Journal of Obstetrics and Gynaecology, 2014; Early Online: 1–5 © 2014 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2014.958439
Luteal-long GnRH agonist versus flexible-multidose GnRH antagonist protocols for overweight and obese patients who underwent ICSI I. Esinler1, G. Bozdag1, D. Esinler2, K. S. Lale3 & H. Yarali1 1Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, 2Zubeyde Hanim Maternity Research Hospital and
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
3Department of Histology and Embryology, Faculty of Medicine, Hacettepe University Ankara, Turkey
A total of 413 consecutive infertile patients (572 cycles) with a body mass index (BMI) of 25 kg/m2 were enrolled into the study. The luteal-long GnRH agonist group (Group I) constituted 211 patients (300 cycles) and the flexible-multidose GnRH antagonist group (Group II) constituted 202 patients (272 cycles). The duration of stimulation (d) (10.1 2.5 vs 9.2 2.0; p 0.01); the total dose of gonadotrophin used (IU) (3,099.4 2,885.0 vs 2,684.0 1,046.4; p 0.05) and the E2 level on the day of hCG (pg/ml) (2,375.8 1,554.6 vs 1,905.6 1,598.8; p 0.01) were significantly lower in Group II when compared with Group I. However, the ongoing pregnancy per embryo transfer (37.0% vs 25.7%; p 0.05) and the implantation rate (25.7% vs 15.6%; p 0.01) were significantly lower in Group II when compared with Group I. In conclusion, we noted that the luteal-long GnRH agonist protocol produced higher implantation rates and higher clinical-ongoing pregnancy rates in overweight and obese patients when compared with the flexible-multidose GnRH antagonist protocol. Keywords: COH, GnRH agonist, GnRH antagonist, ICSI, IVF, OHSS, pregnancy rates
Introduction GnRH antagonist protocols for pituitary suppression in in-vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles began to be used widely by several IVF centres because of their possible advantages over the GnRH agonists protocols, such as no flare effect; lack of hypo-oestrogenism (Ben-Rafael 2012); shorter duration of stimulation (Al-Inany 2002); lower amount of gonadotropin used (Al-Inany 2002); possible lower OHSS risk (Ludwig et al. 2000); more comfortable for the patients and lower cost (Ben-Rafael 2012). According to a recently published metaanalysis, GnRH antagonist and GnRH agonist protocols were the same regarding the ongoing pregnancy rates and live birth rates (Al-Inany et al. 2011). However, none of the studies included into this meta-analysis compared the effect of GnRH agonist and GnRH antagonist protocols in overweight and obese patients. The adverse effect of obesity on natural fecundity has been reported (Harlass et al. 1984; Hollmann et al. 1996). A detrimental effect of obesity on ovarian stimulation response and pregnancy rates in IVF cycles has been reported in some studies
(Lashen et al. 1999; Lewis et al. 1990; Wass et al. 1997). Although obesity is a very important prognostic factor for the success of IVF/ICSI, there is still very limited data in the literature regarding which pituitary suppression protocol should be preferred in overweight and obese patients who undergo IVF/ICSI. Therefore, to add information to the literature, we aim to compare the performance of luteal-long GnRH agonist and flexible-multidose GnRH antagonist protocols in overweight and obese patients who underwent ICSI.
Materials and methods A total of 413 consecutive infertile patients (572 cycles), with a body mass index (BMI) of 25 kg/m2, from 2002 to 2012, were enrolled retrospectively through our computerised IVF database system. Inclusion criteria were: (1) women aged 39 years; (2) patients who underwent flexible-multidose GnRH antagonist cycle or luteal-long GnRH agonist cycle; (3) patients with a BMI of 25 kg/m2; (4) fresh ICSI cycles; (5) cycles in which ejaculate sperm was used for ICSI. We divided these cycles into two groups according to the pituitary suppression protocol employed. Group I (luteal-long GnRH agonist group) constituted 211 patients (300 cycles) who underwent luteal-long GnRH agonist protocol. Group II (flexible-multidose GnRH antagonist group) constituted 202 patients (272 cycles) who underwent flexiblemultidose GnRH antagonist protocol. Group I patients underwent controlled ovarian hyperstimulation consisting of luteal-long leuprolide acetate (Lucrin; Abbott Cedex, Istanbul, Turkey), with or without oral contraceptive pre-treatment (Lo-ovral; Wyeth, Istanbul, Turkey) and gonadotrophin using the step-down protocol. When desensitisation was achieved, as evidenced by plasma E2 levels of 50 pg/ml and the absence of ovarian follicles and endometrial thickness 6 mm on transvaginal ultrasound examination (Barash et al. 1998), daily s.c. injection of recombinant FSH (Gonal-F; Serono, Istanbul, Turkey or Puregon; MSD, Istanbul, Turkey) or urinary FSH (Menogon, Ferring, Istanbul, Turkey) was started. The starting dose of gonadotropin was determined based on the age of the female, antral follicle count at baseline transvaginal ultrasonography, day 3 FSH and E2 levels, body mass index (BMI) and previous ovarian response, if available. Ovarian response was monitored with frequent serum E2 measurements and transvaginal ultrasonography, as described previously (Bukulmez et al. 2000).
Correspondence: I. Esinler, Department of Obstetrics and Gynecology, Division of Reproductive Medicine and Infertility, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara 06100, Turkey. E-mail: [email protected]
2 I. Esinler et al.
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
Table I. The baseline characteristics of Group I (luteal-long GnRH agonist protocol) and Group II (flexible-multidose GnRH antagonist protocol).
