The genuine empty follicle syndrome: Is the king naked?

10 07 2012

To the Editor:

I read with much interest the manuscript by Mesen et al published recently in Fertility and Sterility (1). The authors’ intention was to retrospectively investigate the prevalence of genuine and false empty follicle syndrome (EFS) in a one single private ART unit. Among a total of 18,294 oocyte retrievals performed in 12,359 women, between 2004 and 2009, 46 cycles failed to recover an oocyte. Thirty five of these cycles had low ovarian response, defined as 14 mm diameter on the day of hCG administration, and were excluded from further evaluation. Of the remaining 11 cycles, two cases of genuine EFS and nine cases of false EFS were identified coming to the conclusion that genuine EFS is a extremely rare occurrence that deserves further investigation to understand ovarian biology and infertility.

Let me first acknowledge the efforts invested in this study evaluating a large cohort of ART cycles, performed in one single center, to gain insight into this enigmatic occurrence. Indeed, since the early days of IVF-ET treatment there has been an ongoing debate between investigators regarding EFS’s mere existence, incidence/prevalence, etiology and pathogenesis (2, 3). Despite its low incidence in the general infertile couples undergoing IVF-ET, EFS development has caused considerable concern to patients and doctors; mainly because of its significant implications when counseling these couples about their future reproductive performance. Furthermore, although the term is considered to be contradictio in terminis, it is still in use in current medical literature.

In their study Mesen et al apparently divided the 46 EFS cycles to genuine and false in accordance with a classification suggested earlier (4,5). While genuine EFS was defined as failure to retrieve oocytes from mature ovarian follicles following ovarian stimulation for IVF after apparently normal follicular development and steroidogenesis in the presence of optimal β-hCG levels on the day of oocyte retrieval, false EFS included all cases in which this definition did not apply (5).

Notably, while the investigators have “rigorously” employed this classification, they have extended the definition of genuine EFS by excluding all women with low ovarian response. Unfortunately, doing that, they have missed to report the β-hCG levels (on the day of retrieval) of the 35 women excluded. Additionally, the EFS recurrence rate and cycle cancellation rate, in previous or subsequent cycles, in these patients as compared to patients with positive oocyte retrievals were not investigated. Of the remaining 11 case in this study, only 2 were identified with genuine EFS. Interestingly, one of these two patients also showed manifestations of low ovarian reserve with an average daily gonadotropin dose of 566 IU.

Taken together, it seems that by extending the definition of the genuine EFS, excluding women with low ovarian response, the authors may have a priori and inadvertently excluded cases that may explain the main etiology of genuine EFS in ART practice today; i.e. ovarian aging. Strict employment of the suggested classification into genuine or false EFS and inclusion of the 35 women into evaluation in such a large cohort of ART cycles may have attributed considerably to the ongoing debate regarding the etiology of such occurrence.

Since the early days of IVF-ET treatment low ovarian response been suggested as a possible etiologic factor of EFS (2, 3). In the last few years, several reports (6-9), including our own (7), are accumulating to suggest that a significant part of the genuine EFS encountered in the ART today is associated with the pathophysiology of ovarian aging.

It is of interest to note that our study (7) was not included in Stevenson and Lashen systemic review (5), albeit serum β-hCG levels performance on the retrieval day. It could be probably assumed that if our study (7) has been included in this review (5) and accurate analysis of the data from Aktas et al study (8) has been performed, the erroneous conclusion reached by the authors (5), negating ovarian aging to be a potential cause of the genuine EFS, could have been altered.

Our study was specifically designed to explore whether genuine EFS could be a manifestation of low ovarian reserve (7). Four hundred thirty nine consecutive IVF cycles, performed in 219 women were retrospectively evaluated and divided into three groups. Study group I included 7 cycles with complete absence of oocytes during retrieval. Study group II included 49 cycles below the 10th percentile of the expected number of oocytes recovered. All other cycles were included in the control group. Our study has shown that women with no oocytes during retrieval and women with less than the 10th percentile of the expected number of oocytes retrieved have clear manifestations of low ovarian reserve. This was evident by increased age, higher day 3 FSH level, lower peak E2 level, elevated gonadotropins requirement and lower number of > 14 mm follicles, in the two study groups as compared to controls. We went further to conclude that genuine EFS does not seem to be a “yes or no” phenomenon but rather a gradual biological occurrence related to the basic pathophysiology of ovarian aging.

