Empty follicle syndrome: the possible cause of occurrence.
A retrospective analysis of EFS was performed at the Royan Institute, Tehran, Iran, between May 2012 and September 2013. All first IVF cycles resulting in EFS during the study period were included. The study was approved by the Ethics Committee of the Royan Institute. Written informed consent was taken from each patient to use the data for future scientific research.
Three different stimulation protocols were mainly used for induction of follicular growth. These were long, antagonist, and miniflare protocols. In the long protocol, the ovary was suppressed with gonadotrophin-releasing hormone analog (GnRH-a) Buserelin (CinnaFact, Laboratory, Cinnagen, Iran) therapy, starting from the mid-luteal phase of the previous menstrual cycles. It was followed by stimulation of the ovary using recombinant follicle-stimulating hormone (rFSH) (Gonal-F; Merk-Sereno, Geneva, Switzerland) or human menopausal gonadotrophin (Menopur; Ferring Pharmaceuticals, Germany), and the follicular growth was monitored by using a transvaginal sonography with an SSD-1000 machine (Aloka, Tokyo, Japan). When the size of the follicle reached 18 mm, recombinant hCG (rhCG) (Ovitrelle; Merck-Serono, Geneva, Switzerland), 250 [micro]g was administered, and follicular puncture was performed after 34-36 hours. In the antagonist protocol, on the second day of the menstrual cycle, two ampules of rFSH or Menopur 150 IU, depending on patient's response, were administered and follicular growth was monitored using transvaginal sonography. Antagonist Cetrorelix (Merk-Sereno, Geneva, Switzerland) 0.25 mg/day was administered when the follicular size was 12 mm. After the follicular size had reached 18 mm, rhCG 250 [micro]g was administered, and follicular puncture was performed after 34-36 hours. In the miniflare protocol, on the second day of menstrual cycle the patient received 0.8 [micro]g Buserelin. On the following day, gonadotropins Gonal-F or Menopur was started. The follicular growth was monitored using transvaginal sonography. When the size of the follicle reached 18mm, rhCG, 250 [micro]g was administered, and follicular puncture was performed 34-36 hours later.
In 3,356 cycles with a follicular puncture, no oocytes were recovered from 58 patients even after extensive flushing. The serum [beta]hCG level of these patients were measured on the day of follicular aspiration. The data, including age, follicle stimulating hormone (FSH) level, anti-Mullerain hormone (AMH) level, the number of ampules, and follicles, and [beta]hCG level at the time of puncture were collected from patients' medical records and analyzed using SPSS Statistics (SPSS Inc., Chicago, US) version 18.0. Appropriate statistical analysis was made by using chi-square or Fisher's exact tests for categorical variables and one-way analysis of variance (ANOVA) for continuous factors. A p-value less than 0.050 was considered statistically significant.
Among the 3,356 cycles performed, 58 (1.7%) women who underwent their first IVF cycle and had no oocyte retrieval were enrolled in the study. Their [beta]hCG level was measured on the puncture day. Ten (17.2%) women showed false type and 48 (82.8%) women showed genuine EFS ([beta]hCG level [greater than or equal to]40 mIU/ ml).
The age of the patients ranged from 21 to 43 years, and their body mass index (BMI) ranged from 22 to 28 kg/[m.sup.2]. Indications of infertility treatment were diminished ovarian reserve 37.9% (n=22), male infertility factor 31.3% (n=18), ovulatory dysfunction 12.0% (n=7), unexplained 8.6% (n=5), endometriosis 5.1% (n=3), and tubal and uterine factors 5.1% (n=3).
The variation of protocols in these patients were approximately the same. According to our analysis, the standard long protocol was applied for 32.7% (n=19) of women, the antagonist for 32.7% (n=19) of women, and the miniflare for 34.5% (n=20) of women.
Patients' characteristics and their clinical information were compared according to the stimulation protocols applied [Table 1 and 2]. Most patients were below the age of 40 years (65.5%). Cycles of empty follicles were observed more in patients with baseline FSH levels below 12 mIU/ mL (74.1%), AMH levels below 1 ng/mL (79.3%) and who had less than four follicles (69.0%). As seen in Table 3, the empty follicle rate was significantly higher in women who received the miniflare protocol than when they received the antagonist or the standard long protocols.
EFS is an infrequent event in assisted reproductive technique (ART) cycles, but the economic consequences and emotional frustration of the syndrome are enormous. (20) The incidence of EFS has been estimated at 0.6-7.0% of ART cycles. (5,6,18) This variation may be due to different inclusion criteria. In some studies, poor responders or patients with premature ovulation were enrolled while in others they were not. (3) In our study, the occurrence of EFS was 1.7%, which was similar to another study that recorded 8,292 IVF cycles (18) and a study by Zreik et al. (20)
The high percentage of empty follicles in the miniflare protocol (12.1%) may depend on ovarian reserve and protocol itself. Our data showed that the incidence of diminished ovarian reserve was more than other causes of infertility (37.9%). The applied stimulation protocol for this type of infertility was either miniflare or antagonist, and our findings revealed that the incidence of empty follicle was more in the miniflare protocol compared to the antagonist protocol. Therefore, the type of protocol may have a role in the occurrence of this syndrome. However, based on the fact that the clinician chooses the stimulation protocols based on age, AMH levels, the number of antral follicles etc, of the patient, (21) it may be more reasonable to conclude that this syndrome could be a manifestation of low ovarian reserve than the GnRH agonist flare protocol. This finding is close to the estimate of some investigators, (3,18,20,22) suggesting that genuine EFS could be a variant form of low ovarian reserve. According to the study by Zreik et al, (20) poor ovarian response was found in 29% of the stimulated cycles. Various authors argue that the EFS phenomenon could be clarified by premature ovulation, low ovarian reserve, or hCG-related errors. (2,13) In diminished ovarian reserve, our data indicated that not only the number of antral follicles decreased, but also that the quality of folliculogenesis was impaired. Therefore, the selection of a stimulation protocol for better oocyte recovery is suggested. This finding is similar to the report by Bustillo, (23) in which he pointed out that the syndrome might be related to underlying ovarian dysfunction resulting in impaired follicular maturation and ovulation. In a study conducted by Zreik, (20) he also maintained ovarian aging, through altered folliculogenesis may be involved in the etiology of this syndrome and its recurrence. Another study indicated the syndrome was related to the underlying cause of the women's unexplained infertility, (1) but our findings showed that only 8.6% of patients with empty follicle had unexplained infertility. Our results also showed that 51.7% of women had AMH levels [less than or equal to]0.5 ng/ mL, whereas 25.9% of women had FSH levels [greater than or equal to]12 IU/mL. This finding may imply the stronger role of AMH than FSH in EFS.
