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Use of luteal estrogen supplementation in normal responder patients treated with fixed multidose GnRH antagonist: a prospective randomized controlled study

2007; Elsevier BV; Volume: 89; Issue: 6 Linguagem: Inglês

10.1016/j.fertnstert.2007.08.029

1556-5653

Seyit Temel Ceyhan, Mustafa Başaran, Namık Kemal Duru, Ali Haydar Yılmaz, Ümit Göktolga, İskender Başer,

Endometriosis Research and Treatment

To evaluate the effect of luteal estrogen supplementation on pregnancy rates in normal responder IVF patients treated with recombinant FSH and fixed multidose GnRH antagonist, patients were randomized into two groups to receive vaginal 600 mg/d micronized progesterone for luteal phase supplementation with or without transdermal estrogen supplementation (100 μg/d). Because pregnancy rates and ongoing pregnancy rates were similar with and without estrogen supplementation (50.0% vs. 55.2% and 36.6% vs. 34.4%, respectively), we concluded that luteal estrogen supplementation in fixed multidose GnRH antagonist cycles did not change the pregnancy rates significantly. To evaluate the effect of luteal estrogen supplementation on pregnancy rates in normal responder IVF patients treated with recombinant FSH and fixed multidose GnRH antagonist, patients were randomized into two groups to receive vaginal 600 mg/d micronized progesterone for luteal phase supplementation with or without transdermal estrogen supplementation (100 μg/d). Because pregnancy rates and ongoing pregnancy rates were similar with and without estrogen supplementation (50.0% vs. 55.2% and 36.6% vs. 34.4%, respectively), we concluded that luteal estrogen supplementation in fixed multidose GnRH antagonist cycles did not change the pregnancy rates significantly. Pituitary suppression to prevent premature LH surge is an important component of ovarian stimulation cycles (1Loumaye E. The control of endogenous secretion of LH by gonadotrophin-releasing hormone agonists during ovarian hyperstimulation for in-vitro fertilization and embryo transfer.Hum Reprod. 1990; 5: 357-376PubMed Google Scholar). Pituitary down-regulation with a GnRH agonist is currently the most frequently used method (2Engel J.B. Griesinger G. Schultze-Mosgau A. Felberbaum R. Diedrich K. GnRH agonists and antagonists in assisted reproduction: pregnancy rate.Reprod Biomed Online. 2006; 13: 84-87Abstract Full Text PDF PubMed Scopus (26) Google Scholar). However, GnRH antagonists (cetrorelix, ganirelix) are increasingly used because of the advantages such as having no initial flare effect, no estrogen (E2) deprivation symptoms, shorter duration of treatment, reduced gonadotropin use, rapid reversibility and flexibility (3Shapiro D.B. An overview of GnRH antagonists in infertility treatments. Introduction.Fertil Steril. 2003; 80 (discussion S32–4): S1-S7Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Progesterone (P) supplementation in the luteal phase of IVF cycles down-regulated with GnRH agonist is well established. However, there is no similar consensus for luteal E2 supplementation in cycles down-regulated with GnRH antagonists (4Lukaszuk K. Liss J. Lukaszuk M. Maj B. Optimization of estradiol supplementation during the luteal phase improves the pregnancy rate in women undergoing in vitro fertilization-embryo transfer cycles.Fertil Steril. 2005; 83: 1372-1376Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). Furthermore, the data regarding the E2 supplementation in antagonist cycles is insufficient, and the experience is limited (5Tavaniotou A. Devroey P. Luteal hormonal profile of oocyte donors stimulated with a GnRH antagonist compared with natural cycles.Reprod Biomed Online. 2006; 13: 326-330Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 6Fatemi H.M. Kolibianakis E.M. Camus M. Tournaye H. Donoso P. Papanikolaou E. et al.Addition of estradiol to progesterone for luteal supplementation in patients stimulated with GnRH antagonist/rFSH for IVF: a randomized controlled trial.Hum Reprod. 