Variable
Group I: Luteal-long GnRH agonist protocol
Group II: Flexiblemultidose antagonist protocol
p value
Patients (n) Cycles (n) Cancelled cycles (n, %) Female age (years) Body mass index (kg/m2) Patients with PCOS (%) Duration of infertility (m) Sperm count (millions/ml)* Sperm motility (%) Sperm progressive motility (%)
211 300 65 (21.7) 30.7 4.3 28.4 3.2 5.7 94.1 53.1 39.4 2.4 43.4 19.2 35.9 18.3
202 272 27 (9.9) 30.8 4.4 28.5 3.4 2.5 90.1 62.4 35.9 2.0 43.2 18.8 39.5 19.2
0.01 NS NS NS NS NS NS NS
NS, non-significant; PCOS, polycystic ovary syndrome. *Standard error of mean.
Group II patients underwent controlled ovarian hyperstimulation consisting of cetrorelix (Cetrotide; Serono) with or without oral contraceptive pre-treatment (Lo-ovral; Wyeth) and gonadotrophin using the step-down protocol. When desensitisation was achieved, as evidenced by plasma E2 levels of 50 pg/ml and the absence of ovarian follicles and endometrial thickness 6 mm on transvaginal ultrasound examination (Barash et al. 1998), daily s.c. injection of recombinant FSH (Gonal-F; Serono or Puregon; MSD) or urinary FSH (Menogon) was started. The starting dose of gonadotropin was determined based on the age of the female, antral follicle count at baseline transvaginal ultrasonography, day 3 follicle stimulating hormone (FSH) and oestradiol (E2) levels, body mass index (BMI) and previous ovarian response, if available. Ovarian response was monitored with frequent serum E2 measurements and transvaginal ultrasonography, as described previously (Bukulmez et al. 2000). A flexible multiple GnRH antagonist protocol was used. If serum E2 level was 600 pg/ml and/or if leading follicle exceeding 14 mm in diameter were present, cetrorelix 0.25 mg was initiated as daily injections up to the day of oocyte pick-up. The criterion for hCG (Profasi; Merck Serono, Istanbul, Turkey or Pregnyl; MSD or Ovitrelle; Merck Serono) administration was the presence of three or more follicles exceeding 17 mm in diameter for both groups. Oocyte retrieval was carried out under local anaesthesia using vaginal ultrasound-guided puncture of follicles 36 h after hCG administration. Standard procedures were carried out for gamete-embryo handling and cleavage-stage embryo or blastocyst (day 5) embryo transfer
(ET) was performed under abdominal ultrasonography guidance in all cases using a soft catheter (Wallace, PM Group, Istanbul, Turkey). The luteal phase was supported by daily vaginal progesterone suppositories (Crinone; Merck Serono) starting 1 day after oocyte pick-up. Clinical pregnancy was defined as the presence of an intrauterine gestational sac by transvaginal ultrasonography. Symptomatic patients with moderate or severe ovarian hyperstimulation syndrome (OHSS) were hospitalised (Schenker 1993). The statistical analyses were performed using SPSS version 17.0 (SPSS, Chicago, IL). The c2-test and Fisher’s exact test were used to analyse nominal variables in the form of frequency tables. Normally distributed (Kolmogorov–Smirnov test) parametric variables were tested using Student’s t-test. Non-normally distributed metric variables were analysed using the Mann–Whitney U test. A p value of 0.05 was considered statistically significant. Values were expressed as mean SD, unless stated otherwise. The Institutional Review Board of our university approved the study protocol.
Results Both groups were comparable regarding the women’s ages, the body mass index (BMI) and the duration of infertility (Table I). The duration of stimulation (d) (10.1 2.5 vs 9.2 2.0; p 0.01); the total dose of gonadotrophin used (IU) (3,099.4 2,885.0 vs 2,684.0 1,046.4; p 0.05) and the E2 level on the day of hCG (pg/ml) (2,375.8 1,554.6 vs 1,905.6 1,598.8; p 0.01) were significantly lower in Group II when compared with Group I (Table II). It is of interest that the number of cancelled cycles was significantly higher in Group I (21.7% vs 9.9%; p 0.05). The numbers of retrieved oocyte-cumulus complexes, metaphase II oocytes and two pronucleated oocytes were comparable between groups (Table II). Although the metaphase II oocytes/number of total oocyte-cumulus complexes ratio (83.9% vs 81.2%; p 0.05) was lower in Group II, the fertilisation rate (72.2% vs 75.4%; p 0.05) was higher in Group II when compared with Group I (Table II). The number of embryos transferred was comparable between groups (Table III). Although the rate of day 5 transfers (8.5% vs 24.5%; p 0.01) was higher in Group II, the clinical pregnancy per embryo transfer (41.3% vs 28.8%; p 0.01), the ongoing pregnancy per embryo transfer (37.0% vs 25.7%; p 0.05) and the implantation rate (25.7% vs 15.6%; p 0.01) were significantly lower in Group II when compared with Group I (Table III). Multiple pregnancy rates (36.8% vs 23.4%) were significantly lower in Group II when compared with Group I (Table III). The rate of OHSS requiring hospitalisation and miscarriage rates were comparable between the groups (Table III).
Table II. The controlled ovarian hyperstimulation response of Group I (luteal-long GnRH agonist protocol) and the Group II (flexible-multidose GnRH antagonist protocol).
Variable Duration of stimulation (d) Total dose of FSH used (IU) E2 level on the day of hCG administration (pg/ml) Follicles 17 mm diameter at hCG administration (n) Follicles 15–17 mm diameter at hCG administration (n) Follicles 10–14 mm diameter at hCG administration (n) Endometrial thickness at hCG administration (mm) NS, non-significant.
Group I: Luteallong GnRH agonist protocol
Group II: Flexible-multidose antagonist protocol
p value
10.1 2.5 3099.4 2885.0 2375.8 1554.6 3.8 2.8 3.7 2.8 6.1 5.9 10.9 2.2
9.2 2.0 2684.0 1046.4 1905.6 1598.8 3.3 2.7 3.4 2.8 7.3 6.6 10.6 2.2
0.01 0.05 0.01 NS NS 0.05 NS
Luteal-long GnRH agonist versus flexible-multidose GnRH antagonist protocols 3 Table III. The embryological data and pregnancy outcome of Group I (luteal-long GnRH agonist protocol) and Group II (flexible-multidose GnRH antagonist protocol).
