Addition of GnRH antagonist in cycles of poor responders undergoing IVF

Mehmet A. Akman, Halit F. Erden, Suleyman B. Tosun, Numan Bayazit, Esra Aksoy and Mustafa Bahceci1

IVF Unit, German Hospital, Istanbul, Turkey


    Abstract
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 Abstract
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 Materials and methods
 Results
 Discussion
 References
 
Concern about the use of gonadotrophin-releasing hormone (GnRH) agonists in ovarian stimulation of poor responder IVF patients has arisen from the claim that GnRH agonists might have a direct deleterious effect through their receptors on the ovary. In this study, we compared two ovarian stimulation protocols in which no GnRH agonists were used. In all, 40 patients with a poor response in previous treatment cycles were included. They were divided into two groups: group I (n = 20) received ovarian stimulation for 20 cycles, without the addition of either GnRH agonist or antagonist; while group II (n = 20) patients received ovarian stimulation for 20 cycles, including the administration of a GnRH antagonist (Cetrorelix, 0.25 mg daily) during the late follicular phase. There was no statistically significant difference between the groups for mean age, duration of infertility, baseline FSH concentration, cancellation rate, number of ampoules of gonadotrophin used, number of mature oocytes retrieved, oestradiol concentrations on the day of injection of human chorionic gonadotrophin (HCG), fertilization rate and number of embryos transferred. The clinical pregnancy and implantation rates in group II appeared higher than in group I, but were not significantly different (20 and 13.33% compared with 6.25 and 3.44% respectively). The addition of GnRH antagonists to ovarian stimulation protocols might be a new hope for poor responder IVF patients, but this report is preliminary and further controlled randomized prospective studies with larger sample sizes are required.

Key words: Cetrorelix/GnRH antagonist/IVF/poor responders/pregnancy


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In recent years, the childbearing age of women has tended to increase. Some of these older women may apply to IVF clinics suffering from infertility caused by ovarian ageing. More probably, they present a poor response to ovarian stimulation and so are defined as `poor responders'.

With the first use of gonadotrophin-releasing hormone (GnRH) agonists in ovulation induction (Fleming et al., 1982Go), the success rate in IVF started to increase. GnRH agonists induce desensitization of the gonadotrophic cells of the anterior pituitary gland and prevent the premature LH surges associated with poor outcomes. Conversely, they may cause over-suppression in poor responder patients, leading to a prolonged cycle length and increased treatment cost, without aiding the outcome. Recently, with the discovery of GnRH receptors in the human ovary, some investigators assume that GnRH agonists may have a direct, deleterious effect on the ovary which is especially important for poor responder patients (Craft et al., 1999Go; Leung, 1999Go). In the light of these findings, there is a tendency towards the total elimination of GnRH agonists, while increasing the gonadotrophin dosage for poor responders with diminished ovarian reserves, who are already suppressed. In this study we compare two protocols in which GnRH agonists were eliminated from the stimulation protocols.

Recently, new, safer GnRH antagonists with longer half-lives and high potency have become available for clinical use. These GnRH antagonists act immediately and prevent the LH surge, so prior desensitization for weeks (as with GnRH agonists) is not necessary, nor do they interrupt early folliculogenesis which is critical for these patients with a limited cohort of follicles. The GnRH antagonists are added to the stimulation protocol in the late follicular phase, thus preventing the LH surge which is the most common cause for cycle cancellation in poor responder patients.

In this study, we compared two different stimulation protocols in poor responder IVF patients; one was without any agonist or antagonist medication, the other was with antagonist administration.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our study population consisted of a total of 40 poor responder patients who underwent IVF/embryo transfer cycles. Each one had undergone at least two previous IVF attempts with poor response due to one of the following reasons: baseline FSH concentrations of >15 mIU/ml, oestradiol concentration on the day of human chorionic gonadotrophin (HCG) injection <500 pg/ml, or the number of mature oocytes retrieved was fewer than four. FSH was measured by a standard commercial kit produced by Abbott Laboratories (Abbott Park, IL, USA).

