Human Reproduction, Vol. 16, No. 8, 1671-1675,
August 2001
© 2001 European Society of Human Reproduction and Embryology
Continuous administration of gonadotrophin-releasing hormone agonist during the luteal phase in IVF
Department of Obstetrics and Gynecology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
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Abstract |
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BACKGROUND: It has been reported that ceasing the administration of gonadotrophin-releasing hormone (GnRH) agonist causes a profound suppression of circulating serum gonadotrophins. A comparative prospective and randomized study was conducted to investigate the effect of continuous administration of GnRH agonist during the luteal phase in an ovarian stimulation programme for IVF. METHODS: GnRH agonist was administered intranasally from the midluteal phase of the previous cycle, and pure FSH administration started on cycle day 7. In the continuous-long protocol (cL) group (n = 161 ), GnRH agonist administration was continued until 14 days after oocyte retrieval. In the long protocol (L) group (n = 158 ), GnRH agonist was administered until the day before human chorionic gonadotrophin (HCG) administration. RESULTS: The implantation rate and live birth rate per unit of transferred embryos were significantly higher in the cL group than the L group (P < 0.05 ). Serum LH and FSH concentrations on the day of, and 1 day after, HCG administration were significantly lower in the L group than the cL group (P < 0.01 ). CONCLUSIONS: Continuation of GnRH agonist administration during the luteal phase might facilitate implantation, and prevent the profound suppression of serum gonadotrophins.
Key words: GnRH agonist/implantation/IVF/ovarian stimulation/pregnancy
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Introduction |
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Using gonadotrophin-releasing hormone (GnRH) agonist in combination with pure FSH and/or human menopausal gonadotrophin (HMG) is a well-established method in ovarian stimulation for IVF (Smitz et al., 1992
). Although various regimens of this treatment have been proposed, most studies concerning the regimens of GnRH agonist have focused on when to start GnRH agonist treatment (Tan et al., 1992; Tasdemir et al., 1995; Cramer et al., 1999), and the interval between starting GnRH agonist administration and that of exogenous gonadotrophins (Chang et al., 1993; Damario et al., 1997; Ravhon et al., 2000). When to stop GnRH agonist administration has not been a major topic of investigation, with the exception of a few reports (Hazout et al., 1993; Pantos et al., 1994; Fujii et al., 1997). Undoubtedly, GnRH agonist completes its role as a preventive measure against premature LH surge before human chorionic gonadotrophin (HCG) administration.
As has been reported previously (Fujii et al., 1997), discontinuation of GnRH agonist on the day of starting HMG impairs follicular development and reduces serum oestradiol concentrations. Based on another report (Sungurtekin and Jansen, 1995), it was speculated that this inhibitory action of folliculogenesis after stopping GnRH agonist is caused by the decrease in serum gonadotrophin concentrations due to the lack of endogenous GnRH agonist activity. It was postulated that if the cessation of GnRH agonist causes a decrease in circulating serum gonadotrophin concentrations, then the conventional long protocol in which GnRH agonist is stopped before HCG administration may cause an abrupt fall in gonadotrophin concentration at the early luteal phase, and that unexpected effects due to the hormonal changes may follow. Therefore, a comparative prospective and randomized study was conducted to investigate the effect of continuous administration of GnRH agonist during the luteal phase in an ovarian stimulation programme for IVF.
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Materials and methods |
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Patients
A total of 319 cycles from 319 patients, who underwent IVF or intracytoplasmic sperm injection (ICSI) during the period between February 1997 and March 1999 at Hirosaki University Hospital, were entered into the study after obtaining their informed consent. The regimens of controlled ovarian stimulation described below were determined by the patient's identification number, which was allocated by the University Hospital. In the first half of the study, patients with an odd identification number were chosen for the continuous long protocol (cL), and patients with an even identification number were chosen for the long protocol (L). In the second half, patients with an odd identification number were allocated to the L group, and patients with an even identification number were allocated to the cL group, i.e. the way to determine the allocation was reversed. Each patient participated in only one cycle in the study.