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
Variable Oocyte-cumulus complexes (n) Metaphase II oocytes (n) Metaphase II oocytes/total oocytes (%) 2-pronucleated/metaphase II oocytes (%) 2-pronucleated oocytes (n) Available embryos at day 3 (n) Rate of embryos with 7 blastomeres and 10% fragmentation at day 3 (%) Embryos transferred (n) Rate of day 5 transfers (%) Cycles with embryo freezing (%) Clinical pregnancy/embryo transfer (%) Ongoing pregnancy/embryo transfer (%) Implantation rate (%) OHSS requiring hospitalisation (%) Multiple pregnancy rate (%) Miscarriage rate (%)
Group I: Luteal-long GnRH agonist protocol
Group II: Flexible-multidose antagonist protocol
p value
10.8. 6.8 9.1 6.0 83.9 72.2 6.6 5.0 6.1 4.7 51.8
11.9 7.5 9.7 6.1 81.2 75.4 7.4 4.9 7.0 4.8 65.4
NS NS 0.05 0.05 NS 0.05 0.05
2.0 0.7 8.5 39.1 41.3 37.0 25.7 1.3 36.8 10.3
2.0 0.9 24.5 36.7 28.8 25.7 15.6 1.2 23.4 8.6
NS 0.01 NS 0.01 0.05 0.01 NS 0.05 NS
NS, non-significant.
Discussion In a recently published meta-analysis (45 randomised controlled trials, RCTs; n 7,511), Al-Inany et al. (2011) reported that there was no evidence of a statistically significant difference in rates of live births (nine RCTs; odds ratio (OR) 0.86, 95% CI 0.69–1.08) between GnRH agonist and GnRH antagonist protocols in IVF cycles. There was a statistically significant lower incidence of OHSS in the GnRH antagonist group (29 RCTs; OR 0.43, 95% CI 0.33–0.57). But the clinical pregnancy rate per woman randomised was still significantly lower in the GnRH antagonist group when compared with the GnRH agonist group (41 RCTs (n 6,571), OR 0.84 (0.75–0.94) (Al-Inany et al. 2011). None of the studies included in the meta-analysis were designed specifically for overweight and obese patients. It is obvious that obesity may impair natural fecundity and may also impair IVF/ICSI performance via multiple endocrine and metabolic alterations, including steroid metabolism, altered secretion and action of insulin and other hormones, such as leptin, resistin, ghrelin or adiponectin (Esinler et al. 2008; Fedorcsak et al. 2004; Moschos et al. 2002; Pasquali et al. 2003). Although obesity is a very important prognostic factor for IVF/ICSI success, there is still very limited data in the literature regarding which stimulation protocol should be preferred for overweight and obese patients who undergo IVF/ICSI. Recently, Kumbak et al. (2010) compared the GnRH antagonist with GnRH agonist in 65 patients (27 agonist, 38 antagonist) whose BMI 40 kg/m2 (mean BMI 42.4 3.1 kg/m2 vs 42.1 2.2 kg/m2; p 0.05). They noted that the total amount of gonadotropin (IU) used was significantly higher in the GnRH antagonist group (2,982 1,091 vs 3,956 1,560; p 0.05) when compared with the GnRH agonist group. They also noted that the E2 level on the day of hCG administration (pg/ml) (2,734 1,370 vs 1,717 1,187; p 0.05) and the number of oocyte-cumulus complexes (16.1 7.7 vs 11.8 9.7; p 0.05) were significantly lower in the GnRH antagonist group. Kumbak et al. (2010) concluded that ongoing pregnancy and implantation rates were comparable between GnRH agonist and GnRH antagonist groups. Kim et al. (2012) recently reported that the duration of stimulation (d) (12.0 1.8 vs 13.2 2.0; p 0.05) and the total amount
of gonadotropin used (IU) (1,796.1 527.8 vs 2,125.6 492.5; p 0.05) were significantly lower in the GnRH antagonist protocol in patients with BMI 23 kg/m2. Unfortunately, the authors did not mention the mean BMI of the groups. The clinical pregnancy per embryo transfer (35.3% vs 35.3%) and the implantation rates (13.7% vs 14.9%) were comparable. In 2012, Marci and colleagues investigated the performance of GnRH agonist (n 130) and GnRH antagonist (n 86) in patients with BMI 25 kg/m2. Unfortunately, the authors did not mention the mean BMI of the groups. They reported that the duration of stimulation (d) (15.21 2.36 vs 11.84 2.33; p 0.01) and the total amount of gonadotropin used (IU) (2,228.88 1,109 vs 1,739 1,049; p 0.01) were significantly lower in the GnRH antagonist protocol. However, the clinical pregnancy rates were comparable (20.4% vs 16.2%). In the current study, we noted that the luteal-long GnRH agonist protocol was superior to the flexible-multidose GnRH antagonist protocol regarding implantation rates (25.7% vs 15.6%; p 0.01), clinical pregnancy rates (41.3% vs 28.8%; p 0.01) and ongoing pregnancy rates (37.0% vs 25.7%, p 0.05) in overweight and obese patients. Explanation of these results is necessary. We have to investigate two points: one is the follicular environment and embryo quality, the other is the endometrium. In our study, the numbers of retrieved oocyte-cumulus complexes, metaphase II oocytes and two pronucleated oocytes and the number of embryos transferred were comparable between groups. In addition, the GnRH antagonist protocol produced a higher number of available embryos at day 3 (6.1 4.7 vs 7.0 4.8; p 0.05), a higher rate of embryos with 7 cells at day 3 (51.8% vs 65.4%; p 0.01) and a higher rate of day 5 embryo transfers (8.5% vs 24.5%; p 0.01) when compared with the GnRH agonist group. Therefore, we may clearly say that according to our study, the GnRH antagonist protocol has no detrimental effect on embryo quality. The results of Kaya et al. (2012) support out findings. They recently compared the follicular fluid environment in women undergoing controlled ovarian hyperstimulation with a luteal-long GnRH agonist protocol (40 cycles) or multipledose GnRH antagonist protocol (40 cycles). They noted that the
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