It should be emphasized that we do not exclude other rare etiologies of genuine EFS such as those described in Mesen’s report, manifested by the second patient reported (1) or published recently (10). But it is still our believe that the main cause of genuine EFS in modern ART today, where hCG administration strategy is meticulously implemented, seems to be ovarian aging.
Ovarian aging as an etiologic for the genuine EFS may further explain the wide discrepancy reported in the EFS occurrence rate ranging from 0.5-7% (4). Obviously, patient selection is crucial when studying such an occurrence; a public setting may differ from a private one and liberal policy of ART use (such as in Israel) may diverge from its strict employment.

Ovarian reserve assessment in an ART setting has improved considerably in the last few years especially when the target is to evaluate ovarian response to controlled ovarian hyperstimulation. Both anti-Müllerian hormone and antral follicle count have been shown to be reliable, reproducible and to have high prediction potential for ovarian reserve appraisal (11). It is therefore crucial for future studies aiming to gain insight into the etiology and pathophysiology of genuine EFS to include such valuable clinical tests into their patients’ evaluation.

Johnny S. Younis, M.D.
Reproductive Medicine Unit, Department of Obstetrics & Gynecology, Poriya Medical Center, Tiberias, Israel;
Faculty of Medicine, Bar-Ilan University, Galilee, Israel

1. Mesen TB, Yu B, Richter KS, Widra E, DeCherney AH, Segars JH. The prevalence of genuine empty follicle syndrome. Fertil Steril 2011;96:1375–7.

2. Ben-Shlomo K, Schiff E, Levran D, Ben Rafael Z, Mashiach S, Dor J. Failure of oocyte retrieval during in vitro fertilization: a sporadic event rather than a syndrome. Fertil Steril 1991;53:324–7.

3. Zreik TG, Gracia-Velasco JA, Vergara TM, Arici A, Olive D, Jones EE. Empty follicle syndrome: evidence for recurrence. Hum Reprod 2000;15:999–1002.

4. Bustillo M. Unsuccessful oocyte retrieval: technical artifact or genuine ‘‘empty follicle syndrome.’’ Reprod Biomed Online 2004;8:59–67.

5. Stevenson TL, Lashen H. Empty follicle syndrome: the reality of a controversial syndrome, a systemic review. Fertil Steril 2008;90:691–7.

6. Lorusso F, Depalo R, Tsadilas S, Caradonna F, Di Gilio A, Capotorto MT, Vacca M, Nappi L, Selvaggi L.Is the occurrence of the empty follicle syndrome a predictor that a subsequent stimulated cycle will be an unfavorable one? Reprod Biomed Online 2005;10:571–4.

7. Younis JS, Skournik A, Radin O, Haddad S, Bar-Ami S, Ben-Ami M. Poor oocyte retrieval is a manifestation of low ovarian reserve. Fertil Steril 2005;83:504–7.

8. Aktas M, Beckers N, Van Inzem WG, Verhoeff A, de Jong D. Oocytes in the empty follicle: a controversial syndrome. Fertil Steril 2005;8:1643–8.

9. Baum M, Machtinger R, Yerushalmi GM, Maman E, Seidman DS, Dor J, Hourvitz A. Recurrence of empty follicle syndrome with stimulated IVF cycles. Gynecol Endocrinol 2012;28:293–5.

10. Yariz KO, Walsh T, Uzak A, Spiliopoulos M, Duman D, Onalan G, King MC, Tekin M. Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome. Fertil Steril. 2011;96:e125-30.

11. Younis JS. Ovarian aging: latest thoughts on assessment and management Curr Opin Obstet Gynecol. 2011;23:427-34.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.07.1098

The Authors Respond:

We appreciate the interest by Dr. Younis in our recent manuscript (1) investigating the prevalence of empty follicle syndrome (EFS). The existence of genuine EFS has been a controversial topic since the term was first introduced by Coulam et al. in the 1980s (2). Based on current terminology, EFS has been defined as “false” (failure to administer hCG) and “genuine” (hCG is detectable). We agree with the general thrust of the comments by Dr. Younis, which are that in most cases that occur clinically (3), diminished ovarian reserve (DOR) may explain what is generally called “genuine” EFS. That is, with very few mature oocytes, there may be a mechanical failure which is stochastic, and this is often observed to be the case (4). Further, in such cases, a repeat cycle may yield oocytes. We agree with the suggestion that it would have been helpful to know if the presented cases had undergone previous retrieval. We do not have those data. Based on antral follicle counts, our two patients did not have DOR. Instead, we hypothesize that there are cases of EFS where there is a profound defect that effectively prohibits oocyte recovery, whether because of follicle maturation defect in collagenases, signal transduction in the follicle, or because of failure of oocyte maturation proper.

