Human Reproduction, Vol. 14, No. 6, 1426-1430,
June 1999
© 1999 European Society of Human Reproduction and Embryology
Luteal phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles
1 Center for Reproductive Medicine, University Hospital and Medical School, Dutch-speaking Brussels Free University, Laarbeeklaan 101, 1090 Brussels, Belgium and 2 ASTA Medica AG, Frankfurt Main, Germany
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Abstract |
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The luteal phase hormonal profile and the clinical outcome of 69 patients undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) after ovarian stimulation with human menopausal gonadotrophin (HMG) and the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix were analysed. Twenty-four patients received Cetrorelix 0.5 mg (group I) while in 45 patients Cetrorelix 0.25 mg was administered (group II). Human chorionic gonadotrophin (HCG) was used as luteal support. Nine clinical pregnancies were obtained in group I (37.5%) and 12 in group II (26.6%). These results were not significantly different. Serum progesterone and oestradiol concentrations did not differ between the two groups either in pregnant or non-pregnant patients. An expected decrease of the same hormones was observed 8 days after the pre-ovulatory HCG injection in non-pregnant women. With regard to serum luteinizing hormone concentrations, a decrease was observed 2 days after the pre-ovulatory HCG injection and was maintained at almost undetectable levels throughout the entire luteal phase in both conception and non-conception cycles of group I and group II. This study demonstrates that different doses of GnRH antagonist do not have any impact on the luteal phase of IVF/ICSI cycles when hormonal support is given.
Key words: GnRH antagonist/ICSI/IVF/luteal phase
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Introduction |
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Hormonal support of the luteal phase in patients undergoing oocyte retrieval and embryo transfer is routinely used. In the `pre-agonists era', Edwards and Steptoe were the first to postulate luteal phase inadequacy resulting from ovarian stimulation as a cause of failure of in-vitro fertilization (IVF) cycles (Edwards and Steptoe,1980
). However, the advantage of administering different forms of luteal supplementation was not demonstrated (Daya, 1988).
With the introduction of the gonadotrophin-releasing hormone agonists (GnRHa), used in ovarian stimulation cycles to avoid premature luteinizing hormone (LH) surge, luteal phase inadequacy was reported (Smitz et al., 1987, 1988). A meta-analysis of different clinical trials demonstrated beneficial effects of luteal support when ovarian stimulation was carried out with human menopausal gonadotrophin (HMG) in association with GnRHa (Soliman et al., 1994).
More recently, GnRH antagonists have become available for clinical use. They bind to the GnRH receptors and, unlike GnRHa, cause an immediate inhibition of gonadotrophin release without inducing an initial stimulatory response (Reissmann et al., 1995). Whether GnRH antagonists induce down-regulation of pituitary GnRH receptors is still a subject of investigation (Schally et al., 1995). Recently, it has been demonstrated that chronic administration of the GnRH antagonist Cetrorelix in rats causes an important downregulation of pituitary GnRH receptors (Srkalovic et al., 1990; Pinski et al., 1992, 1996).
Although a lot of information is available on the luteal phase of cycles stimulated by HMG and GnRHa, few studies have analysed the corpus luteum function after the use of GnRH antagonists (Frydman et al., 1991; Albano et al., 1998).
In this retrospective study we investigate the luteal phase and the clinical outcome of patients who underwent ovarian stimulation with HMG and different doses of GnRH antagonist (Cetrorelix; ASTA Medica AG, Frankfurt am Main, Germany) and who received luteal supplementation.
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Materials and methods |
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We evaluated the luteal phase of 69 volunteer women selected as part of a phase II dose-finding study designed to assess the minimal efficacy dose of the GnRH antagonist Cetrorelix in preventing premature LH surges during ovarian stimulation. The study was approved by the ethical committee of the Medical Campus of the Brussels Free University. All couples who consented to participate in the study were required to sign a written informed consent.
Ovarian stimulation was carried out with HMG (Menogon; Ferring, Kiel, Germany) in combination with the GnRH antagonist Cetrorelix, as previously described (Albano et al., 1997). Patients receiving hormonal luteal support were considered for this study. Twenty-four patients, aged 29–39 (mean ± SD; 32.5 ± 2.5) received Cetrorelix 0.5 mg daily, starting from day 6 of HMG treatment (group I); in 45 patients, aged 22–37 (mean ± SD; 30.4 ± 3.8) Cetrorelix 0.25 mg was administered (group II). The criteria for administration of HCG and details of oocyte retrieval and embryo transfer have been already described (Albano et al., 1997). In these patients, at least one good-quality embryo was transferred into the uterine cavity after IVF, or intracytoplasmic sperm injection (ICSI) was performed. Luteal phase was supported by one injection of 1500 IU of human chorionic gonadotrophin (HCG) every 4 days, starting on the day of embryo transfer, for a total of three injections.
