Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial

Mehmet A. Akman, Halit F. Erden, Suleyman B. Tosun, Numan Bayazit, Esra Aksoy and Mustafa Bahceci,

IVF Unit, German Hospital, Istanbul, Turkey


    Abstract
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 Abstract
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 Materials and methods
 Results
 Discussion
 References
 
The management of poor responders in IVF has always been a big problem. The ideal approach has yet to be formulated. In this study we aim to compare two alternative stimulation protocols. A total of 48 poor responder patients described from previous cycles were included and grouped into two: group I consisted of 24 patients in 24 cycles in which leuprolide acetate (40 µg s.c. per day) was initiated on cycle day 2 followed by exogenous gonadotrophins on cycle day 3; group II consisted of 24 patients in 24 cycles in which ovarian stimulation included gonadotrophin-releasing hormone (GnRH) antagonist (cetrorelix, 0.25 mg daily during late follicular phase) administration. While only the oestradiol concentrations on the day of HCG were lower in group II compared with group I, the clinical pregnancy and implantation rates among groups did not show any significance. The impact of these two regimens in ovarian stimulation of poor responders seem to be same and to establish these results further randomized studies with larger sample sizes are required.

Key words: cetrorelix/GnRH antagonist/IVF embryo transfer/microdose GnRH agonist flare-up/poor responders


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In IVF, the management of poor responders referred to ovarian stimulation protocols is a problem. As women are delaying childbearing, the number of patients referred to IVF centres has tended to increase. Older patients present a poor response in ovarian stimulation, with prolonged duration and also increased cost of treatment.

There have been various reports to formulate the ideal stimulation protocol for these patients. It has been documented that cycle cancellation is common for this particular group of patients, mostly due to premature LH surges. To overcome the extra suppression while preventing the premature LH surges, various researchers have advocated decreasing the dosage and the timing of gonadotrophin-releasing hormone (GnRH) agonists, such as in microdose GnRH agonist flare-up regimens (Scott and Navot, 1994Go; Schoolcraft et al., 1997Go; Surrey et al., 1998Go). The recent introduction of GnRH antagonists into clinical practice might be a new hope for the poor responder patients (Craft et al., 1999Go). Their addition to ovarian stimulation during late follicular phase will prevent the premature LH surges while not causing any suppression in the early follicular phase which is a critical period for those patients with decreased ovarian reserves.

In this study we aim to compare the efficacy of these two alternative strategies, namely microdose flare-up regimen and ovarian stimulation with GnRH antagonist addition in poor responder patients undergoing IVF.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 48 poor responder patients who underwent IVF–embryo transfer cycles was included in the study population. Determination of poor response was a clinical judgement, including at least two failed IVF attempts due to one of the following reasons: baseline follicle stimulating hormone (FSH) concentrations >15 mIU/ml (conversion factor to SI unit 1.00) or oestradiol concentration on the day of human chorionic gonadotrophin (HCG) injection <500 pg/ml or the number of mature oocytes retrieved less than four. Follicle stimulating hormone was measured by a standard commercial kit produced by Abbott Laboratories (Abbott Park, IL, USA).

This study was approved by the Ethics Committee of the German Hospital and informed consent was obtained from all patients before entry in the study. The demographic data are shown in Table IGo.


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Table I. Demographic data and cycle characteristics with pregnancy outcome
 
While azoospermic patients were excluded, micromanipulation including intracytoplasmic sperm injection and assisted hatching was performed in all cycles.

The patients were prospectively randomized into two groups: group I consisted of 24 patients in 24 cycles in which low dose oral contraceptive (Desolett®; Organon, Oss, The Netherlands) started on cycle day 1 of the previous cycle for 21 days. On the second day of menstruation leuprolide acetate (Lucrin®; Abbott, Cedex, France) (40 µg s.c. per day) was initiated on cycle day 2 followed by exogenous gonadotrophins administered on cycle day 3; group II consisted of 24 patients in 24 cycles in which exogenous gonadotrophins were started on day 2 and later 0.25 mg of cetrorelix (Cetrotide®; Asta Medica, Frankfurt, Germany) was administered daily when the leading follicle reached 14 mm in diameter until the HCG injection.

All patients in each group received 300 IU of pure FSH (pFSH) (Metrodin HP®; Serono Laboratories, Aubonne, Switzerland) together with 300 IU of human menopausal gonadotrophin (HMG) (Humegon®; Organon Laboratories) daily for 4 days. While HMG dose remained constant until the injection of HCG, pFSH dose was adjusted individually according to the response of the ovaries and the oestradiol concentrations. Once the follicles reached 16 mm in greatest diameter, when the oestradiol concentrations showed a decline or plateau, the LH surge was detected, measuring blood concentrations three times daily: when LH was >10 mIU/ml and progesterone concentration was >1 ng/ml, the LH surge was established and cycles were cancelled accordingly.