2006; 21: 2628-2632Crossref PubMed Scopus (47) Google Scholar). Both serum P and E2 were shown to decrease in the luteal phase of GnRH agonist cycles (7Laufer N. Navot D. Schenker J.G. The pattern of luteal phase plasma progesterone and estradiol in fertile cycles.Am J Obstet Gynecol. 1982; 143: 808-813Abstract Full Text PDF PubMed Scopus (50) Google Scholar). Administration of P for luteal support is almost standard (8Pritts E.A. Atwood A.K. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.Hum Reprod. 2002; 17: 2287-2299Crossref PubMed Scopus (254) Google Scholar). The use of E2 in the luteal phase of agonist down-regulated cycles was shown to improve pregnancy rates (4Lukaszuk K. Liss J. Lukaszuk M. Maj B. Optimization of estradiol supplementation during the luteal phase improves the pregnancy rate in women undergoing in vitro fertilization-embryo transfer cycles.Fertil Steril. 2005; 83: 1372-1376Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 9Farhi J. Weissman A. Steinfeld Z. Shorer M. Nahum H. Levran D. Estradiol supplementation during the luteal phase may improve the pregnancy rate in patients undergoing in vitro fertilization–embryo transfer cycles.Fertil Steril. 2000; 73: 761-766Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Luteal hormonal profile is different in the antagonist cycles. Tavaniotou et al. (5Tavaniotou A. Devroey P. Luteal hormonal profile of oocyte donors stimulated with a GnRH antagonist compared with natural cycles.Reprod Biomed Online. 2006; 13: 326-330Abstract Full Text PDF PubMed Scopus (42) Google Scholar) reported that serum P levels in antagonist cycles may be higher than that of normal cycles with decreased serum E2 levels. Therefore, benefits of E2 supplementation on ovarian response might be more prominent in antagonist cycles compared to agonist cycles. In this study, we aimed to investigate the effect of luteal E2 supplementation on pregnancy rates in normal responder patients treated with fixed multidose GnRH antagonist for pituitary suppression. During the study period, February 2006 through June 2006, 60 normal responder primary infertile patients attending the outpatient clinics of the Infertility and Reproductive Medicine Unit of Gülhane Military Medical Hospital were included in this study. The study was approved by Institutional Ethics Committee of Gülhane Military Medical Academy. Written informed consent was obtained from each participant. Criteria for normal responder patients included the following: age <36 years, day 3 FSH ≤10 IU/L, day 3 E2 10 mIU/mL. Clinical pregnancy was defined as the presence of an intrauterine gestational sac on ultrasonographic examination. Ongoing pregnancy was defined as the presence of an intrauterine gestational sac with fetal heart beat at the 13th week of amenorrhea. Cobas Modular E170 Analytics (Roche Diagnostics, Mannheim, Germany) was used to measure FSH, LH, E2, and P levels. Intra- and interassay coefficients of variations were as follows: FSH (analytical sensitivity: <0.10 mIU/mL, intraassay coefficient of variation [CV]: 2.5%, interassay CV: 3.6%), LH (analytical sensitivity: 0.10 mIU/mL, intraassay CV: 0.7%, interassay CV: 1.6%), E2 (analytical sensitivity: 5.0 pg/mL, intraassay CV: 1.70%, interassay CV: 2.2%), P (analytical sensitivity: 0.03 ng/mL, intraassay CV: 0.9%, interassay CV: 2.0%). Based on the difference of pregnancy rate between the two groups a sample size of 800 patients (400 patients in each group) was required to detect a differrence of 10% (α = 0.05 and power = 80%). It was not possible to reach the calculated 400 cases in each group for the achievement of power 80% at a 5% significance level under the conditions at one center. SPSS 11.5 (SPSS Inc., Chicago, IL) statistical package for Windows was used for statistical analyses. Student's t test for independent samples and Mann-Whitney U test were used to compare parametric and nonparametric data between groups, respectively. The χ2 test and Fisher's exact test were used to analyze the frequencies of nominal variables in crosstables. Analyses were performed on a