Morning blood samples were taken every day after the pre-ovulatory HCG injection until the day of the embryo transfer and every 4 days during the subsequent luteal phase. All serum measurements were normalized to the day of the pre-ovulatory HCG administration (day 0). Samples were analysed for oestradiol, progesterone, LH and FSH using radioimmunoassays as previously described (Smitz et al., 1992).
Pregnancy was confirmed by a rise in serum HCG concentrations on two consecutive occasions at least 7 days after the last HCG injection. Clinical pregnancy was determined by ultrasound demonstration of an amniotic sac at 7 weeks.
Statistical analysis for the comparison of means was performed using the Wilcoxon test. For comparison of means of serum hormone concentrations, analysis of variance (ANOVA) with repeated measures was used, whereas for comparison of implantation rates, pregnancy rates and delivery rates between the two groups, 
2 analysis was used. Statistical significance was defined as P < 0.05.
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Results |
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Table I
shows the clinical outcome of group I (24 patients) and group II (45 patients). There were nine conception cycles in group I (37.5%) with one miscarriage at 16 weeks and one interstitial pregnancy, resulting in seven deliveries (29.1%) and nine children born (seven singletons and two twins). In group II, 14 conception cycles (31.1%) were obtained with one miscarriage at 20 weeks and one tubal pregnancy, resulting in 10 deliveries (22.2%) and 13 children born (seven singletons and three twins). These results were not significantly different.
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When conception and non-conception cycles were compared in the two groups, no statistical difference was observed with regard to the mean age (± SD) of patients, mean number of cumulus–oocyte complexes retrieved, mean number of normally fertilized oocytes, mean number of transferable embryos, mean number of transferred embryos and mean number of frozen embryos (Table II
).
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Serum progesterone concentrations did not differ between group I and group II in conception or in non-conception cycles. An increase in serum progesterone concentration was observed the day after the pre-ovulatory HCG injection. However, from day 8 of the luteal phase onwards a progressive decrease of the same hormone was observed in non-conception cycles (Figure 1
). No differences in serum oestradiol concentrations were observed between pregnant patients who received 0.5 mg (group I) and 0.25 mg (group II) Cetrorelix and non-pregnant patients who received different doses of the GnRH antagonist. A decline in serum oestradiol concentrations was also observed on day 8 of the luteal phase in non-conception cycles (data not shown). With regard to LH serum concentration, no statistical difference was observed between group I and II. A decrease in LH concentrations was observed 2 days after the pre-ovulatory HCG injection in both groups, progressively reaching undetectable levels (Figure 2).
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) and group II (
). No differences were observed between the two different dose groups (group I = 0.5 mg, group II = 0.25 mg Cetrorelix. Serum progesterone concentrations were not different between conception cycles of group I (
) and group II (•).
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In this study, no patients developed severe ovarian hyperstimulation syndrome (OHSS). Three patients in group I (12.5%) and one patient in group II (2.2%) experienced moderate OHSS (grade III) with abdominal distension, nausea, moderate ovarian enlargement (5–10 cm by ultrasound examination), moderate haemoconcentration (haematocrit 45–47), and ascites (Golan et al., 1989
). These results were not statistically significant. |
Discussion |
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Recently, several studies have confirmed the efficacy of GnRH antagonists in avoiding the premature endogenous LH surge during ovarian stimulation in IVF cycles (Diedrich et al., 1994
; Olivennes et al., 1994, 1995). In all these studies, the luteal phase was supported either by means of vaginal micronized progesterone (Olivennes et al., 1994, 1995) or by i.m. HCG injection (Diedrich et al., 1994). However, the need for corpus luteum hormonal support after the use of GnRH antagonist has not been yet investigated.
Few studies have analysed the corpus luteum function after the use of GnRH antagonists either in spontaneous or in ovarian stimulation cycles. Normal luteal phase, in terms of duration and serum progesterone concentrations, in 10 normo-ovulatory women to whom GnRH antagonist (Nal-Glu) was successfully administered to prevent LH surge and ovulation in natural cycles were previously reported (Ditkoff et al., 1991). In a study conducted to evaluate the efficacy of the GnRH antagonist Nal-Glu in preventing serum LH surge in ovarian stimulation cycles using clomiphene citrate and HMG, the luteal phase of five volunteer women not attempting pregnancy to whom HCG was administered in order to induce ovulation were analysed (Frydman et al., 1991). They did not observe luteal phase defects.
