1 Assisted Conception Unit, Tree Root Walk, Sheffield and 2 Obstetrics and Gynaecology, University of Sheffield, Sheffield, UK
3 To whom correspondence should be addressed at: Assisted Conception Unit, Level 1 Jessop Wing, Tree Root Walk,Sheffield S10 2SF, UK. e-mail: dflok@yahoo.com
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Abstract |
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Key words: empty follicle syndrome/GnRH agonist/GnRH antagonist/IVF/oocyte retrieval
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Introduction |
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Methods and Results |
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The first cycle was carried out with a GnRH antagonist down-regulated cycle using ganirelix (Orgalutran®; Organon, UK). Ovarian stimulation was carried out starting on menstrual cycle day 2 with 200 IU of recombinant FSH (rec-FSH) (Puregon®; Organon, UK). Cycle monitoring was carried out using both ultrasound scanning and LH and estradiol (E2) assays. The GnRH antagonist was administered on cycle day 6 (when the serum E2 level was 1000 pmol/l) and continued until the day of hCG administration. Final oocyte maturation was triggered by administering 10 000 IU u-hCG (Pregnyl®; Organon, UK) at 35 h prior to oocyte retrieval. The criteria for administering hCG were the presence of a lead follicle
18 mm and at least two more follicles measuring
16 mm. Oocyte retrieval was carried out using ultrasound-guided transvaginal needle aspiration while the patient was receiving sedation and analgesia.
No oocytes were recovered from a total of 15 follicles, even after extensive flushing. No cumulus mass or immature oocytes were seen, and few granulosa cells were identified upon analysis of the aspirates and flushes. The serum level of hCG measured on the day of follicular aspiration was 548 IU/l, confirming correct dose administration by the patient.
The second IVF cycle was performed 5 months later using a long GnRH agonist down-regulation protocol. Pituitary down-regulation was achieved using GnRH agonist (buserelin; Suprefact®; Shire Pharmaceuticals Ltd, UK) (0.5 mg daily, s.c.) which was started at the mid-luteal phase of the cycle preceding the stimulation cycle and continued until the day of hCG administration. Upon confirmation of adequate down-regulation (endometrium <5 mm thickness and inactive ovaries), rec-FSH 200 IU was given daily for ovarian stimulation. The final oocyte maturation and oocyte retrieval were carried out as described above.
No oocytes or cumulus cells, and few granulosa cells were detected in the follicular fluid collected from the left ovary. Serum hCG and progesterone levels were found to be 199 IU/l and 13.2 nmol/l respectively. The procedure was abandoned and a further 5000 IU u-hCG from a different batch was administered. The second oocyte retrieval was performed 24 h later, and no oocytes were obtained. Serum hCG and progesterone levels of 300 IU/l and 30.5 nmol/l respectively were recorded on the day of the second oocyte retrieval.
In the third cycle, a GnRH antagonist protocol was used as described for the first cycle. However, final oocyte maturation was triggered using 200 µg buserelin s.c., instead of u-hCG. Serum LH and progesterone levels, measured at 24 h after buserelin injection, were 91.1 IU/l and 21.6 pmol/l respectively. When follicular aspiration was conducted 36 h later, nine metaphase II oocytes were retrieved from nine follicles. Eight of the nine oocytes fertilized normally at 20 h post insemination. Two 7-cell embryos were transferred at 72 h after oocyte collection using a Sydney IVF catheter (Cook Ireland Ltd, Ireland), and four embryos were considered of sufficiently high quality to be cryopreserved.
Vaginally administered progesterone (200 mg) pessaries (Cyclogest®; Shire Pharmaceuticals Ltd) were used for luteal phase support. No pregnancy was achieved in that cycle, and the patient is currently being followed up for a frozen embryo replacement cycle.
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Discussion |
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In this case report, the serum levels of hCG and progesterone were confirmatory of the correct timing and doses of hCG administered. As there were no published reports on the occurrence of EFS with the GnRH antagonist protocol, the present authors resorted to the use of a more familiar long GnRH agonist down-regulation protocol in the second cycle of treatment. However, in this second cycle no oocytes were retrieved at 35 h after triggering with 1000U u-hCG from a different batch. The incidence of occurrence of EFS in two successive cycles is not known, especially in a patient with a history of three spontaneous pregnancies.
It has been suggested that some patients may need a longer exposure to hCG in order for their cumulusoocyte complex (COC) to detach from the follicular wall (Hassan et al., 1998), and especially in those patients where GnRH agonist and gonadotrophin are used in combination (Tarlatzis, 1992
). Indeed, oocytes could be recovered when retrievals were repeated 24 h after the first failed recovery in the presence of both normal serum hCG and progesterone (Ubaldi et al., 1997
; Hassan et al., 1998
). Nonetheless, the repeated failure despite a 24-h delay and further dose of u-hCG in the presence of luteinization suggested a problem which was specific to COC detachment. As this patient had conceived previously on three occasions, spontaneous ovulation must have occurred, thereby excluding the presence of an intrinsic defect in the LH receptor or ovulation.
