Interpretation of Empty follicle syndrome

Empty follicle syndrome (EFS) has been defined as a condition in which no oocytes are retrieved from mature ovarian follicles with apparently normal follicular development and estradiol levels, after Controlled ovarian hyper stimulation (COH) for an assisted reproductive technology (ART) cycle, despite repeated aspiration and flushing. No oocytes are retrieved even after many ultrasounds; estradiol levels which show many potential follicles, Empty follicle syndrome are a frustrating situation at times.

It is not uncommon to hear women report that their IVF-egg retrieval yielded far fewer eggs than was expected and that when asking for an explanation they were told by their doctor that many of their follicles were “empty” and contained no eggs. This is at best an oversimplification of a complex situation, or at worst a flagrant misstatement; all follicles by definition must contain eggs.

True, it is not unusual or irregular for egg retrieval to yield a few less eggs than the number of follicles would suggest. However, when less than 50% of follicles >15mm fail to yield eggs, something is wrong. So how and why does it happen?

·         First, The LH surge that precedes spontaneous ovulation and also with the hCG trigger shot given to induce ovulation following the use of fertility drugs, the egg undergoes “ripening” to prepare for fertilization. This involves (among other events) a rapid halving in the number of its chromosomes (meiosis). At the same time, enzymes are released that loosen the cells (cumulus oophorus) that surround and bind the egg to the inner wall of the follicle. This is necessary to enable the egg to come free at ovulation and/or at the time of egg retrieval.

·         The problem is that with poorly developed eggs, the latter mechanism often fails, leaving such eggs tightly “stuck” to the follicle wall and unable to come free, often in spite of vigorous attempts to flush them loose. That is why the more difficult it is to successfully aspirate an egg at egg retrieval, the more likely it is that such an egg is chromosomally abnormal and “incompetent” i.e. incapable of developing into a normal pregnancy. This state of affairs is most commonly encountered in women with diminished ovarian reserve i.e. “poor responders”, women over 40 and in women with polycystic ovarian syndrome who do not receive an optimal protocol of controlled ovarian hyper stimulation.

So the term “Empty Follicle Syndrome” is a misnomer! Yet the circumstances surrounding failure of numerous follicles to yield the eggs they contain at the time of egg retrieval only serves to underscore the need to individualize COH protocols and to time the administration of the “hCG trigger”, precisely.

Risk Factors of Empty follicle syndrome:

·         The risk factor for Empty follicle syndrome increases with age.

·         About 24% of patients between the age of 35 to 39 years of age; 57% for those; 40 years of age.

·         It has also 20% chances of recurrence; the risk of recurrence increases with advancing age of the patient.

Causes of Empty follicle syndrome:

·         Inappropriate timing of hCG

·         PCOS

·         Dysfunctional folliculogenesis, in which oocyte atresia occurs with normal hormonal response

·         Genetic factors

·         Advanced ovarian ageing through altered folliculogenesis

Types of empty follicle syndrome:

Empty follicle syndrome can be classified into 2 types

·         Genuine Empty follicle syndrome (GEFS)

·         False Empty follicle syndrome (FEFS)

1.   Genuine Empty follicle syndrome (GEFS):

Genuine Empty follicle syndrome is defined as failure to retrieve oocytes from mature follicles apparently after Controlled Ovarian stimulation for IVF.

It may be due to dysfunctional folliculogenesis, the oocytes fail to retrieve even with normal follicular development; steroidogenesis in presence of optimal beta human choriogonadotrophin (bhCG) levels on the oocyte retrieval

2.  False Empty follicle syndrome (FEFS):

False Empty follicle syndrome (FEFS) is defined as failure to retrieve oocytes in presence of low beta human choriogonadotrophin hormone (bhCH) level on the day of oocyte retrieval

It is basically due to human errors or pharmaceutical reasons

The egg undergoes “ripening” to prepare for fertilization by LH surge which precedes spontaneous ovulation also hCG; various fertility drugs are given to induce ovulation. Enzymes are released at the same time that loosens the cells (cumulus oophorus) that surround and bind the egg to the inner wall of the follicle. This is necessary to enable the egg to come free at ovulation and/or at the time of egg retrieval. The problem is that with poorly developed eggs, the latter mechanism often fails, leaving such eggs tightly “stuck” to the follicle wall and unable to come free, often in spite of vigorous attempts to flush them loose.

That is why the more difficult it is to successfully aspirate an egg at egg retrieval, the more likely it is that such an egg is chromosomally abnormal and incapable of developing into a normal pregnancy. EFS do not represent a permanent patho-physiological condition and most cases occur only sporadically. The ovarian follicles of patients with so-called EFS may not actually be devoid of viable oocytes. The problem seems to be that of inadequate pre-ovulatory follicular changes arising from either poor bioavailability of LH or hCG or too short an interval between the onset of these changes and follicular aspiration.

EFS do not predict a reduced fertility potential in future cycles. Nevertheless, whatever the cause of EFS, such patients should be counseled regarding its possibility of recurrence and future poor prognosis.

The empty follicle syndrome (EFS) is a frustrating condition in which no oocytes are retrieved in an IVF cycle. Although this is an infrequent event in IVF patients, the economic consequences as well as the emotional frustration of a cancelled cycle due to the inability to obtain oocytes are enormous. The mechanisms responsible for EFS remain obscure, though many hypotheses have been put forward ranging from dysfunctional folliculogenesis to a drug-related problem. We found that the EFS is a rare event (1.8% of oocyte retrievals) but with profound implications for counseling the couple about their future reproductive performance. The chances of recurrence of EFS increase with the age of the patient (24% recurrence rate for the 35–39 year age group, and 57% for those over 40 years). We postulate that ovarian ageing, through altered folliculogenesis, may be implicated in the etiology of EFS and its recurrence.