per-treatment basis. Type I error was set at .05. Values were expressed as mean ± standard deviation (SD) (minimum–maximum), frequency (%), or ratio (%). Two groups were comparable regarding the baseline characteristics, including female age, basal FSH, E2 level on hCG day, mean duration of stimulation, number of oocytes, M2 oocytes, embryos, and transferred embryos (Table 1). Clinically mild ovarian hyperstimulation syndrome (OHSS) was observed in two patients (6.7%) in the E2 supplemented group. There was no OHSS among patients who did not receive E2 supplementation.Table 1Baseline parameters, cycle characteristics, and treatment results of patients with and without luteal estrogen supplementation.CharacteristicGroup 1 (No suppl., N = 29)Group 2 (E2 suppl., N = 30)PFemale age (years)30.9 ± 3.5 (23–35)31.4 ± 2.6 (25–35).53Aetiology of infertility Unexplained23 (79.3%)17 (56.7%)NS Male factor2 (6.9%)4 (13.3%) Tubal factor4 (13.8%)9 (30.0%)BMI (kg/m2)22.5 ± 1.3 (19.1–24.2)22.9 ± 1.3 (20.4–24.5).16D3 FSH (mIU/mL)5.6 ± 1.1 (2.9–7.4)5.2 ± 1.1 (3.1–7.3).14Gonadotropin (rFSH) use (IU)2,057 ± 603 (1,050–3,100)1,988 ± 530 (1,350–3,050).64Duration of stimulation (days)9.0 ± 1.1 (7–11)9.1 ± 1.0 (7–11).75Duration of GnRH antagonist use (days)3.4 ± 1.1 (2–5)4.0 ± 1.0 (2–5).68E2 the day of hCG (pg/mL)1,793.2 ± 849.4 (375–3,775)1,959.9 ± 1,014.8 (810–4,975).62No. of oocytes10.2 ± 3.5 (3–16)12.0 ± 3.6 (6–19).20No. of M2 oocytes6.7 ± 3.9 (0–12)8.1 ± 3.7 (1–14).32No. of embryos available5.9 ± 3.8 (0–11)5.6 ± 3.0 (0–11).64No. of embryos transferred2.1 ± 1.2 (0–4)1.8 ± (0–3).12Cycle cancellation (%)5/29 (17.2)5/30 (16.7).95Clinical pregnancy rate per started cycle (%)13/29 (44.8)13/30 (43.3).91Clinical pregnancy per embryo transfer (%)13/21 (61.9)13/23 (56.5).72Ongoing pregnancy rate (%)10/29 (34.4)11/30 (36.6).86Note: Values are expressed as mean ± SD with range or ratio (%) in parentheses; NS = not significant; BMI = body mass index. Open table in a new tab Note: Values are expressed as mean ± SD with range or ratio (%) in parentheses; NS = not significant; BMI = body mass index. Pregnancy rates, clinical pregnancy rates, pregnancy rates per embryo transfer, and ongoing pregnancy rates were not significantly different in either of these groups (Table 1). Some patients were cancelled before transfer because of poor embryo quality. In Turkey, up to three cycles are covered by the goverment insurance system. The couple lose their right if they have embryo transfer despite poor embryo quality. As a result of this, the pregnancy rates per transfer concerning our study appeared to be high. Yet, the pregnancy rates per starting cycle was 44.8% in group 1 versus 43.3 in group 2 (P=.91, not significant). Luteal hormonal changes justify the use of luteal P (7Laufer N. Navot D. Schenker J.G. The pattern of luteal phase plasma progesterone and estradiol in fertile cycles.Am J Obstet Gynecol. 1982; 143: 808-813Abstract Full Text PDF PubMed Scopus (50) Google Scholar). Progesterone supplementation of the luteal phase in IVF cycles was shown to improve treatment outcome in agonist down-regulated cycles (8Pritts E.A. Atwood A.K. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.Hum Reprod. 2002; 17: 2287-2299Crossref PubMed Scopus (254) Google Scholar). Some researchers recommended luteal E2 supplementation after the GnRH agonist (9Farhi J. Weissman A. Steinfeld Z. Shorer M. Nahum H. Levran D. Estradiol supplementation during the luteal phase may improve the pregnancy rate in patients undergoing in vitro fertilization–embryo transfer cycles.Fertil Steril. 2000; 73: 761-766Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). However, the strength of this recommendation is weaker compared to progesterone supplementation (8Pritts E.A. Atwood A.K. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.Hum Reprod. 2002; 17: 2287-2299Crossref PubMed Scopus (254) Google Scholar). Antagonists have entirely different mechanisms of action (3Shapiro D.B. An overview of GnRH antagonists in infertility treatments. Introduction.Fertil Steril. 