A total of 10 000 units of HCG were administered i.m. when the leading follicle reached 17–18 mm in diameter followed 35 h later by an ultrasound-guided transvaginal oocyte retrieval. While all the embryos were transferred on day 3 after oocyte collection, patients received supplemental progesterone in oil in a dose of 100 mg daily, started on the day of oocyte collection throughout the luteal phase. Clinical pregnancy was established when there were gestational sacs seen on ultrasonography. As the parameters were not normally distributed, we performed Mann–Whitney U-test and {chi}2-test where applicable. P < 0.05 was considered significant.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient and cycle characteristics are shown in Table IGo. The median ages and duration of infertility were not different between groups. While the baseline FSH concentrations, the median number of pure FSH and HMG ampoules consumed, the median number of follicles grown and oocytes aspirated were not different, the oestradiol concentrations on the day of HCG in group I were significantly higher compared with group II. Comparison of the rate of the mature ones and subsequently the fertilization rates and the number of embryos transferred did not show any significance. Cancellation rates were not different between groups. In group I, a total of five cycles was cancelled: two cycles were cancelled due to premature LH surges with increased progesterone concentrations, two were due to poor folliculogenesis and the other cycle was due to fertilization failure. In group II, a total of six cycles was cancelled, two due to poor folliculogenesis, two due to premature LH surges and two due to fertilization failure (Table IGo).

While the clinical pregnancy/transfer and implantation rates were higher in group I than in group II, they did not reach statistical significance (Table IGo). One pregnancy in each group miscarried and the ongoing pregnancy/transfer rate did not show any statistical difference (Table IGo).


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Despite the technological advances, IVF still continues to be a very expensive way of overcoming fertility problems. The cost of the treatment is closely related to the amount of gonadotrophins used, which is especially important for the poor responder patients. Increased cost and duration of treatment together with high cycle cancellations have always been a problem in ovarian stimulation of poor responders undergoing IVF. It is widely accepted that the ideal ovarian stimulation protocol for these patients has yet to be formulated.

Various reports documented the efficacy of the strategies decreasing the amount of GnRH agonist administration (Navot et al., 1991Go; Feldberg et al., 1994Go). It has been well established that the flare-up regimen is an important approach to the poor responder IVF patients. Padilla et al. reported this effect with a standard dose of GnRH agonist (Padilla et al., 1996Go). They increased the dosage of gonadotrophins in cycles of patients who failed the lupron screening test, namely poor responders. Schoolcraft et al., in a prospective study, assessed the efficacy of microdose GnRH agonist (40 µg leuprolide acetate per day), FSH and GH for the stimulation of the poor responder IVF patients, and found this protocol to be superior to the standard protocols for the treatment (Schoolcraft et al., 1997Go). Additionally, Surrey et al. evaluated the effects of microdose flare-up regimen in poor responders and reported that this stimulation protocol enhanced the clinical outcome (Surrey et al., 1998Go). Recently, Leondires et al. compared the efficacy of microdose flare-up and luteal phase GnRH agonist with a standard dose (Leondires et al., 1999Go). They found the same clinical efficacy while there were more cycle cancellations with the microdose group. In this study, they did not include the poor responders, and surprisingly reported the same clinical outcome with the microdose regimen. With a larger sample it is likely that this result would not be seen. As demonstrated previously, the microdose flare regimen is more suitable for those who showed poor response previously. In a study evaluating the effect of IVF for the poor responders to ovulation induction, Lashen et al. investigated the first cycles of IVF of 124 patients with normal day 3 follicle stimulating hormone (3–12 IU/l), who had produced less than five follicles within a 2 year period (Lashen et al., 1999Go). They divided the patients into three groups, according to the number of follicles produced: A (one or two follicles), B (three follicles) and C (four follicles). They employed intranasal GnRH agonists given daily from day 21 of the cycle and found that the clinical pregnancy rate/cycle in the three groups was comparable with their overall rate in the study period (25.5%) and suggested that poor responders with a normal day 3 FSH may still achieve a pregnancy rate similar to that of normal responders.