4 I. Esinler et al. luteal-long GnRH agonist protocol and multiple-dose GnRH antagonist protocol seem to have similar effects on the follicular microenvironment in women undergoing controlled ovarian hyperstimulation (mean BMI 23.8 kg/m2 vs 22.3 kg/m2; p 0.05). Clinical pregnancy (37.5% vs 37.5%), live birth rate (32.5% vs 30%) per embryo transfer and implantation rate (18.4% vs 18.7%) was comparable. Cota et al. (2012) recently noted that oocyte morphology did not change in GnRH antagonist cycles. The second possible reason for low implantation (25.7% vs 15.6%; p 0.01) and low clinical pregnancy rates (41.3% vs 28.8%; p 0.01) of GnRH antagonist cycles in our study is endometrium. Although we transferred a comparable number of embryos and higher rate of day 5 embryo transfers, GnRH antagonist cycles produced lower implantation rates and lower clinical pregnancy rates. Our results may suggest a detrimental effect of GnRH antagonist protocol on endometrium in overweight and obese patients. The impact of GnRH antagonist and GnRH agonist protocols on endometrial receptivity has yielded conflicting results. Orvieto et al. (2008) investigated the effect of GnRH agonist (403 cycles) and GnRH antagonist (309 cycles) protocols on endometrial receptivity (patient’s BMI values were not mentioned). They noted that the GnRH agonist group showed significantly higher endometrial thickness (11.2 2.4 mm vs 10.6 2.0 mm; p 0.05) and a higher pregnancy rate (31.3% vs 24.6%; p 0.05), suggestive of a higher endometrial receptivity, compared with the GnRH antagonist group. The presence of GnRH receptors on the endometrium was demonstrated previously and the GnRH gene expression was present through the whole menstrual cycle, in particular, increased during the secretory phase (Dong et al. 1998; Raga et al. 1998; Takeuchi et al. 1998). Endometrial GnRH expression may play a paracrine/autocrine role in the implantation. Furthermore, there are sufficient data which suggest that GnRH antagonist is an inhibitor of cell cycle by decreasing the synthesis of growth factors in the endometrium (Hernandez 2000). As a result, there is a possibility that GnRH antagonists may compromise the endometrial development. However, Sirayapiwat et al. (2007) recently showed that GnRH antagonist has no effect on the endometrium of regularly menstruating women, as assessed by endometrial thickness, histological dating and morphometric analysis, while serum E2 and LH levels were lowered by GnRH antagonist. The impact of obesity on endometrial receptivity was investigated in an oocyte donation model (Bellver et al. 2007). A total of 2.656 patients undergoing their first oocyte donation cycle were enrolled in this retrospective study. The recipients were stratified based on BMI as 20.0 kg/m2 (n 471), 20.0–24.9 kg/m2 (n 1613), 25.0–29.9 kg/m2 (n 450) and 30.0 kg/m2 (n 122). Implantation, pregnancy, miscarriage and ongoing pregnancy rates were comparable among all BMI subgroups, although there was a trend of inferior outcome with higher BMI subgroups. Ongoing pregnancy rates were significantly lower in the overweight and obese groups compared with the underweight and normal groups. These data imply that endometrial receptivity might be decreased in overweight and obese females. The main limitation of our study was that it was a retrospective one. But we thought that the sample size of our study was adequate and the design of the study (inclusion and exclusion criteria) increased the power of the study. In conclusion, we noted that the luteal-long GnRH agonist protocol produced higher implantation rates and higher clinicalongoing pregnancy rates in overweight and obese patients when compared with the flexible-multidose GnRH antagonist protocol. To clarify this result, further studies should be designed for overweight and obese patients.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Al-Inany H. 2002. GnRH agonist versus antagonist therapy. Human Reproduction 17:1413; author reply 1413–1414. Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J et al. 2011. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews (5):CD001750. Barash A, Weissman A, Manor M, Milman D, Ben-Arie A, Shoham Z. 1998. Prospective evaluation of endometrial thickness as a predictor of pituitary down-regulation after gonadotropin-releasing hormone analogue administration in an in vitro fertilisation program. Fertility and Sterility 69:496–499. Bellver J, Melo MA, Bosch E, Serra V, Remohi J, Pellicer A. 2007. Obesity and poor reproductive outcome: the potential role of the endometrium. Fertility and Sterility 88:446–451. Ben-Rafael Z. 2012. Agonist or antagonist: what is preferable for in vitro fertilisation? Gynecological Endocrinology 28(Suppl 1):18–21. Bukulmez O, Yarali H, Yucel A, Sari T, Gurgan T. 2000. Intracytoplasmic sperm injection versus in vitro fertilisation for patients with a tubal factor as their sole cause of infertility: a prospective, randomized trial. Fertility and Sterility 73:38–42. Cota AM, Oliveira JB, Petersen CG, Mauri AL, Massaro FC, Silva LF et al. 2012. GnRH agonist versus GnRH antagonist in assisted reproduction cycles: oocyte morphology. Reproductive Biology and Endocrinology 10:33. Dong KW, Marcelin K, Hsu MI, Chiang CM, Hoffman G, Roberts JL. 1998. Expression of gonadotropin-releasing hormone (GnRH) gene in human uterine endometrial tissue. Molecular Human Reproduction 4:893–898. Esinler I, Bozdag G, Yarali H. 2008. Impact of isolated obesity on ICSI outcome. Reproductive Biomedicine Online 17:583–587. Fedorcsak P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N et al. 2004. Impact of overweight and underweight on assisted reproduction treatment. Human Reproduction 19:2523–2528. Harlass FE, Plymate SR, Fariss BL, Belts RP. 1984. Weight loss is associated with correction of gonadotropin and sex steroid abnormalities in the obese anovulatory female. Fertility and Sterility 42:649–652. Hernandez ER. 2000. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists. Human Reproduction 15:1211–1216. Hollmann M, Runnebaum B, Gerhard I. 1996. Effects of weight loss on the hormonal profile in obese, infertile women. Human Reproduction 11:1884–1891. Kaya A, Atabekoglu CS, Kahraman K, Taskin S, Ozmen B, Berker B et al. 2012. Follicular fluid concentrations of IGF-I, IGF-II, IGFBP-3, VEGF, AMH, and inhibin-B in women undergoing controlled ovarian hyperstimulation using GnRH agonist or GnRH antagonist. European Journal of Obstetrics, Gynecology, and Reproductive Biology 164:167–171. Kim CH, Moon JW, Kang HJ, Ahn JW, Kim SH, Chae HD et al. 2012. Effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase compared with GnRH agonist long protocol in non-obese and obese patients with polycystic ovary syndrome undergoing IVF/ICSI. Clinical and Experimental Reproductive Medicine 39:22–27. Kumbak B, Akbas H, Sahin L, Karlikaya G, Karagozoglu H, Kahraman S. 2010. Ovarian stimulation in women with high and low body mass index: GnRH agonist versus GnRH antagonist. Reproductive Biomedicine Online 20:314–319. Lashen H, Ledger W, Bernal AL, Barlow D. 1999. Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilisation. Human Reproduction 14:712–715. Lewis CG, Warnes GM, Wang XJ, Matthews CD. 1990. Failure of body mass index or body weight to influence markedly the response to ovarian hyperstimulation in normal cycling women. Fertility and Sterility 53:1097–1099. Ludwig M, Felberbaum RE, Devroey P, Albano C, Riethmuller-Winzen H, Schuler A et al. 2000. Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonist Cetrorelix (Cetrotide) in controlled ovarian stimulation for assisted reproduction. Archives of Gynecology and Obstetrics 264:29–32. Marci R, Lisi F, Soave I, Lo Monte G, Patella A, Caserta D et al. 2012. Ovarian stimulation in women with high and normal body mass index: GnRH agonist versus GnRH antagonist. Gynecological Endocrinology 28:792–795.
Luteal-long GnRH agonist versus flexible-multidose GnRH antagonist protocols 5
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
Moschos S, Chan JL, Mantzoros CS. 2002. Leptin and reproduction: a review. Fertility and Sterility 77:433–444. Orvieto R, Meltzer S, Rabinson J, Zohav E, Anteby EY, Nahum R. 2008. GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of endometrial receptivity. Fertility and Sterility 90:1294–1296. Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. 2003. Obesity and reproductive disorders in women. Human Reproduction Update 9:359–372. Raga F, Casan EM, Kruessel JS, Wen Y, Huang HY, Nezhat C et al. 1998. Quantitative gonadotropin-releasing hormone gene expression and immunohistochemical localisation in human endometrium throughout the menstrual cycle. Biology of Reproduction 59:661–669.
Schenker JG. 1993. Prevention and treatment of ovarian hyperstimulation. Human Reproduction 8:653–659. Sirayapiwat P, Suwajanakorn S, Triratanachat S, Niruthisard S. 2007. The effects of GnRH antagonist on the endometrium of normally menstruating women. Journal of Assisted Reproduction and Genetics 24:579–586. Takeuchi S, Futamura N, Minoura H, Toyoda N. 1998. Possible direct effect of gonadotropin releasing hormone on human endometrium and decidua. Life Sciences 62:1187–1194. Wass P, Waldenstrom U, Rossner S, Hellberg D. 1997. An android body fat distribution in females impairs the pregnancy rate of in-vitro fertilisation-embryo transfer. Human Reproduction 12:2057–2060.
Luteal-long GnRH agonist versus flexible-multidose GnRH antagonist protocols for overweight and obese patients who underwent ICSI I. Esinler1, G. Bozdag1, D. Esinler2, K. S. Lale3 & H. Yarali1 1Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, 2Zubeyde Hanim Maternity Research Hospital and
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
3Department of Histology and Embryology, Faculty of Medicine, Hacettepe University Ankara, Turkey
A total of 413 consecutive infertile patients (572 cycles) with a body mass index (BMI) of 25 kg/m2 were enrolled into the study. The luteal-long GnRH agonist group (Group I) constituted 211 patients (300 cycles) and the flexible-multidose GnRH antagonist group (Group II) constituted 202 patients (272 cycles). The duration of stimulation (d) (10.1 2.5 vs 9.2 2.0; p 0.01); the total dose of gonadotrophin used (IU) (3,099.4 2,885.0 vs 2,684.0 1,046.4; p 0.05) and the E2 level on the day of hCG (pg/ml) (2,375.8 1,554.6 vs 1,905.6 1,598.8; p 0.01) were significantly lower in Group II when compared with Group I. However, the ongoing pregnancy per embryo transfer (37.0% vs 25.7%; p 0.05) and the implantation rate (25.7% vs 15.6%; p 0.01) were significantly lower in Group II when compared with Group I. In conclusion, we noted that the luteal-long GnRH agonist protocol produced higher implantation rates and higher clinical-ongoing pregnancy rates in overweight and obese patients when compared with the flexible-multidose GnRH antagonist protocol. Keywords: COH, GnRH agonist, GnRH antagonist, ICSI, IVF, OHSS, pregnancy rates
Introduction GnRH antagonist protocols for pituitary suppression in in-vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles began to be used widely by several IVF centres because of their possible advantages over the GnRH agonists protocols, such as no flare effect; lack of hypo-oestrogenism (Ben-Rafael 2012); shorter duration of stimulation (Al-Inany 2002); lower amount of gonadotropin used (Al-Inany 2002); possible lower OHSS risk (Ludwig et al. 2000); more comfortable for the patients and lower cost (Ben-Rafael 2012). According to a recently published metaanalysis, GnRH antagonist and GnRH agonist protocols were the same regarding the ongoing pregnancy rates and live birth rates (Al-Inany et al. 2011). However, none of the studies included into this meta-analysis compared the effect of GnRH agonist and GnRH antagonist protocols in overweight and obese patients. The adverse effect of obesity on natural fecundity has been reported (Harlass et al. 1984; Hollmann et al. 1996). A detrimental effect of obesity on ovarian stimulation response and pregnancy rates in IVF cycles has been reported in some studies
(Lashen et al. 1999; Lewis et al. 1990; Wass et al. 1997). Although obesity is a very important prognostic factor for the success of IVF/ICSI, there is still very limited data in the literature regarding which pituitary suppression protocol should be preferred in overweight and obese patients who undergo IVF/ICSI. Therefore, to add information to the literature, we aim to compare the performance of luteal-long GnRH agonist and flexible-multidose GnRH antagonist protocols in overweight and obese patients who underwent ICSI.