In line with these results, there are still some questions about the existence of genuine EFS. Strong evidence suggests that genuine EFS does exist and it is likely a cause of infertility, including microscopic evidence of genuine EFS with a case of borderline EFS, very few mature or immature oocytes obtained from several mature follicles, and the presence of the genetic basis for EFS. (3,24) On the other hand, other authors denied the existence of genuine EFS because of successful treatment in a recurrent EFS case (25) and by giving reasons that EFS is just a matter of mathematical coincidence. (3,26,27) In aggregate, this study shows that EFS is a misleading term and that its occurrence is associated with either hCG-related errors or low ovarian reserve.
Low serum AMH levels and a small number of follicles after ovarian stimulation is the manifestation of diminished ovarian reserve. Thus, we suggest that EFS could be a manifestation of low ovarian reserve.
Received: 7 June 2015
Accepted: 5 August 2015
The authors declared no conflicts of interest. The authors wish to express their gratitude to Royan Institute for their full support and funding.
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Tahereh Madani * and Nadia Jahangiri
Department of Endocrinology and Female Infertility, Royan Institute for Reproductive Biomedicine, Tehran, Iran
Table 1: Comparison of the patients' characteristics according to the stimulation protocols applied. Variable Long (n = 19) Antagonist (n = 19) Age (years) * < 40 78.9 (15) 57.9 (11) [greater than or 21.1 (4) 42.1 (8) equal to] 40 BMI (kg/[m.sup.2]) ** 24.5 [+ or -] 1.1 26.0 [+ or -] 2.6 Infertility duration ** 7.7 [+ or -] 2.3 8.6 [+ or -] 5.9 Variable Miniflare (n = 20) Total (n = 58) Age (years) * < 40 60.0 (12) 65.5 (38) [greater than or 40.0 (8) 34.5 (20) equal to] 40 BMI (kg/[m.sup.2]) ** 27.6 [+ or -] 5.6 26.2 [+ or -] 3.8 Infertility duration ** 7.6 [+ or -] 6.2 7.9 [+ or -] 5.3 Variable p-value Age (years) * < 40 0.321 [greater than or equal to] 40 BMI (kg/[m.sup.2]) ** 0.322 Infertility duration ** 0.879 * Data presented as percentage (n number). ** Data presented as mean [+ or -] SD. Table 2: Comparison of the patients' clinical information according to the stimulation protocols applied. Variable Long Antagonist Miniflare Total (n = 19) (n = 19) (n = 20) (n = 58) FSH level (IU/mL) < 12 94.7 (18) 63.2 (12) 65.0 (13) 74.1 (43) [greater than or 5.3 (1) 36.8 (7) 35.0 (7) 25.9 (15) equal to] 12 AMH level (ng/mL) [less than or 26.3 (5) 47.4 (9) 80.0 (16) 51.7 (30) equal to] 0.5 0.6-1 42.1 (8) 26.3 (5) 15.0 (3) 27.6 (16) > 1 31.6 (6) 26.3 (5) 5.0 (1) 20.7 (12) Ampules < 44 57.9 (11) 73.7 (14) 65.0 (13) 65.5 (38) [greater than or 42.1 (8) 26.3 (5) 35.0 (7) 34.5 (20) equal to] 44 Follicles < 4 31.6 (6) 84.2 (16) 90.0 (18) 69.0 (40) [greater than or 68.4 (13) 15.8 (3) 10.0 (2) 31.0 (18) equal to] 44 Variable p-value FSH level (IU/mL) < 12 0.043 [greater than or equal to] 12 AMH level (ng/mL) [less than or 0.018 equal to] 0.5 0.6-1 > 1 Ampules < 44 0.591 [greater than or equal to] 44 Follicles < 4 < 0.0001 [greater than or equal to] 44 FSH: follicle stimulating hormone; AMH: anti-Mullerian hormone. Data presented as percentage (n number). Table 3: Comparison of empty follicle rate according to stimulation protocols applied. Protocol Empty follicle rate p-value Long 0.7 (19/2677) Antagonist 3.7 (19/514) Miniflare 12.1 (20/165) < 0.0001 Data presented as percentage (n number).
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|Title Annotation:||ORIGINAL ARTICLE|
|Author:||Madani, Tahereh; Jahangiri, Nadia|
|Publication:||Oman Medical Journal|
|Date:||Nov 1, 2015|
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