What is Empty Follicle Syndrome and ways to prevent it.

By MD, PhD, MSc (gynecologist), BSc, MSc (psychologist), BSc, MSc (embryologin) and MD (gynecologist).
Last Update: 10/19/2021

Empty Follicle Syndrome (EFS) occurs when no eggs are retrieved after follicular puncture. This alteration occurs in a small percentage of women who are stimulated for an assisted reproduction treatment and no eggs are found when the follicles are aspirated.

This syndrome was first described in 1986 by Coulam, and has been known to exist ever since. However, the causes that result in the empty follicle syndrome are unknown.

In this article, we'll see what characterizes EFS and how to detect it, as well as the possible treatments or solutions that exist for this syndrome.

Empty Follicle Syndrome

During the ovarian puncture, the gynecologist aspirates the follicles in order to extract the eggs and later retrieve them in the laboratory. However, in patients with EFS, the egg fails to detach from the follicle wall and is not retrieved.

EFS is undetectable during ovarian stimulation, as it is characterized by good follicular growth throughout the monitoring phase and adequate blood estradiol levels. Therefore, this syndrome does not present any symptoms until the time of puncture.

The causes of EFS can be classified into two main groups according to their origin: due to a failure in the administration of the treatment medication or due to intrinsic patient causes.

False Empty Follicle Syndrome

False EFS is due to errors or abnormalities in the medications administered for ovarian stimulation.

When the follicles have reached an optimal diameter during the stimulation phase, the woman is prepared for the puncture. For this purpose, the woman is administered hCG, also known as trigger, which promotes:

  • Maturation of the egg, necessary so that the fertilization of the egg is possible.
  • The release of the egg from the follicule wall, as it produces changes in the structure of the connective tissue that makes it more loose.
  • Ovulation, which is the release of the egg into the female reproductive tract, it usually occurs about 40 hours after the triggeradministration. However, this event is not desirable and is to be avoided at all costs.

This is why the programming of the puncture is attempted 36 hours after the injection when it's estimated that the egg has matured, but ovulation has not occurred yet.

Errors in time, day, or type of administration of the trigger can cause problems with the necessary time (35-36 hours) for the maturation of the eggs, and therefore, eggs would not be obtained in the ovarian puncture. Misadministration of this drug may also result in insufficient hormone levels to trigger egg maturation.

Other possible errors that could lead to Empty Follicle Syndrome are abnormalities in the trigger medication itself, since it may be outdated or have a decreased effectivity, so it would produce less effect in the patient's body because its depleted active ingredient.

True Empty Follicle Syndrome

True Empty Follicle Syndrome is when the stimulation protocol and trigger administration, follicular growth, and estradiol levels have performed correctly throughout the cycle, yet no eggs have been retrieved from the follicles absorbed by an ovarian puncture.

Another characteristic that makes us think that we are dealing with a case of true EFS is that patients usually continue to respond in the same way in subsequent cycles.

Although the cause that provokes this syndrome in patients is unknown, it has been observed that it affects more frequently women over 40 years old, with low ovarian reserve or obesity. Therefore, this alteration has been related to the aging of the ovaries and a malfunction in the growth and maturation of the follicles.

Another possible cause that could be related to EVS can be explained by genetic alterations that could predispose to this syndrome. This would explain the cases of Empty Follicle Syndrome in young people who do not present alterations in hormonal metabolism or other causes that could predispose them to EFS.

Treatment for Empty Follicle Syndrome

Many studies have highlighted this problem as well as the economic expense and moral burden EFS entails in assisted reproduction treatments.

Luckily, it is a rare event that occurs in only 0.5% to 7% of stimulated assisted reproduction treatments.

Those patients with false EFS due to errors in trigger administration will be able to:

  • Determine the hCG levels in the blood to know if they are correct or if a new hCG injection is needed.
  • Repeat the puncture if hCG administration has been within the last 36 hours.
  • Attempt a new cycle of ovarian stimulation, taking extreme precautions in the administration of medication and aspirating the follicles twice in the puncture.

However, only true EFS reaches 1% of these cases and its prognosis is bleak. This is why many clinics prefer to offer the patient an ovodonation cycle as an alternative option after the impossibility of retrieving mature eggs during several stimulation cycles.

IVF with donor eggs is probably the most confusing of all fertility treatments, and oftentimes, a misleading one. Transparency is one of our strict selection criteria when it comes to recommending fertility clinics to our readers. You can create your Fertility Report now to filter clinics based on our selection criteria and get an individual report based on your preferences with answers to your queries and most importantly, to prevent potential frauds.

Other studies have proposed in vitro oocyte maturation (IVM) as an alternative for these patients, since it does not require trigger injection. In this study, 7 women with at least 3 cycles of conventional IVF where no mature eggs were retrieved were analyzed. All of them underwent IVM and 2 women achieved successful pregnancies.

Despite this isolated article that promises to be hopeful for patients with EFS, it should be noted that IVM is an underused technique and its usefulness is not reliable yet. This is because the success rates obtained by this technique are low. This is why very few clinics offer this treatment to their patients.

FAQs from users

Why can an empty puncture occur?

By Blanca Paraíso MD, PhD, MSc (gynecologist).

An empty puncture is a situation in which no oocytes are retrieved during an ovarian punction even though there is a correct growth in the follicles. When we encounter this situation we refer to it as Empty Follicle Syndrome.

Some studies show this can occur in up to 7% of patients that undergo IVF, even though the vast majority of cases can be explained by problems in the hormonal treatment (incorrect administration, outdated HCG...). It is estimated that True Empty Follicle Syndrome is only present in 0.02% of patients.