The introduction of GnRH antagonists to clinical practice may be a new hope for the poor responder patients. GnRH antagonists are added late in follicular phase, thereby not disturbing the early follicular phase, which is very critical for these patients. Additionally, they prevent the premature LH surges, which is the most common cause for cancellation in poor responder patients. Recently various reports have appeared in the literature documenting their success when used in ovarian stimulation protocols (Frydman et al., 1992Go; Diedrich et al., 1994Go; Olivennes et al., 1998Go). Craft et al. evaluated the effect of GnRH antagonist use in 31 IVF/gamete intra-Fallopian transfer (GIFT) cycles of difficult responders (Craft et al., 1999Go). Among them, 18 patients (24 cycles) were poor responders. Although this study did not reach statistical significance, the cycle cancellation was less compared with the previous agonist protocol, more oocytes at a lower dose of FSH were produced and two live births resulted. Since a deleterious effect of the agonists directly on the ovary might be the reason for the failure of those with a limited ovarian reserve, they suggested that the antagonist use for these poor responder patients might provide a new hope.

In a recent review evaluating the ovarian stimulation protocols for poor responder patients, Surrey and Schoolcraft comment that GnRH antagonist use for these patients is intriguing but has not been evaluated yet (Surrey and Schoolcraft, 2000Go). Here we aimed to compare these two alternative regimens and found almost the same clinical efficacy. Additionally both GnRH agonists and the antagonists were preventing the premature LH surges in these poor responders; the flare effect of the endogenous FSH hormone on the limited cohort of follicles might be the reason for a better response in the microdose flare-up regimen.

In conclusion, in this study we compared a new regimen using the GnRH antagonists with the microdose GnRH agonist flare-up regimen in poor responders. The clinical outcome is almost the same and to establish these results further randomized studies with larger sample sizes are required.


    Notes
 
1 To whom correspondence should be addressed at: Abdi Ipekci Cad, Azer Is Merkezi, No=44, Nisantasi, Istanbul, Turkey.E-mail: mbahceci{at}hotmail.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Craft, I., Gorgy, A., Hill, J. et al. (1999) Will GnRH antagonists provide a new hope for patients considered `difficult responders' to GnRH agonist protocols? Hum. Reprod., 14, 2959–2962.[Abstract/Free Full Text]

Diedrich, K., Diedrich, E., Santos, E. et al. (1994) Suppression of the endogenous LH-surge by the GnRH antagonist cetrorelix during ovarian stimulation. Hum. Reprod., 9, 788–791.[Abstract]

Feldberg, D., Farhi, J., Ashkenazi, J. et al. (1994) Minidose gonadotrophin-releasing hormone agonist is the treatment of choice in poor responders with high follicle stimulating hormone levels. Fertil. Steril., 62, 343–346.[ISI][Medline]

Frydman, R., Cornel, C., de Ziegler, D. et al. (1992) Spontaneous luteinizing hormone surges can be reliably prevented by the timely administration of a gonadotrophin releasing hormone antagonist (Nal-Glu) during the late follicular phase. Hum. Reprod., 7, 930–933.[Abstract]

Lashen, H., Ledger, W., Lopez-Bernal, A. et al. (1999) Poor responders to ovulation: is proceeding to in-vitro fertilization worthwhile? Hum. Reprod., 14, 964–969.[Abstract/Free Full Text]

Leondires, M.P., Escalpes, M., Segars, J.H. et al. (1999) Microdose follicular phase gonadotrophin-releasing hormone agonists (GnRH-a) compared with luteal phase GnRH-a for ovarian stimulation at in vitro fertilization. Fertil. Steril., 72, 1018–1023.[ISI][Medline]

Navot, D., Rosenwaks, Z., Anderson, F. et al. (1991) Gonadotrophin releasing hormone agonist induced ovarian hyperstimulation: low dose side effects in women and monkeys. Fertil. Steril., 55, 1069–1075.[ISI][Medline]

Olivennes, F., Alvarez, S., Bouchard, P. et al. (1998) The use of a new GnRH-antagonist (cetrorelix) in IVF–ET with a single dose protocol: a dose finding study of 3 versus 2 mg. Hum. Reprod., 13, 2411–2414.[Abstract]

Padilla, S.L., Dugan, K., Maruschak, Y. et al. (1996) Use of the flare-up protocol with high dose human follicle stimulating hormone and human menopausal gonadotrophins for in vitro fertilization in poor responders. Fertil. Steril., 65, 796–799.[ISI][Medline]

Schoolcraft, W., Schlenker, T., Gee, M. et al. (1997) Improved controlled hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol. Fertil. Steril., 67, 93–97.[ISI][Medline]

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Surrey, E.S. and Schoolcraft, W.B. (2000) Evaluating strategies for improving ovarian response of the poor responders undergoing assisted reproductive techniques. Fertil. Steril., 73, 667–676.[ISI][Medline]

Surrey, E.S., Bower, J., Hill, D.M. et al. (1998) Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil. Steril., 69, 419–424.[ISI][Medline]

Submitted on October 23, 2000; accepted on January 31, 2001.