Despite the recent report of successful oocyte retrieval using rec-hCG in a similar case (Peñarrubia et al., 1999), there is a lack of theoretical rationale to explain how this approach would work differently with the already proven bioavailability of u-hCG administered. The utilization of endogenous ovulatory gonadotrophin surges (as proven effective from the patients history) using either a natural cycle IVF or a stimulatory cycle that allows for a natural LH surge, was seen as a more logical approach. Triggering an endogenous gonadotrophin surge has become a possibility with the introduction of the antagonist regime into IVF programmes. GnRH antagonists provide an immediate, but reversible, inhibition of a premature LH surge. The inhibitory effect on gonadotrophin release can be competitively overridden by exogenous administration of either GnRH or a GnRH agonist. The substitution of u-hCG administration by a single dose of GnRH agonist for triggering ovulation has been used successfully in IVF cycles for patients at high risk of developing ovarian hyperstimulation syndrome (Itskoitz-Eldor et al., 1993
).
The present case is the first to be reported of EFS in an antagonist IVF cycle, in which u-hCG failed to trigger ovulatory changes permitting successful recovery of oocytes using both agonist and antagonist protocols. It is also the first case whereby GnRH agonist was used to trigger ovulation instead of the traditional hCG for the treatment of EFS, thereby adding a new management option to this uncommon yet distressing and challenging condition.
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References |
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Ben-Shlomo, I., Schiff, E., Levran, D., Ben-Rafael, Z., Mashiach, S. and Dor, J. (1991) Failure of oocyte retrieval during in vitro fertilization: a sporadic event rather than a syndrome. Fertil. Steril., 55, 324327.[ISI][Medline]
Coulam, C., Bustillo, M. and Schulman, J. (1986) Empty follicle syndrome. Fertil. Steril., 46, 11531155.[ISI][Medline]
Hassan, H.A., Saleh, H.A., Khalil, O., Baghdady, I. and Ismaiel, I. (1998) Double oocyte aspiration may be a solution for empty follicle syndrome: case report. Fertil. Steril., 69, 138139.[CrossRef][ISI][Medline]
Itskoitz-Eldor, J., Levron, J. and Kol, S. (1993) Use of gonadotrophin releasing hormone agonist to cause ovulation and prevent the ovarian hyperstimulation syndrome. Clin. Obstet. Gynecol., 36, 701710.[ISI][Medline]
Meniru, G.I. and Craft, I.L. (1997) Evidence from a salvaged treatment cycle supports an aetiology for the empty follicle syndrome that is related to terminal follicular developmental events. Hum. Reprod., 12, 23852387.[Abstract]
Ndukwe, G., Thornton, S., Fishel, S., Dowell, K., Aloum, M. and Green, S. (1997) Curing empty follicle syndrome. Hum. Reprod., 12, 2123[Medline]
Papier, S., Lipowicz, R., De Vincentiis, S., Nodar, F., Olmedo, S.B. and Acosta, A. (2000) Pregnancy obtained by the transfer of frozen-thawed embryos originating from a rescued empty follicle syndrome cycle. Fertil. Steril., 74, 603604.[CrossRef][ISI][Medline]
Peñarrubia, J., Balasch, J., Fábregues, F., Creus, M., Cívico, S. and Vanrell, J.A. (1999) Recurrent empty follicle syndrome successfully treated with recombinant human chorionic gonadotrophin: case report. Hum. Reprod., 14, 17031706.
Quintans, C.J., Donaldson, M.J., Blanco, L.A. and Pasqualini, R.S. (1998) Empty follicle syndrome due to human errors: its occurrence in an in-vitro fertilization programme. Hum. Reprod., 13, 27032705.
Tarlatzis, B.C. (1992) Oocyte collection and quality. Assist. Reprod. Rev., 2, 16.
Ubaldi, F., Nagy, Z., Janssenwillen, C., Smitz, J., Van Steirteghem, A. and Devroey, P. (1997) Ovulation by repeated human chorionic gonadotrophin in empty follicle syndrome yields a twin clinical pregnancy. Hum. Reprod., 12, 454456.[ISI][Medline]
Zegers-Hochschild, F., Fernandez, E., Mackenna, A., Fabres, C., Altieri, E. and Lopez, T. (1995) The empty follicle syndrome: a pharmaceutical industry syndrome. Hum. Reprod., 10, 22622265.[Abstract]
Submitted on April 29, 2003; accepted on July 7, 2002.