Materials and methods A total of 413 consecutive infertile patients (572 cycles), with a body mass index (BMI) of 25 kg/m2, from 2002 to 2012, were enrolled retrospectively through our computerised IVF database system. Inclusion criteria were: (1) women aged 39 years; (2) patients who underwent flexible-multidose GnRH antagonist cycle or luteal-long GnRH agonist cycle; (3) patients with a BMI of 25 kg/m2; (4) fresh ICSI cycles; (5) cycles in which ejaculate sperm was used for ICSI. We divided these cycles into two groups according to the pituitary suppression protocol employed. Group I (luteal-long GnRH agonist group) constituted 211 patients (300 cycles) who underwent luteal-long GnRH agonist protocol. Group II (flexible-multidose GnRH antagonist group) constituted 202 patients (272 cycles) who underwent flexiblemultidose GnRH antagonist protocol. Group I patients underwent controlled ovarian hyperstimulation consisting of luteal-long leuprolide acetate (Lucrin; Abbott Cedex, Istanbul, Turkey), with or without oral contraceptive pre-treatment (Lo-ovral; Wyeth, Istanbul, Turkey) and gonadotrophin using the step-down protocol. When desensitisation was achieved, as evidenced by plasma E2 levels of 50 pg/ml and the absence of ovarian follicles and endometrial thickness 6 mm on transvaginal ultrasound examination (Barash et al. 1998), daily s.c. injection of recombinant FSH (Gonal-F; Serono, Istanbul, Turkey or Puregon; MSD, Istanbul, Turkey) or urinary FSH (Menogon, Ferring, Istanbul, Turkey) was started. The starting dose of gonadotropin was determined based on the age of the female, antral follicle count at baseline transvaginal ultrasonography, day 3 FSH and E2 levels, body mass index (BMI) and previous ovarian response, if available. Ovarian response was monitored with frequent serum E2 measurements and transvaginal ultrasonography, as described previously (Bukulmez et al. 2000).
Correspondence: I. Esinler, Department of Obstetrics and Gynecology, Division of Reproductive Medicine and Infertility, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara 06100, Turkey. E-mail: [email protected]
2 I. Esinler et al.
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
Table I. The baseline characteristics of Group I (luteal-long GnRH agonist protocol) and Group II (flexible-multidose GnRH antagonist protocol).
Variable
Group I: Luteal-long GnRH agonist protocol
Group II: Flexiblemultidose antagonist protocol
p value
Patients (n) Cycles (n) Cancelled cycles (n, %) Female age (years) Body mass index (kg/m2) Patients with PCOS (%) Duration of infertility (m) Sperm count (millions/ml)* Sperm motility (%) Sperm progressive motility (%)
211 300 65 (21.7) 30.7 4.3 28.4 3.2 5.7 94.1 53.1 39.4 2.4 43.4 19.2 35.9 18.3
202 272 27 (9.9) 30.8 4.4 28.5 3.4 2.5 90.1 62.4 35.9 2.0 43.2 18.8 39.5 19.2
0.01 NS NS NS NS NS NS NS
NS, non-significant; PCOS, polycystic ovary syndrome. *Standard error of mean.