Procedures for IVF
Ovarian stimulation and IVF was performed as previously described (Fujii et al., 1997). GnRH agonist (Suprecur®; Hoechst, Tokyo, Japan
) 600 µg/day was administered i.n. twice daily from the midluteal phase of the previous cycle, and pure FSH (Fertinorm-P®; Serono, Tokyo, Japan
) administration started on day 7 of the cycle. In both protocols, pure FSH (225 IU) was routinely administered i.m. for 2 days, followed by 150 IU until the mean follicular diameter had reached 18 mm. At 48 h after the final pure FSH administration, 5000 IU of HCG (hCG-Mochida®; Mochida, Tokyo, Japan
) was administered. Oocyte retrieval was performed 34–36 h later using ultrasound-guided transvaginal aspiration. For patients treated with conventional IVF, insemination with 105 washed motile spermatozoa/ml (~2x104 spermatozoa per oocyte
) was performed 4 h after oocyte retrieval. For patients treated with ICSI, a spermatozoon was injected into each metaphase II oocyte. Fewer than four cleaved embryos were transferred into the uterine cavity of each patient between 48 and 72 h after oocyte retrieval. The luteal phase was supported by daily oral administration of 10 mg dydrogesterone (Duphaston®; Daiichi-Seiyaku, Tokyo, Japan
) given daily for 14 days, and HCG 2500 IU i.m. on the day of embryo transfer, 7 days after oocyte retrieval. A clinical pregnancy was defined as ultrasound visualization of a gestational sac or histological evidence of trophoblast. In the cL group, GnRH agonist administration was continued until 14 days after oocyte retrieval, when a pregnancy test was performed. In the L group, GnRH agonist was administered until the day before HCG administration. The two protocols differed only when administration of the GnRH agonist was stopped.
Hormone measurements
In both protocols, routine blood sampling for hormonal examination was performed on six occasions: on the initial and final days of pure FSH stimulation; on the day of HCG administration; on the day of oocyte retrieval; on the day of embryo transfer; and 7 days after oocyte retrieval (midluteal phase). Each blood sample was taken before the administration of any medicines. Plasma was assayed for LH, FSH, oestradiol and progesterone using enhanced chemi-iluminescence enzyme immunometric assays (Diagnostic Products Corp., Los Angeles, CA, USA). The lower limit of sensitivity of each bioassay was 0.2 mIU/ml for LH, 0.2 mIU/ml for FSH, 8 pg/ml for oestradiol, and 0.2 ng/ml for progesterone. The intra- and inter-assay coefficients of variation never exceeded 10% and 8% respectively in all cases.
Statistical analysis
Results were analysed using either the unpaired Student's t-test or Fisher's Exact probability test of frequency distribution. A P-value < 0.05 was considered significant.
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Results |
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In total, 161 cycles used the cL protocol, and 158 cycles the L protocol (Table I
). The age of both patient and husband, the number of previous embryo transfer attempts, cause of infertility, method used for fertilization, and total dosage of pure FSH were similar in the two groups. Both the number of oocytes retrieved and that of oocytes fertilized were also similar in the two groups, as were the fertilization rate, the number of embryos transferred and the cancellation rate. The clinical pregnancy rate per transfer was higher in the cL group than in the L group, but the difference was not significant (P < 0.05
). However, the multiple pregnancy rate per pregnancy, the implantation rate per unit of transferred embryos and the live birth rate per unit of transferred embryos were significantly higher in the cL group than the L group (P < 0.05
). The abortion rate per pregnancy was similar for both groups (Table 1). Among 117 babies born, 116 were healthy; one baby born to a 37-year-old mother who received the cL protocol had trisomy 21.
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With regard to hormone measurements, serum oestradiol and progesterone concentrations were similar between the two groups throughout the cycle (Table II
). In contrast, serum LH and FSH concentrations on and after the day of HCG administration were significantly lower in the L group than in the cL group (Table III; Figure 1).
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), and the continuous-long protocol group (•), during treatment. Results are expressed as mean ± SEM; *P < 0.01; 
P < 0.0001; 
P < 0.005. |
Discussion |
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The introduction of pituitary suppression with GnRH agonist has provided several advantages in ovarian stimulation for IVF treatment. GnRH agonist allows for better oocyte maturation (Pieters et al., 1991
), increases the number of oocytes recovered and fertilized (Liu et al., 1992), and has also led to improved pregnancy rates and fewer cancelled cycles (Smitz et al., 1992). Although prolonged administration of a GnRH agonist before HMG stimulation may cause a reduced ovarian response (Ravhon et al., 2000), the long protocol of GnRH agonist has been reported as an efficient method (Tan et al., 1992; Tasdemir et al., 1995; Cramer et al., 1999).
