Fertility Specialist Medical Group, San Diego, California, USA
1 To whom correspondence should be addressed at: University of Wisconsin-Madison, Department of Obstetrics and Gynecology, H4/628 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. e-mail: doclalalindheim{at}aol.com
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Abstract |
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Key words: controlled ovarian hyperstimulation/GnRH antagonists/IVF/oocyte donation
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Introduction |
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However, decreases in serum estradiol, pregnancy rate (PR) and implantation rate (IR) have been reported in GnRH antagonist-stimulated cycles (Ganirelix Dose Finding Study Group, 1998; Fauser et al., 1999
; Felberbaum and Diedrich, 1999
), suggesting an adverse effect of GnRH antagonists on either oocyte quality, embryo development or the endometrium. Oocyte donation provides a unique model to eliminate confounding variables that typically occur when comparing groups of patients undergoing IVF. The aim of the present study was to gain further insight and present preliminary results using GnRH antagonists in oocyte donation cycles, and also to assess their impact on clinical outcomes.
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Materials and methods |
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Subjects
Between July 2000 and June 2001, oocyte donors (n = 32) underwent 40 cycles using ovarian hyperstimulation with recombinant FSH (rec-FSH; Follistim; Organon) and GnRH antagonist (Antagon; Organon, Inc., West Orange, NJ, USA). The mean (± SEM) age of all oocyte donors was 27.7 ± 0.7 (range 2136) years. All donors had normal cycle day 23 serum FSH levels (5.0 ± 0.6 mIU/ml) and serum estradiol levels (33.8 ± 2.8 pg/ml). The recipients [n = 31; mean age 43.1 ± 0.7 (range 3654) years] underwent 40 fresh embryo transfer cycles. Severe male factor (<1 x 106 sperm/ml) and hydrosalpinges were excluded from the evaluation, since the latter has been shown previously adversely to affect implantation in donor oocyte cycles (Cohen et al., 1999).
COH protocol
Prior to cycle stimulation, all oocyte donors received 12 months treatment with oral contraceptives (Mircette; Organon, Inc.) for cycle synchronization. Following a withdrawal bleed, ovarian stimulation was started on day 2 with three ampoules per day of rec-FSH for the first 4 days of treatment, and adjusted according to ovarian response. From cycle day 6 of stimulation, daily injection of GnRH antagonist (0.25 mg, s.c.) was added. All cycles were monitored using transvaginal ultrasound and serum estradiol levels, starting on cycle day 5 of stimulation. When three or more follicles reached 1820 mm, hCG was given to trigger ovulation. Transvaginal oocyte aspiration was performed 36 h later, under ultrasound guidance. Recipients were synchronized to an oocyte donor using a regimen of oral micronized estradiol and i.m. progesterone (Sauer et al., 1995).
Following fertilization, embryos were assessed and assigned using a standardized scoring system [cell number x symmetry (symmetric = 3; slightly asymmetric = 2; asymmetric = 1) x fragmentation (<10% = 4; 1020% = 3; 2030% = 2; >30% = 1)]. After 72 h, the embryos were transferred transcervically to the recipients uterus under ultrasound guidance. Pregnancy was confirmed by serial beta-hCG measurement at 9 and 12 days after embryo transfer.
Hormone assays
Serum samples were assayed on cycle day 2 for FSH (DPC, Los Angeles, CA, USA) and estradiol (DPC) using CIA Immulite kits. The intra- and inter-assay coefficients of variation (CV) were 5.4 and 8.1% for FSH, and 6.3 and 6.4% for estradiol.
Statistical analysis
Statistical analyses were performed using the SPSS statistical package. A chi-square and a t-test were used to assess differences between groups, and stepwise logistic regression was used to assess correlations. A P-value < 0.05 was considered statistically significant.
The measured outcomes included dose of gonadotrophins, days of stimulation, serum estradiol levels, number of oocytes, fertilization rate (FR), embryo score, IR and pregnancy rate (PR). Clinical pregnancies were defined as the presence of a fetal heart beat on ultrasonographic examination. Ongoing pregnancies were defined as pregnancies after 12 weeks from the embryo transfer.
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Results |
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Discussion |
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To discern the impact on folliculogenesis and endometrial level is difficult in conventional IVF cycles. However, the ovum donation model allows for the study of isolated parameters that may affect outcome, by standardizing for embryo quality and endometrial receptivity. Overall, in the present study, a decrease in serum estradiol, which was seen in almost one-third of the cycles, resulted in a significant reduction in pregnancy outcome following GnRH antagonist treatment. While these adverse effects were not seen with respect to cycle stimulation or embryo quality, it still suggests an adverse effect of GnRH antagonists on folliculogenesis and embryo development that cannot be seen morphologically. As such, the plateau or decrease in serum estradiol in the late follicular phase of some cycles may be the result of over-suppression of LH by GnRH antagonists that, seemingly, is important in oocyte maturation of somebut curiously not allcycles. The specific role of LH in folliculogenesis and oocyte maturation is unclear. However, it is believed that LH is necessary to stimulate androgen substrate by the theca cells (Adashi, 1996; Gougeon, 1996
) and in the late follicular phase acts in synergy with FSH to support follicular growth (Erickson et al., 1979
). It is possible that the use of gonadotrophins with both LH and FSH preparations would eliminate this effect.