All the patients included were very difficult responders in whom various protocols including microdose GnRH agonist flare-up and long protocols were all applied without any success. Where azoospermic patients were excluded, micromanipulation including intracytoplasmic sperm injection (ICSI) and assisted hatching were performed in all cycles.

The poor responders were prospectively randomized into two groups. Randomization was based on the consecutive number method. Group I included 20 patients and 20 cycles, who underwent ovarian stimulation with no GnRH agonist or antagonist administration. Group II consisted of 20 patients and 20 cycles in which 0.25 mg of Cetrorelix (Cetrotide; Asta Medica, Frankfurt, Germany) was administered daily when the leading follicle reached 14 mm in diameter until the day of HCG injection.

Starting on cycle day 2, all patients in each group received 300 IU of pure FSH (Metrodin; Serono Laboratories, Aubonne, Switzerland) together with 300 IU of human menopausal gonadotrophin (HMG, Humegon; Organon Laboratories, Oss, The Netherlands) daily for 4 days. While the HMG dose remained constant until the day of injection of HCG, the dose of FSH was individually adjusted, according to the response of the ovaries and the concentration of oestradiol.

HCG (10 000 IU) was administered i.m. when the leading follicle reached 17–18 mm in diameter, followed 35 h later by an ultrasound-guided transvaginal oocyte retrieval. All patients who underwent embryo transfer received supplemental progesterone throughout the luteal phase. Pregnancy was established when at least two serum ß-HCG titres drawn a minimum of 10 days after embryo transfer were noted to be rising and gestational sacs were seen on ultrasonography. Abortions were defined as births prior to 20 weeks gestation. Statistical analyses were carried out using Student's t-test and the {chi}2 test; P < 0.05 was considered to be statistically significant.


    Results
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 Abstract
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 Materials and methods
 Results
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The patient and cycle characteristics with pregnancy outcome are shown in Table IGo. There were no differences between the groups with regard to mean age, duration of infertility, FSH and LH concentrations on cycle day 3, number of ampoules used, the oestradiol, progesterone and LH concentrations on the day of HCG injection, number of mature oocytes retrieved, fertilization rates and the number of embryos transferred. Nor did the cancellation rates differ between the groups. In group I, four cycles were cancelled; two because of premature LH surges in parallel with increased progesterone concentrations, one because of poor folliculogenesis and one because of fertilization failure. In group II, five cycles were cancelled either due to poor folliculogenesis (n = 2), no oocyte aspirated (n = 1), or fertilization failure (n = 2). While the clinical pregnancy/transfer and implantation rates appeared higher in group II than in group I, they were not significantly different (20 and 13.33% compared with 6.25 and 3.44% respectively).


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Table I. Patient and cycle characteristics with pregnancy outcome
 

    Discussion
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 Materials and methods
 Results
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Despite the improvements in assisted reproduction brought about by advanced technological facilities, the ideal approach to poor responders who have been identified from previous attempts, has yet to be formulated. If a pregnancy cannot be achieved, it is not easy to convince people to enrol in an oocyte donation programme as an alternative. Even as a last resort, religious and cultural factors may prevent these patients from accepting oocytes from someone else. Therefore, it is vital to tailor a stimulation protocol to achieve maximum oocyte retrieval and pregnancy for these poor responder patients.

There are some concerns about the use of GnRH agonists for poor responder patients. They already have a diminished ovarian reserve and the use of GnRH agonists might cause additional suppression, so elongating the cycle length, increasing the cost of treatment and, more probably, impairing the outcome. Various studies have attempted to determine the most efficient protocol for GnRH agonists; mostly by altering the dose and timing of the administration. One study (Navot et al., 1991Go) evaluated the effect of low doses of GnRH agonists on the outcome of IVF cycles and determined that, with these low doses, agonists can still prevent premature LH surges, thus allowing better ovarian stimulation and so resulting in a higher number of oocytes retrieved. In another study (Feldberg et al., 1994Go), which aimed to discover the most appropriate dose for the poor responders, three treatment protocols using mid-luteal Decapeptyl administration were compared. The minidose GnRH agonist administration of 0.1 mg daily until menstruation, followed by 0.05 mg daily was found to be a better choice than regular strategies. Another study (Scott and Navot, 1994Go) used microdoses of GnRH agonists (20 µg leuprolide acetate twice daily) and reported a larger number of oocytes recruited with a decreased requirement for gonadotrophin. In the literature, there are several reports which suggest a better outcome with a microdose flare-up regimen, either with or without the addition of growth hormone (Schoolcraft et al., 1997Go; Surrey et al., 1998Go).