While we agree with the common prevalence of DOR, our interest was, and remains, those cases where repeat retrieval is highly unlikely to be of benefit. Specifically, we are interested in EFS cases where DOR is not a consideration, but for which a genetic condition is likely. We, like others, have observed repeated failure to retrieve oocytes where more than 20 follicles were present—indicating a profound defect in oocyte/follicle maturation. That was the focus of our manuscript, and was why we specifically excluded the patients for whom DOR might have contributed to the situation at hand. Stated differently, we are most interested in defining genetic causes, such as sequencing of the Turkish sisters with presumed genuine EFS, originally described by Onalan et al. in 2003 (5) and was later attributed to an autosomal recessive mutation of the luteinizing hormone/choriogonodotropin receptor (6). This case documents a profound genetic cause of EFS that is not DOR-related (6). This case, to our thinking, indicates the king is not naked! That is, EFS is a syndrome that, in very rare cases, has a distinct cause; within the EFS phenotype there is a subset of patients with a distinct molecular disorder that results in empty follicle disease!

We appreciate, as documented by Younis (2), that DOR is perhaps the most likely clinically encountered situation. However, it seems that our disagreements are principally semantic and relate to the inadequate terminology that is in use for EFS. To that end, we suggest the following terminology:

1. False EFS (no hCG is given or detectable). The likelihood of repeat is low.

2. EFS with positive hCG likely due to DOR. The possibility for recovery of oocytes is reasonable for a repeated cycle (formerly “genuine” EFS). This is often encountered clinically.

3. EFS with positive hCG not likely due to DOR (formerly “genuine” EFS).The possibility for recovery of oocytes is uncertain, since some of these patients will have a defect in genes or products that are essential for oocyte retrieval. Such cases are rare, as we have documented. The causes of this syndrome may be defined with further study.

4. EF disease where a distinct etiology has been established (6). Clinically, there may be phenotypic variation in severity, which will depend upon etiology. We further suspect that there may be several distinct causes of EF disease, since several genes in animals cause the phenotype and there is a cascade of events that is required for proper release of oocytes in natural conception and at ART.

Again, we greatly appreciate the dialog regarding this rare, but important, syndrome and disease. We hope these comments will help clarify the confusion that has haunted this rare condition. Our hope is that further analysis of EF disease, although extremely rare, will help evolve the understanding of female reproduction and in turn improve patient care.

Tolga Berlo Mesen, M.D.a,b, James H. Segars, M.D.a
aNational Institute of Child Health and Human Development, Program in Reproductive and Adult
Endocrinology, Bethesda, Maryland
bDepartment of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, North Carolina

1. Mesen TB, Yu B, Richter KS, Widra E, DeCherney AH, Segars JH. The prevalence of genuine empty follicle syndrome. Fertil Steril 2011;96:1375–7.

2. Coulam CB, Bustillo M, Schulman JD. Empty follicle syndrome. Fertil Steril 1986;46:1153–5.

3. Younis JS, Skournik A, Radin O, Haddad S, Bar-Ami S, Ben-Ami M. Poor oocyte retrieval is a manifestation of low ovarian reserve. Fertil Steril. 2005;83:504-7.

4. Van Heusden AM, van Santbrink EJ, de Jong D. The empty follicle syndrome is dead! Fertil Steril 2008;89:746.

5. Onalan G, Pabuçcu R, Onalan R, Ceylaner S, Selam B. Empty follicle syndrome in two sisters with three cycles: case report. Hum Reprod 2003;18:1864–7.

6. Yariz KO, Walsh T, Uzak A, Spiliopoulos M, Duman D, Onalan G, King MC, Tekin M. Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome. Fertil Steril. 2011;96:e125-30.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.07.1099




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