The unpredictable effect of GnRH antagonists is puzzling. Decreases in serum estradiol could not be predicted based on parameters such as age, basal FSH/estradiol, ovarian morphology or cycle day-5 estradiol. Interestingly, eight donors underwent a repeat cycle using the same protocol. Two of these women who had a decrease in serum estradiol following GnRH antagonist treatment in their first cycle resulting in no pregnancies did not show this effect in their second cycle, the results being one spontaneous abortion and one ongoing pregnancy. Three donors who had a normal response in their first cycle that resulted in two ongoing pregnancies, showed a decline in their second cycle that resulted in one spontaneous abortion.
The use of GnRH antagonists has facilitated short and simple treatment, and is particularly attractive for oocyte donors where prolonged pituitary suppression and a risk of OHSS are significant issues. However, such use of GnRH anatagonists has an unpredictable effect on estradiol production during follicular recruitment that appears adversely to affect pregnancy outcome if a decline in serum estradiol occurs. Further study is needed to clarify the effect of GnRH antagonists on serum estradiol, and how this may impact on pregnancy outcomes.
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FOOTNOTES |
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References |
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Cohen, M.A., Lindheim, S.R. and Sauer, M.V. (1999) Hydrosalpinges adversely affects implantation in donor oocyte cycles. Hum. Reprod., 14, 10871089.
Dekel, N., Lewysohn, O., Ayalon, D. and Hazum, E. (1988) Receptors for GnRH are present in rat oocytes. Endocrinology 123, 12051207.[Abstract]
deJong, D., Macklon, N.S., Mannaerts, B.M., Coelingh Bennink, H.J. and Fauser, B.C. (1998) High dose gonadotrophin-releasing hormone antagonist (ganirelix) may prevent ovarian hyperstimulation caused by ovarian stimulation for in-vitro fertilization. Hum. Reprod., 13, 573575.[Abstract]
Emons, G., Schroder, B., Ortmann, O., Westphalen, S., Shulz, K.D. and Schally, A.V. (1993) High affinity binding and direct antiproliferative effects of GnRH analogs in human endometrial cancer cell lines. J. Clin. Endocrinol. Metab., 77, 14581464.[Abstract]
Erickson, G.F., Wang, C. and Hsueh, A.J.W. (1979) FSH induction of functional LH receptors in granulosa cells cultured in a chemically defined medium. Nature, 279, 336338.[ISI][Medline]
Fauser, B.C.J.M., Devroey, P., Yen, S.S., Gosden, R., Crowley, W.F., Jr, Baird, D.T. and Bouchard, P. (1999) Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Hum. Reprod., 14, 28612686.
Felberbaum, R.E. and Diedrich, K. (1999) Ovarian stimulation for IVF/ICSI with gonadotrophins and GnRH analogues: agonist and antagonist. Hum. Reprod., 14 (Suppl. 1), 207221.
Ganirelix Dose Finding Study Group (1998) A double-blind, randomized, dose finding study to assess the efficacy of the GnRH antagonist Ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum. Reprod., 13, 30233031.[Abstract]
Gougeon, A. (1996) Regulation of ovarian follicular growth development in primatesfacts and hypothesis. Endocr. Rev., 17, 121155.[ISI][Medline]
Neveu, S., Hedon, B., Bringer, J., Gilbert, F., Arnal, F., Deschamps, F., Cristol, P., Chabab, A., Diafouka, F. and Mares, P. (1987) Ovarian stimulation by a combination of gonadotropin-releasing hormone agonist and gonadotropins for in vitro fertilization. Fertil. Steril., 47, 639643.[ISI][Medline]
Porter, R.N., Smith, W., Craft, J.L., Abdulwahid, N.A. and Jacobs, H.S. (1984) Induction of ovulation for in-vitro fertilisation using buserelin and gonadotropins. Lancet, 2, 12841285.
Sauer, M.V., Paulson, R.J., Francis, M.M., Macaso, T.M. and Lobo, R.A (1995) Preimplantation adoption: establishing pregnancy using donated oocytes and spermatozoa. Hum. Reprod., 10, 14191422.[Abstract]
The North American Ganirelix Study Group: Fluker, M., Grifo, J., Leader, A., Levy, M., Meldrum, D., Mausher, S.J., Rinehart, J., Rosenwaks, Z., Scott, R.T., Schoolcraft, W. and Shapiro, D.B. (2001) Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertil. Steril., 75, 3845.[CrossRef][ISI][Medline]
Submitted on April 22, 2003; accepted on June 26, 2003.