Despite the profound inhibition of gonadotrophin secretion after GnRH antagonist administration, previous studies have demonstrated that the pituitary remains responsive to single or serial i.v. boluses of GnRH (Chillik et al., 1987; Gordon et al., 1990; Felberbaum et al., 1995). On the basis of these observations, the irrelevance of luteal phase supplementation in patients undergoing ovarian stimulation with HMG in association with GnRH antagonists may be postulated. However, we had previously observed a short luteal phase and low serum oestradiol and progesterone concentrations in three of six patients who did not receive any luteal supplementation after ovarian stimulation with HMG and Cetrorelix 0.5 mg (Albano et al., 1998). These were the first patients selected for a phase II dose-finding study designed to assess the minimal efficacy dose of the GnRH antagonist Cetrorelix to prevent premature LH surges during ovarian stimulation. The luteal phase of all the subsequent patients included in the study was supplemented by means of HCG injection.
A direct inhibitory effect of the antagonists on the gonadal cells may be postulated. Specific high-affinity receptors for GnRH have been found in the ovaries of many mammals and rats (Clayton and Catt, 1981), as well as in human ovaries (Bramley et al., 1985; Latouche et al., 1989). The effect of GnRH agonists on the ovary has already been investigated, but the results remain uncertain. In-vitro studies have shown no action of GnRH agonist on human granulosa cells (Casper et al., 1982), while an inhibition of gonadotrophin-induced steroidogenesis of granulosa cells has been detected (Tureck et al., 1982). Moreover, a reduction of corpus luteum steroidogenesis with a short luteal phase was detected in normo-ovulatory volunteer women to whom a GnRH agonist was administered in the midluteal phase (Casper and Yen, 1979). An impaired function of the corpus luteum with a decrease in progesterone secretion, in pregnant rats treated with a GnRH agonist has been observed (Sridaran, 1987). To our knowledge, there are few studies in the literature investigating the effect of GnRH antagonist on human ovarian steroidogenesis. A controlled study (Minaretzis et al., 1995) compared the efficacy of the GnRHa luprolide acetate (250 µg s.c. daily, starting on cycle day 1) with the efficacy of the GnRH antagonist Nal-Glu (5 mg daily, starting when the leading follicle was 
15 mm diameter) in suppressing LH secretion during ovarian stimulation for IVF. Moreover, they investigated whether the in-vivo administration of these analogues could effect the granulosa–lutein cell steroidogenesis in vitro. They observed a significantly lower serum oestradiol concentration in the antagonist group than in the agonist group on the day of the HCG administration, although no difference was observed in the total number of HMG ampoules administered. The results of the in-vitro study showed a lower oestradiol concentration in the granulosa–lutein cells from antagonist-treated women than in the granulosa–lutein cells from the agonist-treated ones. However, progesterone production by granulosa–lutein cells was similar in both groups. These results might be associated with a direct effect of the antagonist on granulosa–lutein cell aromatase activity and support what was observed in vitro in a previous study (Spona et al., 1985). An in-vivo study, conducted in pregnant rats, also showed a direct inhibitory effect of a GnRH antagonist (antide) at the level of the corpus luteum (Srivastava et al., 1994). On the contrary, normal ovarian steroidogenesis was observed in human granulosa–lutein cells cultured in vitro and exposed in vivo either to a GnRH antagonist or to a GnRHa (Ortmann et al. 1998). These findings did not support the hypothesis of a GnRH-dependent autocrine system that regulates steroidogenesis in human ovaries.