The causes for this Syndrome are unknown but it is thought that alterations in the folliculogenesis (formation of the follicles and ovules) could be the main cause. These alterations can be caused by advanced maternal age, bad ovarian quality, or genetic factors.

This could cause:

  • An early degeneration of the oocytes explaining the lack of them in the punction.
  • Lack of detachment of the oocyte from the follicle wall. During ovulation, the luteinizing hormone triggers a series of mechanisms that imply the softening of the follicle´s adhesive tissue, allowing the oocyte to detach from the follicle wall.

Another suggestion we can find is the repetition of the cycle with recombinant hCG, luteinizing hormone, or the trigger of ovulation with the liberation of an agonist of the gonadotropin hormone. If after all of these suggestions the problem persists, ovodonation could be an option.

What is Empty Follicle Syndrome due to?

By Dra. Rut Gómez de Segura MD (gynecologist).

We refer to Empty Follicle Syndrome (EFS) when the patient is administered correctly the last dose of stimulation and no oocytes are found after the puncture. The lack of physiological response to this last injection is unknown. This lack of reaction can be seen more frequently in women 40 or older, with low ovarian reserve or obesity.

In response to this problem, specialists advise starting a new treatment with a different stimulation protocol or suggest ovodonation in more severe cases.
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Can my Assisted Reproduction cycle be ruined if I don´t inject hCG at the indicated time?

By Laura Parra Villar BSc, MSc (embryologin).

Yes, the success of the assisted reproduction treatment can be compromised if the injection of hCG is administered the wrong way or at the wrong time.

This injection is the last one before the ovarian puncture and is administered, 36 hours before the punction. Its administration promotes a high peak in the LH hormone that helps the oocytes mature and release 38 - 40 hours after its administration, the release is undesirable and must be prevented.

An error in the time of the administration can prevent the oocytes to be retrieved, this can be caused by a False Empty Follicle Syndrome or that the patient has already ovulated.

What alternatives exist for patients with True Empty Follicle Syndrome?

By Laura Parra Villar BSc, MSc (embryologin).

If after a couple of ovarian stimulation syndrome cycles no oocytes are retrieved and the patient is given the diagnosis of True Empty Follicle Syndrome, the first option fertility clinics suggest is ovodonation.

Another suggested technique consists of the maturation of the oocytes in vitro, but this technique is hardly used in fertility clinics.

What are the symptoms of Empty Follicle Syndrome?

By Laura Parra Villar BSc, MSc (embryologin).

Empty Follicle Syndrome (EFS) has no symptoms. Therefore it´s frustrating for specialists as well as for patients, as EFS is not diagnosed during the ovarian stimulation phase, it can only be diagnosed after performing the ovarian puncture and not obtaining any oocytes.

However, a series of measures can be taken into account to prevent this in recurring patients: making sure the patient has understood the hormonal treatment administration instructions, increase the dose of hCG, change the stimulation protocols, or suction repeatedly the same follicle.

As stated above, there are many stimulation protocols that doctors use in their treatments. The physician's role is to study the patient and assign an appropriate stimulation protocol based on her clinical history. If you are about to start an assisted reproduction treatment with ovarian stimulation and want to know more about this procedure, you can continue reading our article: Ovarian Stimulation Protocols for IVF - Process & Medications Used

Another problem that assisted reproduction experts often encounter in infertility centers is a poor response to hormone treatments. If the stimulation produces few or poor-quality eggs, it can be an impediment to the success of the treatment. This situation occurs more frequently in older women who have delayed childbearing. We recommend the article: Ovarian Stimulation Protocols for IVF - Process & Medications Used, if you want to learn more about this topic.

Our editors have made great efforts to create this content for you. By sharing this post, you are helping us to keep ourselves motivated to work even harder.

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FAQs from users: 'Why can an empty puncture occur?', 'What is Empty Follicle Syndrome due to?', 'Can my Assisted Reproduction cycle be ruined if I don´t inject hCG at the indicated time?', 'What alternatives exist for patients with True Empty Follicle Syndrome?' and 'What are the symptoms of Empty Follicle Syndrome?'.

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Authors and contributors

 Blanca Paraíso
Blanca Paraíso
MD, PhD, MSc
Gynecologist
Bachelor's Degree in Medicine and Ph.D from the Complutense University of Madrid (UCM). Postgraduate Course in Statistics of Health Sciences. Doctor specialized in Obstetrics & Gynecology, and Assisted Procreation. More information about Blanca Paraíso
License: 454505579
 Cristina  Algarra Goosman
Cristina Algarra Goosman
BSc, MSc
Psychologist
Graduated in Psychology by the University of Valencia (UV) and specialized in Clinical Psychology by the European University Center and specific training in Infertility: Legal, Medical and Psychosocial Aspects by University of Valencia (UV) and ADEIT.
More information about Cristina Algarra Goosman
Member number: CV16874
 Laura Parra Villar
Laura Parra Villar
BSc, MSc
Embryologin
Graduate in Biology from the University of Valencia (UV) and embryologist with a Master's degree in Biotechnology of Human Reproduction from the University of Valencia in collaboration with the Valencian Institute of Infertility (IVI). More information about Laura Parra Villar
Licence number: 3325-CV
Dra. Rut Gómez de Segura
Dra. Rut Gómez de Segura
MD
Gynecologist
Graduation in Medicine and Surgery from the University of Alcalá de Henares. Specialization in Obstetrics and Gynecology at the Hospital Costa del Sol in Marbella. Dr Rut Gómez de Segura currently works as medical director in the fertility center ProcreaTec in Madrid. More information about Dra. Rut Gómez de Segura
Licence number: 28/2908776

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