IVF Unit, German Hospital, Istanbul, Turkey
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Abstract |
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Key words: Cetrorelix/GnRH antagonist/IVF/poor responders/pregnancy
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Introduction |
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With the first use of gonadotrophin-releasing hormone (GnRH) agonists in ovulation induction (Fleming et al., 1982), 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., 1999
; Leung, 1999
). 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.
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Materials and methods |
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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 1718 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 2 test; P < 0.05 was considered to be statistically significant.
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Results |
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Discussion |
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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., 1991) 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., 1994
), 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, 1994
) 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., 1997
; Surrey et al., 1998
).
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., 1992; Diedrich et al., 1994
; Olivennes et al., 1995
). 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., 1995
, 1998
; Albano et al., 1997
). 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., 1997; Lidor et al., 2000
), 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.
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Notes |
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References |
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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, 25592962.
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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, 880885.[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, 419424.[ISI][Medline]
Submitted on February 23, 2000; accepted on June 29, 2000.