premature Luteinization: This theory suggests the follicles mature too rapidly, causing premature luteinization of the theca cells, thereby disrupting the ovulatory signals to the oocytes and may not allow oocyte release at the time of the scheduled retrieval procedure.
  • hCG Administration Issues: Human Chorionic Gonadotropin (hCG) plays a crucial role in oocyte maturation. Improper timing or dosage of hCG administration could potentially contribute to EFS.
  • Technical Limitations During Oocyte Retrieval: In some cases, technical difficulties during the egg retrieval process itself might result in the aspiration of empty follicles.
  • Genuine EFS: This rare form of EFS is characterized by the true absence of oocytes within the follicles. Unfortunately, it often remains undetected until the actual oocyte retrieval attempt.
  • Ovarian Aging: A 2007 study that analyzed data from over 200 cycles and found a higher risk of EFS in women over 40, suggesting a link with ovarian aging.

Thus, the underlying mechanisms of EFS remain unclear, and further research is necessary to establish definitive causes and improve preventative measures.

How to Treat Empty Follicle Syndrome

Traditionally, EPS treatment options have included rescheduling oocyte retrieval, administering additional doses of urinary hCG (u-hCG) from different batches, or using recombinant hCG (rec-hCG). However, these methods may not always be effective, particularly in cases where there is low bioavailability of administered hCG or inherent defects in the biological activity of the hCG batch.

In a case study, a woman experienced EFS despite using hCG (a common trigger for oocyte maturation) in both agonist and antagonist cycles. The study showed success in retrieving oocytes by using GnRH agonist instead of hCG, potentially bypassing limitations associated with hCG. This suggests using GnRH agonist to trigger ovulation as a possible treatment for EFS. However, further research is needed to confirm its wider applicability as this is a single case report. 

Most importantly, to treat EFS, fertility clinics need to provide customized approaches tailored to each individual’s circumstances. These include:

  • Personalized Protocol: Developing a treatment plan that suits the patient’s specific requirements and medical history.
  • Monitoring: Regular monitoring of follicular development and hormone levels to anticipate and address any potential issues.
  • Proficiency in Egg Retrieval: Employing experienced professionals who can perform precise and meticulous egg retrieval procedures to reduce the risk of Empty Follicle Syndrome.

Empty Follicle Syndrome (EFS) Diagnosis

Diagnosing Empty Follicle Syndrome (EFS) can be challenging due to its confirmation often occurring during the oocyte retrieval stage itself. However, some pre-retrieval assessments might offer clues:

  • Hormonal Analysis: Evaluating hormone levels can potentially reveal signs of premature luteinization, a potential indicator of EFS.
  • Follicular Analysis: A detailed examination of follicular growth and maturation patterns can be informative.
  • Review of Stimulation Protocol: A review of the ovarian stimulation protocol used can help identify any potential issues that might contribute to EFS.

It is important to note that these assessments are not definitive for diagnosing EFS but can raise suspicion and guide further management decisions.

What Is The Risk Of Recurrence Of EFS?

A study estimated the risk of recurrence of Empty Follicle Syndrome (EFS) to be approximately 20%. This risk tends to increase with advancing age of the female partner. Therefore, it is crucial for patients who have experienced an EFS cycle to be counseled about the potential for recurrence of this syndrome in subsequent IVF cycles, as well as the associated implications for diminished pregnancy rates. .

The risk of recurrence also increases with age. It is approximately 24% among patients aged 35 to 39 years and notably higher at around 57% for those who are over 40 years old 

Can a Follicle Be Empty?

Yes, it is possible for a follicle to be empty, as seen in Empty Follicle Syndrome. Although this reality may be difficult to accept, it is crucial to understand that with appropriate treatment, conception can be achieved.

Can PCOS Cause Empty Follicles?

One finding showed that polycystic ovary syndrome (PCOS) was more common in patients with EFS (P = 0.041). This suggests that PCOS can cause empty follicles. However, this does not directly imply that PCOS causes empty follicles. 


Empty Follicle Syndrome (EFS) presents a complex challenge in IVF treatment, with potential causes ranging from premature luteinization of the follicles to issues with hCG administration and technical limitations during oocyte retrieval. While the recurrence risk of EFS is notable, doctors need to ensure that they counsel  patients appropriately about personalized treatment options and potential outcomes. 

Ongoing research and advancements in fertility treatments offer hope for improved and positive outcomes for those facing EFS.


Author links open overlay panelAlberto Revelli, review, A. this, Aktas, M., Ben-Shlomo, I., Choi, J., Coulam, C. B., Engmann, L., Franco, J. G., Hassan, H. A., Lorusso, F., Mesen, T. B., Ndukwe, G., Papier, S., Reichman, D. E., Stevenson, T. L., Heusden, A. M. van, Younis, J. S., Asada, Y., Banker, M., … Castillo, J. C. (2017, May 23). Empty follicle syndrome revisited: Definition, incidence, aetiology, early diagnosis and treatment. Reproductive BioMedicine Online. https://www.sciencedirect.com/science/article/abs/pii/S1472648317302389 

Author links open overlay panelTolga B. Mesen M.D. a b, a, b, c, & ObjectiveTo describe the prevalence of “genuine” empty follicle syndrome (EFS) and “false” EFS at assisted reproductive technology (ART).DesignRetrospective cohort.SettingLarge private fertility center.Patient(s)A total of 12. (2011, November 27). The prevalence of genuine empty follicle syndrome. Fertility and Sterility. https://www.sciencedirect.com/science/article/pii/S0015028211026227 

Deepika, K., Rathore, S., Garg, N., & Rao, K. (2015a). Empty follicle syndrome: Successful pregnancy following dual trigger. Journal of human reproductive sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601177/ 

Deepika, K., Rathore, S., Garg, N., & Rao, K. (2015b). Empty follicle syndrome: Successful pregnancy following dual trigger. Journal of human reproductive sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601177/ 

Kim, J. H., & Jee, B. C. (2012, December). Empty follicle syndrome. Clinical and experimental reproductive medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548070 

Vutyavanich, T., Piromlertamorn, W., & Ellis, J. (2010, March 30). Immature oocytes in “apparent empty follicle syndrome”: A case report. Case Reports in Medicine. https://www.hindawi.com/journals/crim/2010/367505/

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