However, consequences of profound LH suppression resulting from discontinuation of the agonist administration are still under discussion. When GnRH agonist administration is interrupted, this is followed by an abrupt fall in the serum concentration of
the alpha-subunit of gonadotrophin (Oppenheimer et al., 1992), and a recovery period of hypophyseal synthesis which is usually observed for approximately one week (Winslow et al., 1992; Sungurtekin and Jansen, 1995). If GnRH agonist administration was interrupted early in the follicular phase, a profound LH suppression after stopping GnRH agonist lessens the ovarian response to FSH and increases the cancellation rate (Fujii et al., 1997; Cedrin-Durnerin et al., 2000). In the case of poor responders, however, the consequences of stopping GnRH agonist may be different. It has been reported (Faber et al., 1998) that cessation of GnRH agonist at the onset of menses was favourable for poor responders and produced a satisfactory pregnancy rate, whereas others (Dirnfeld et al., 1999) showed that the cessation brought no further advantage.
The findings of the current study are in line with these previous reports. It was reconfirmed that gonadotrophin responsiveness to daily GnRH agonist administration was preserved, and that interruption of the agonist induced a marked decrease in serum LH concentrations. However, this study is the first to question whether GnRH agonist administration in ovarian stimulation should be stopped before HCG administration. The only differences in serum hormone concentrations between the two groups were observed in gonadotrophins during the luteal phase. Recent reports have shown that profound suppression of LH during ovarian stimulation might increase the risk of early pregnancy loss (Westergaard et al., 2000). However, it is difficult to conjecture that altered luteal function or endometrial receptivity might be the reason why the cL protocol produced a higher implantation rate, as both groups were receiving progesterone and follow-up HCG. Moreover, the current data did not reveal any difference between protocols in serum oestradiol and progesterone concentrations during the luteal phase. These results indicate that our hypothesis, which focused on the altered implantation milieu due to the profound suppression of gonadotrophins after stopping GnRH agonist, were incorrect. Recently, it was reported that administration of GnRH agonist throughout the luteal phase enhanced the fecundity (Raga et al., 1998a), showing results that are concordant with those of the current study. These authors have also demonstrated the presence of GnRH and its receptor in preimplantation human embryos (Raga et al. 1999a) and endometrial stromal cells (Raga et al., 1998b, 1999b). Therefore, a possible explanation for the promotion of implantation in the cL group might lie in the direct action of GnRH agonist as the regulation in the embryo–endometrial interactions and the facilitation of embryonal development.
The routine use of this continuous administration of GnRH agonist has some disadvantages, however. First, prolonged administration will be an economic burden for patients undergoing IVF. Second, the effects of GnRH agonist on embryo implantation in the uterus are not completely clear, although it has been reported that inadvertent exposure of fetuses to GnRH agonist during pregnancy has no specific hazardous effects among newborns (Smitz et al., 1991; Jackson et al., 1992; Elefant et al., 1995). The current result also proved the administration of GnRH agonist to be harmless to the early stage of implantation, and also to subsequent fetal development.
In summary, this study has demonstrated that continuation of GnRH agonist administration during the luteal phase might facilitate implantation. Recently, a GnRH antagonist has been developed and a trial of its practical use performed (Craft et al., 1999; Olivennes et al., 2000). It is certain that a GnRH antagonist will be more valid to prevent a premature LH surge than would a GnRH agonist. However, since unexpected effects of stopping GnRH agonist administration were observed, the pharmacological actions of the antagonist must be closely investigated not only during its administration but also after its cessation.
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Acknowledgements |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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The authors thank Ms Eriko Funamizu for conducting the enhanced chemi-iluminescence enzyme immunometric assays, and Ms Kimberley Mann, The Student Centre, the University of Adelaide, Australia for reviewing the English.
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Notes |
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1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan. E-mail: shunsaku{at}cc.hirosaki-u.ac.jp
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Submitted on November 16, 2000; accepted on April 30, 2001.
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