What is Empty Follicle Syndrome?

How common is empty follicle syndrome?

Let’s look at the stats on this one. As per studies, the incidence of empty follicle syndrome stands at about 0.045-3.45% of cases. 

But here’s the thing we need to talk about. The stats also differ based on whether it’s false or genuine empty follicle syndrome.

And when you really look at it, the incidence of genuine empty follicle syndrome stands at 0.016%. Which, in simple terms, is very rare.

What are the causes of empty follicle syndrome?

The primary cause behind empty follicle syndrome depends on whether it's false EFS or genuine EFS.

In fact, let’s get into the differences between false EFS and genuine EFS and what causes them.

False empty follicle syndrome

This occurs when there’s a failure to retrieve eggs during the egg collection procedure.  due to low beta HcG levels or circulating LH levels within the body. A very rare cause is also technical errors caused during egg retrieval. In this case, we usually get no eggs or eggs that have undergone cell death. 

Here’s a better understanding of these scenarios: 

Cause 1: If hCG trigger was injected late or incorrectly 

If the hCG trigger was injected late or incorrectly, this can lead to false empty follicle syndrome. 

Usually on the day of egg retrieval, the levels of beta hCG are detected via serum HcG levels. If the hCG trigger was injected late, or incorrectly, it can lead to low levels of hCG before your egg retrieval, and thus lead to cases of false empty follicle syndrome. 

Now, what do these levels have to do with egg retrieval, you ask? Let’s nerd out the reason 🤓

The right levels of beta hCG are crucial because they help eggs detach from the follicular wall and float in the follicular fluid, making them accessible enough to be aspirated from the ovaries. 

And without the right levels, this doesn’t happen, making it harder for the egg and its surrounding cells to detach from the follicular wall.

Infact, some studies even mention how a beta hCG level of >40IU/L is needed for this process to occur. 

In some cases, if the hCG trigger was injected right, its effect can be impaired if the timing of the egg collection surgery doesn’t match the ovulation timing:

• The egg retrieval is carried out too early (before 34 hours from the injection, where the eggs may not have detached from the follicular wall)
• The egg retrieval is carried out too late (after 38 hours from the injection, where the biggest follicles may have spontaneously ovulated)

Cause 2: Technical errors during egg collection

There are chances of technical errors, such as defects with the aspiration system (the vacuum system used to retrieve eggs) or mistakes made by the operator (such as incomplete aspiration of follicles by inexperienced physicians or doctors). 

However, the chances of these occurring are very rare as clinics do rigorous checks on the equipment and have trained doctors and physicians on site at all times.

📚Also read: Things to know before choosing a fertility clinic 

Genuine empty follicle syndrome

This is a rare condition where no eggs are retrieved during the egg collection procedure despite administering hCG trigger the right way. While research is ongoing, it is understood that genetic factors are the main underlying cause for genuine EFS. 

Cause 1: Genetic factors

To date, genetic factors have been known to be the main cause behind genuine EFS. These genetic factors affect specific developmental processes or affect the action of hormones in the body, leading to genuine EFS.  

• It was found in a study that patients with genuine EFS had an increased expression of some genes in their follicles which affected normal growth and development of the follicle (👀 and this, in turn, affects the growth of the egg too!)
• Studies also found a mutation in the gene coding for the LH (Leutinizing hormone) or hCG receptor, causing a block in the pathway of LH signal (this is basically why even when the trigger is administered right, it fails to work on patients with genuine EFS 🤯)
• Some patients may have a slower response to hCG, needing more time for follicular maturation and a delayed egg collection procedure 
• Mutations in the outer layer of the egg, the zona pellucida have also been associated with genuine EFS. Mutations in ZP1 or ZP3 proteins usually lead to collapsed or degenerated eggs being retrieved

How to Treat Empty Follicle Syndrome?

The treatment for empty follicle syndrome comes down to its type and your medical history:

Treatment for False Empty Follicle Syndrome 

• In cases where the hCG trigger is the issue, a second, rescue dose of the trigger is provided and a second egg retrieval is done
• On the clinic’s end- making sure that the equipment for egg retrieval is error-free and carrying out a urinary or blood hCG test on the day of retrieval check for incorrect hCG administration

Treatment for Genuine Empty Follicle Syndrome 

Although a bit tougher than treating the false type, this condition usually requires a closer look at existing protocols, the chance of genetic variants and alternatives as well, if needed.

• You may be asked to repeat the cycle with a different batch of hCG, recombinant HCG, or recombinant LH - which could lead to gentler stimulation
• Instead of hCG, your doctor could use GnRH agonist as the trigger for ovulation in an antagonist cycle. This helps induce an endogenous LH surge, avoiding slow or delayed responses to hCG
• In cases where no other options work, you may be provided the choice to go with donor eggs

How to prevent empty follicle syndrome?

Empty follicle syndrome usually goes undetected during ovarian stimulation, mainly as the follicles seem normal in growth and development, and there are no prominent symptoms either. 

But there are some precautions that you and your healthcare provider can take when risk factors are present:

• Medical history: Revisit your medical history for any family history of EFS and make sure to let your heathcare provider know
• Correct hCG Administration: Make sure that you have the right dosage and instructions for injecting hCG. Errors in administration can lead to false EFS, and re-administration of hCG from a different batch can be effective.
• Delayed Oocyte Retrieval: Ensure that you communicate any details that may delay the procedure with your clinic, and try avoiding any such delays as well. In cases of unavoidable delay, you may be asked to undergo a second egg retrieval. 
• Monitoring hCG Levels: Measuring serum beta-hCG levels 36 hours post-hCG administration can help predict EFS and guide timely interventions.

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Frequently Asked Questions

1. Why would follicles be empty?

Empty follicle syndrome occurs when no eggs are retrieved during an IVF or egg-freezing cycle, despite seemingly normal follicular development. The main causes include premature ovulation before retrieval, genetic factors affecting egg development, or issues with the ovulation trigger shot (like improper timing or administration). 

2. Can you get pregnant with empty follicle syndrome?

Yes, pregnancy is possible with empty follicle syndrome, but it depends on the type. If it's "false" empty follicle syndrome (related to trigger shot issues), changing protocols in subsequent cycles often leads to successful egg retrieval. With "true" empty follicle syndrome, pregnancy is a bit challenging as the causes are mostly genetic, but it is still possible through options like donor eggs or embryo adoption.

3. How rare is empty follicle syndrome?

Empty follicle syndrome is quite rare, affecting approximately 0.045-3.45% of cases.  IVF cycles. The "true" form is even rarer, with estimates suggesting it affects less than 0.016% of all cases

4. Are there any symptoms of empty follicle syndrome?

There are typically no noticeable symptoms of empty follicle syndrome. It's usually diagnosed only during the egg retrieval procedure when no eggs are collected despite normal hormone levels and follicle growth on ultrasound. There are no physical symptoms that would alert someone to this condition before attempting an IVF cycle or egg freezing.