2003; 80 (discussion S32–4): S1-S7Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Therefore, their use might require substantially different treatment protocols. de Jong et al. (12de Jong D. Macklon N.S. Eijkemans M.J. Mannaerts B.M. Coelingh Bennink H.J. Fauser B.C. Dynamics of the development of multiple follicles during ovarian stimulation for in vitro fertilization using recombinant follicle-stimulating hormone (Puregon) and various doses of the gonadotropin-releasing hormone antagonist ganirelix (Orgalutran/Antagon).Fertil Steril. 2001; 75: 688-693Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar) showed that late follicular LH, androstenedione, and E2 levels decreased in agonist cycles in a dose-related fashion. GnRH receptors were demonstrated in ovaries, uterus, and placenta (13Weiss J.M. Oltmanns K. Gurke E.M. Polack S. Eick F. Felberbaum R. et al.Actions of gonadotropin-releasing hormone antagonists on steroidogenesis in human granulosa lutein cells.Eur J Endocrinol. 2001; 144: 677-685Crossref PubMed Scopus (40) Google Scholar). GnRH receptors on granulosa cells in the ovary might explain the different effects of the GnRH agonist and antagonists on luteal hormonal dynamics (14Latouche J. Crumeyrolle-Arias M. Jordan D. Kopp N. Augendre-Ferrante B. Cedard L. et al.GnRH receptors in human granulosa cells: anatomical localization and characterization by autoradiographic study.Endocrinology. 1989; 125: 1739-1741Crossref PubMed Scopus (143) Google Scholar). An agonistic effect of GnRH agonists on the ovary may prevent further decrease in E2, whereas the pure antagonistic action of GnRH antagonists might cause a more profound decrease of E2. There is evidence to support differential effects of GnRH antagonists on ovarian granulosa–lutein cell steroidogenesis (15Minaretzis D. Alper M.M. Oskowitz S.P. Lobel S.M. Mortola J.F. Pavlou S.N. Gonadotropin-releasing hormone antagonist versus agonist administration in women undergoing controlled ovarian hyperstimulation: cycle performance and in vitro steroidogenesis of granulosa-lutein cells.Am J Obstet Gynecol. 1995; 172: 1518-1525Abstract Full Text PDF PubMed Scopus (59) Google Scholar). On the other hand, Weiss et al. (13Weiss J.M. Oltmanns K. Gurke E.M. Polack S. Eick F. Felberbaum R. et al.Actions of gonadotropin-releasing hormone antagonists on steroidogenesis in human granulosa lutein cells.Eur J Endocrinol. 2001; 144: 677-685Crossref PubMed Scopus (40) Google Scholar) reported that neither cetrorelix nor ganirelix has any significant in vitro effect on ovarian steroidogenesis (16Tarlatzis B.C. Kolibianakis E.M. Direct ovarian effects and safety aspects of GnRH agonists and antagonists.Reprod Biomed Online. 2002; 5: 8-13Abstract Full Text PDF PubMed Scopus (21) Google Scholar). A short duration of the action of antagonists prevents a continued direct effect on hormonal levels during the luteal phase. However, a decreased number of follicles in the antagonist cycles might also explain this difference (17Olivennes F. Belaisch-Allart J. Emperaire J.C. Dechaud H. Alvarez S. Moreau L. et al.Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin).Fertil Steril. 2000; 73: 314-320Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). Therefore, although the exact mechanism is not known yet, Tavaniotou et al. (5Tavaniotou A. Devroey P. Luteal hormonal profile of oocyte donors stimulated with a GnRH antagonist compared with natural cycles.Reprod Biomed Online. 2006; 13: 326-330Abstract Full Text PDF PubMed Scopus (42) Google Scholar) showed significantly decreased estrogen levels in contrast to significantly increased progesterone levels in antagonist cycles. The drawback of our study is a limited sample size and thus a limited power. Further powerful randomized control trials are required to delineate the role of E2 supplementation in the antagonist cycle. In conclusion, this study demonstrated that in normal responder patients, E2 supplementation in fixed multidose antagonist cycles did not change pregnancy rates or the ongoing pregnancy rates significantly.