The present study analyses the luteal phase of 69 patients treated with HMG and two different doses of GnRH antagonist, and who received hormonal luteal support. We decided to supplement these patients on the basis of the above observations. Serum progesterone concentrations did not differ between pregnant patients receiving either 0.5 mg (group I) or 0.25 mg (group II) Cetrorelix and between non-pregnant patients in the two different dose groups (Figure 1
). A typical post-ovulatory increase in progesterone was observed after HCG injection in both groups as a result of luteinization of granulosa cells by a direct HCG effect on the ovary. Previous studies found lower plasma progesterone concentrations in non-pregnant patients, for 3 days following oocyte retrieval than in pregnant patients, when ovarian stimulation was carried out with clomiphene citrate and HMG (Yovich et al., 1985). In our study, no difference in serum progesterone concentration was observed, in the early luteal phase, between non-pregnant and pregnant patients in groups I and II. From day 8 onwards, a decrease in serum progesterone concentrations was observed in non pregnant patients. A decrease in serum LH concentrations was detected 2 days after the pre-ovulatory HCG injection and was maintained at almost undetectable levels throughout the entire luteal phase in both conception and non-conception cycles of group I and group II (Figure 2). The same results have been observed in patients treated with GnRHa (Smitz et al., 1988). On the basis of the finding that antagonists do not cause a prolonged pituitary suppression, the low LH concentrations observed in the luteal phase may be attributed to negative feedback from the HCG-induced increased steroid levels on pituitary secretion, although this has not been demonstrated in clomiphene citrate/HMG cycles (Smitz et al., 1988). Furthermore, the decrease in serum progesterone and oestradiol concentrations observed in non-pregnant patients in the late-luteal phase did not, perhaps, reach sufficiently low concentrations to activate a positive LH feedback response. However, in a study conducted by Demoulin et al., the decline of serum LH concentrations in the luteal phase of women treated with GnRHa/HMG was attributed not only to the administration of the agonist but also to the administration of the pre-ovulatory dose of HCG (Demoulin et al., 1991). In this study, 30 patients underwent ovarian stimulation with a combination of clomiphene citrate and HMG and 35 patients were treated with GnRHa and HMG for IVF. In both groups, ovulation was induced by HCG injection. A significant reduction in LH concentration was observed 12 h after HCG administration in patients treated with GnRHa/HMG. Moreover, a significant LH decrease was observed in the mid-luteal phase of patients treated either with clomiphene citrate/HMG or with GnRHa/HMG. The authors concluded that HCG may act directly on the hypothalamic–pituitary axis by inducing a negative feedback control on the gonadotrophs. These results accord with the results of a recent in-vitro study where inhibition of LH secretion has been observed after long-term exposure of immortalized GnRH neurons to HCG (Mores et al., 1996). However, further studies are needed to assess whether the low serum LH concentration observed in the luteal phase of cycles supplemented with HCG is due either to the high steroid concentrations produced by the corpus luteum after HCG injection or to a direct effect of HCG on the output of LH secretion.
Clinical pregnancy rates per transfer did not differ between group I (37.5%) and group II (26.6%); neither did delivery rate per transfer (29.1 and 22.2% respectively). No cases of severe OHSS were observed in either group. Three patients in group I and one patient in group II experienced moderate OHSS (12.5 and 2.2% respectively).
In conclusion, this study demonstrates that different doses of GnRH antagonist do not have any negative impact on the luteal phase when HCG is given as luteal support. Serum progesterone and oestradiol concentrations are similar after the administration of 0.5 mg and 0.25 mg Cetrorelix in both conception and non-conception cycles. However, the answer to the question of whether there is any need to supplement the luteal phase after the use of GnRH antagonist for ovarian stimulation is still unanswered.
The relationship of oestradiol and progesterone concentrations with endometrial histology in HMG/GnRH antagonist cycles supplemented or not supplemented during the luteal phase needs to be investigated.
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Acknowledgments |
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The authors wish to thank the clinical, paramedical and laboratory staff of the Center for Reproductive Medicine. We are very grateful to the study coordinators Mrs Andrea De Brabanter, Mrs Marleen Magnus, Mrs Pascale Haegeman and Mrs Anne Prothmann. Furthermore, the authors wish to thank Mr Frank Winter of the Language Education Centre of our University for correcting the manuscript. We thank Mrs Marie-Paule Derde of the Biostatistical department.
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Notes |
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3 To whom correspondence should be addressed
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References |
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Submitted on July 13, 1998; accepted on February 4, 1999.
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 A. TAVANIOTOU, J. SMITZ, C. BOURGAIN, and P. DEVROEY Ovulation Induction Disrupts Luteal Phase Function Ann. N.Y. Acad. Sci., September 1, 2001; 943(1): 55 - 63. [Abstract] [Full Text] [PDF]
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A. Tavaniotou, C. Albano, J. Smitz, and P. Devroey Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix Hum. Reprod., April 1, 2001; 16(4): 663 - 667. [Abstract] [Full Text] [PDF]
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The European Orgalutran Study Group, G. Borm, and B. Mannaerts Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial Hum. Reprod., July 1, 2000; 15(7): 1490 - 1498. [Abstract] [Full Text] [PDF]
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