Group II patients underwent controlled ovarian hyperstimulation consisting of cetrorelix (Cetrotide; Serono) with or without oral contraceptive pre-treatment (Lo-ovral; Wyeth) and gonadotrophin using the step-down protocol. When desensitisation was achieved, as evidenced by plasma E2 levels of 50 pg/ml and the absence of ovarian follicles and endometrial thickness 6 mm on transvaginal ultrasound examination (Barash et al. 1998), daily s.c. injection of recombinant FSH (Gonal-F; Serono or Puregon; MSD) or urinary FSH (Menogon) was started. The starting dose of gonadotropin was determined based on the age of the female, antral follicle count at baseline transvaginal ultrasonography, day 3 follicle stimulating hormone (FSH) and oestradiol (E2) levels, body mass index (BMI) and previous ovarian response, if available. Ovarian response was monitored with frequent serum E2 measurements and transvaginal ultrasonography, as described previously (Bukulmez et al. 2000). A flexible multiple GnRH antagonist protocol was used. If serum E2 level was 600 pg/ml and/or if leading follicle exceeding 14 mm in diameter were present, cetrorelix 0.25 mg was initiated as daily injections up to the day of oocyte pick-up. The criterion for hCG (Profasi; Merck Serono, Istanbul, Turkey or Pregnyl; MSD or Ovitrelle; Merck Serono) administration was the presence of three or more follicles exceeding 17 mm in diameter for both groups. Oocyte retrieval was carried out under local anaesthesia using vaginal ultrasound-guided puncture of follicles 36 h after hCG administration. Standard procedures were carried out for gamete-embryo handling and cleavage-stage embryo or blastocyst (day 5) embryo transfer
(ET) was performed under abdominal ultrasonography guidance in all cases using a soft catheter (Wallace, PM Group, Istanbul, Turkey). The luteal phase was supported by daily vaginal progesterone suppositories (Crinone; Merck Serono) starting 1 day after oocyte pick-up. Clinical pregnancy was defined as the presence of an intrauterine gestational sac by transvaginal ultrasonography. Symptomatic patients with moderate or severe ovarian hyperstimulation syndrome (OHSS) were hospitalised (Schenker 1993). The statistical analyses were performed using SPSS version 17.0 (SPSS, Chicago, IL). The c2-test and Fisher’s exact test were used to analyse nominal variables in the form of frequency tables. Normally distributed (Kolmogorov–Smirnov test) parametric variables were tested using Student’s t-test. Non-normally distributed metric variables were analysed using the Mann–Whitney U test. A p value of 0.05 was considered statistically significant. Values were expressed as mean SD, unless stated otherwise. The Institutional Review Board of our university approved the study protocol.
Results Both groups were comparable regarding the women’s ages, the body mass index (BMI) and the duration of infertility (Table I). The duration of stimulation (d) (10.1 2.5 vs 9.2 2.0; p 0.01); the total dose of gonadotrophin used (IU) (3,099.4 2,885.0 vs 2,684.0 1,046.4; p 0.05) and the E2 level on the day of hCG (pg/ml) (2,375.8 1,554.6 vs 1,905.6 1,598.8; p 0.01) were significantly lower in Group II when compared with Group I (Table II). It is of interest that the number of cancelled cycles was significantly higher in Group I (21.7% vs 9.9%; p 0.05). The numbers of retrieved oocyte-cumulus complexes, metaphase II oocytes and two pronucleated oocytes were comparable between groups (Table II). Although the metaphase II oocytes/number of total oocyte-cumulus complexes ratio (83.9% vs 81.2%; p 0.05) was lower in Group II, the fertilisation rate (72.2% vs 75.4%; p 0.05) was higher in Group II when compared with Group I (Table II). The number of embryos transferred was comparable between groups (Table III). Although the rate of day 5 transfers (8.5% vs 24.5%; p 0.01) was higher in Group II, the clinical pregnancy per embryo transfer (41.3% vs 28.8%; p 0.01), the ongoing pregnancy per embryo transfer (37.0% vs 25.7%; p 0.05) and the implantation rate (25.7% vs 15.6%; p 0.01) were significantly lower in Group II when compared with Group I (Table III). Multiple pregnancy rates (36.8% vs 23.4%) were significantly lower in Group II when compared with Group I (Table III). The rate of OHSS requiring hospitalisation and miscarriage rates were comparable between the groups (Table III).
Table II. The controlled ovarian hyperstimulation response of Group I (luteal-long GnRH agonist protocol) and the Group II (flexible-multidose GnRH antagonist protocol).
Variable Duration of stimulation (d) Total dose of FSH used (IU) E2 level on the day of hCG administration (pg/ml) Follicles 17 mm diameter at hCG administration (n) Follicles 15–17 mm diameter at hCG administration (n) Follicles 10–14 mm diameter at hCG administration (n) Endometrial thickness at hCG administration (mm) NS, non-significant.
Group I: Luteallong GnRH agonist protocol
Group II: Flexible-multidose antagonist protocol
p value
10.1 2.5 3099.4 2885.0 2375.8 1554.6 3.8 2.8 3.7 2.8 6.1 5.9 10.9 2.2
9.2 2.0 2684.0 1046.4 1905.6 1598.8 3.3 2.7 3.4 2.8 7.3 6.6 10.6 2.2
0.01 0.05 0.01 NS NS 0.05 NS
Luteal-long GnRH agonist versus flexible-multidose GnRH antagonist protocols 3 Table III. The embryological data and pregnancy outcome of Group I (luteal-long GnRH agonist protocol) and Group II (flexible-multidose GnRH antagonist protocol).
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
Variable Oocyte-cumulus complexes (n) Metaphase II oocytes (n) Metaphase II oocytes/total oocytes (%) 2-pronucleated/metaphase II oocytes (%) 2-pronucleated oocytes (n) Available embryos at day 3 (n) Rate of embryos with 7 blastomeres and 10% fragmentation at day 3 (%) Embryos transferred (n) Rate of day 5 transfers (%) Cycles with embryo freezing (%) Clinical pregnancy/embryo transfer (%) Ongoing pregnancy/embryo transfer (%) Implantation rate (%) OHSS requiring hospitalisation (%) Multiple pregnancy rate (%) Miscarriage rate (%)
Group I: Luteal-long GnRH agonist protocol
Group II: Flexible-multidose antagonist protocol
p value
10.8. 6.8 9.1 6.0 83.9 72.2 6.6 5.0 6.1 4.7 51.8
11.9 7.5 9.7 6.1 81.2 75.4 7.4 4.9 7.0 4.8 65.4
NS NS 0.05 0.05 NS 0.05 0.05
2.0 0.7 8.5 39.1 41.3 37.0 25.7 1.3 36.8 10.3
2.0 0.9 24.5 36.7 28.8 25.7 15.6 1.2 23.4 8.6
NS 0.01 NS 0.01 0.05 0.01 NS 0.05 NS
NS, non-significant.