With the development of new, potent, safer GnRH antagonists, a new hope appeared for poor responder IVF patients. Recently, their clinical efficacy has been well demonstrated in various reports (Frydman et al., 1992Go; Diedrich et al., 1994Go; Olivennes et al., 1995Go). They are added in the late follicular phase of ovarian stimulation and are not involved in the early folliculogenesis period, which is critical for these patients. Two administration protocols have been suggested for antagonist use: (i) multiple daily and (ii) single dose injections. Both protocols have been shown to be equally effective (Olivennes et al., 1995Go, 1998Go; Albano et al., 1997Go). In our study we chose multiple daily injections: when the leading follicle reached 14 mm in diameter, we started 0.25 mg Cetrorelix injections daily.

Although these two protocols do not interfere with the early period of folliculogenesis, the difference observed between the pregnancy rates (although it was not statistically significant), might have been due to premature luteinization. While two cycles were cancelled due to premature luteinization in patients where no GnRH antagonist was administered (group I), no cycles were cancelled in group II, where GnRH antagonists were added. Although they did not reach statistical significance, the progesterone and LH concentrations on the day of HCG administration were higher in group I than the ones with GnRH antagonist addition. This difference might be better documented in future studies with larger sample sizes. As a response to recent findings (Albano et al., 1997Go; Lidor et al., 2000Go), we included HMG in our ovarian stimulation protocol in order to prevent premature luteinization, in the patients who had previously shown a poor response.

In this study, prompted by various concerns about GnRH agonist use in poor responders, we compared the traditional strategy of increasing the gonadotrophin dosage during the early folliculogenesis period, with or without the later addition of GnRH antagonist. While the cycle cancellation rates did not differ, we reported more pregnancies in the antagonist cycles, but the difference was not statistically significant. This report is preliminary and further controlled randomized prospective 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
 
Albano, C., Smitz, J., Camus, M. et al. (1997) Comparison of different doses of gonadotropin-releasing hormone antagonist cetrorelix during controlled ovarian hyperstimulation. Fertil. Steril., 67, 917–922.[ISI][Medline]

Craft, I., Gorgy, A., Hill, J. et al. (1999) Will GnRH antagonists provide new hope for patients considered `difficult responders' to GnRH agonist protocols? Hum. Reprod., 12, 2559–2962.

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 gonadotropin-releasing hormone agonist is the treatment of choice in poor responders with high follicle stimulating hormone levels. Fertil. Steril., 62, 343–346.[ISI][Medline]

Fleming, R., Adam, A.H., Barlow, O.H. et al. (1982) A new systemic treatment for infertile women with abnormal hormone profiles. Br. J. Obstet. Gynaecol., 89, 80–83.[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 gonadotropin releasing hormone antagonist (Nal-Glu) during the late follicular phase. Hum. Reprod., 7, 930–933.[Abstract]

Leung, P.C.K. (1999) GnRH receptor and potential action in human ovary. Gynaecol. Endocrinol., 13, 10.

Lidor, A.L., Cohen, B., Seidman, D.S. et al. (2000) Preferred treatment of infertile women older than 37 years of age who demonstrated premature luteinization in the first evaluation cycle. Fertil. Steril., 73, 321–324.[ISI][Medline]

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

Olivennes, F., Fanchin, R., Bouchard, P. et al. (1995) Scheduled administration of GnRH antagonist (Cetrorelix) on day 8 of in vitro fertilization cycles: a pilot study. Hum. Reprod., 10, 1382–1386.[Abstract]

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]

Schoolcraft, W., Schlenker, T., Gee, M. et al. (1997) Improved controlled ovarian 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]

Scott, R.T. and Navot, D. (1994) Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil. Steril., 61, 880–885.[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 February 23, 2000; accepted on June 29, 2000.