Discussion In a recently published meta-analysis (45 randomised controlled trials, RCTs; n 7,511), Al-Inany et al. (2011) reported that there was no evidence of a statistically significant difference in rates of live births (nine RCTs; odds ratio (OR) 0.86, 95% CI 0.69–1.08) between GnRH agonist and GnRH antagonist protocols in IVF cycles. There was a statistically significant lower incidence of OHSS in the GnRH antagonist group (29 RCTs; OR 0.43, 95% CI 0.33–0.57). But the clinical pregnancy rate per woman randomised was still significantly lower in the GnRH antagonist group when compared with the GnRH agonist group (41 RCTs (n 6,571), OR 0.84 (0.75–0.94) (Al-Inany et al. 2011). None of the studies included in the meta-analysis were designed specifically for overweight and obese patients. It is obvious that obesity may impair natural fecundity and may also impair IVF/ICSI performance via multiple endocrine and metabolic alterations, including steroid metabolism, altered secretion and action of insulin and other hormones, such as leptin, resistin, ghrelin or adiponectin (Esinler et al. 2008; Fedorcsak et al. 2004; Moschos et al. 2002; Pasquali et al. 2003). Although obesity is a very important prognostic factor for IVF/ICSI success, there is still very limited data in the literature regarding which stimulation protocol should be preferred for overweight and obese patients who undergo IVF/ICSI. Recently, Kumbak et al. (2010) compared the GnRH antagonist with GnRH agonist in 65 patients (27 agonist, 38 antagonist) whose BMI 40 kg/m2 (mean BMI 42.4 3.1 kg/m2 vs 42.1 2.2 kg/m2; p 0.05). They noted that the total amount of gonadotropin (IU) used was significantly higher in the GnRH antagonist group (2,982 1,091 vs 3,956 1,560; p 0.05) when compared with the GnRH agonist group. They also noted that the E2 level on the day of hCG administration (pg/ml) (2,734 1,370 vs 1,717 1,187; p 0.05) and the number of oocyte-cumulus complexes (16.1 7.7 vs 11.8 9.7; p 0.05) were significantly lower in the GnRH antagonist group. Kumbak et al. (2010) concluded that ongoing pregnancy and implantation rates were comparable between GnRH agonist and GnRH antagonist groups. Kim et al. (2012) recently reported that the duration of stimulation (d) (12.0 1.8 vs 13.2 2.0; p 0.05) and the total amount
of gonadotropin used (IU) (1,796.1 527.8 vs 2,125.6 492.5; p 0.05) were significantly lower in the GnRH antagonist protocol in patients with BMI 23 kg/m2. Unfortunately, the authors did not mention the mean BMI of the groups. The clinical pregnancy per embryo transfer (35.3% vs 35.3%) and the implantation rates (13.7% vs 14.9%) were comparable. In 2012, Marci and colleagues investigated the performance of GnRH agonist (n 130) and GnRH antagonist (n 86) in patients with BMI 25 kg/m2. Unfortunately, the authors did not mention the mean BMI of the groups. They reported that the duration of stimulation (d) (15.21 2.36 vs 11.84 2.33; p 0.01) and the total amount of gonadotropin used (IU) (2,228.88 1,109 vs 1,739 1,049; p 0.01) were significantly lower in the GnRH antagonist protocol. However, the clinical pregnancy rates were comparable (20.4% vs 16.2%). In the current study, we noted that the luteal-long GnRH agonist protocol was superior to the flexible-multidose GnRH antagonist protocol regarding implantation rates (25.7% vs 15.6%; p 0.01), clinical pregnancy rates (41.3% vs 28.8%; p 0.01) and ongoing pregnancy rates (37.0% vs 25.7%, p 0.05) in overweight and obese patients. Explanation of these results is necessary. We have to investigate two points: one is the follicular environment and embryo quality, the other is the endometrium. In our study, the numbers of retrieved oocyte-cumulus complexes, metaphase II oocytes and two pronucleated oocytes and the number of embryos transferred were comparable between groups. In addition, the GnRH antagonist protocol produced a higher number of available embryos at day 3 (6.1 4.7 vs 7.0 4.8; p 0.05), a higher rate of embryos with 7 cells at day 3 (51.8% vs 65.4%; p 0.01) and a higher rate of day 5 embryo transfers (8.5% vs 24.5%; p 0.01) when compared with the GnRH agonist group. Therefore, we may clearly say that according to our study, the GnRH antagonist protocol has no detrimental effect on embryo quality. The results of Kaya et al. (2012) support out findings. They recently compared the follicular fluid environment in women undergoing controlled ovarian hyperstimulation with a luteal-long GnRH agonist protocol (40 cycles) or multipledose GnRH antagonist protocol (40 cycles). They noted that the
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
4 I. Esinler et al. luteal-long GnRH agonist protocol and multiple-dose GnRH antagonist protocol seem to have similar effects on the follicular microenvironment in women undergoing controlled ovarian hyperstimulation (mean BMI 23.8 kg/m2 vs 22.3 kg/m2; p 0.05). Clinical pregnancy (37.5% vs 37.5%), live birth rate (32.5% vs 30%) per embryo transfer and implantation rate (18.4% vs 18.7%) was comparable. Cota et al. (2012) recently noted that oocyte morphology did not change in GnRH antagonist cycles. The second possible reason for low implantation (25.7% vs 15.6%; p 0.01) and low clinical pregnancy rates (41.3% vs 28.8%; p 0.01) of GnRH antagonist cycles in our study is endometrium. Although we transferred a comparable number of embryos and higher rate of day 5 embryo transfers, GnRH antagonist cycles produced lower implantation rates and lower clinical pregnancy rates. Our results may suggest a detrimental effect of GnRH antagonist protocol on endometrium in overweight and obese patients. The impact of GnRH antagonist and GnRH agonist protocols on endometrial receptivity has yielded conflicting results. Orvieto et al. (2008) investigated the effect of GnRH agonist (403 cycles) and GnRH antagonist (309 cycles) protocols on endometrial receptivity (patient’s BMI values were not mentioned). They noted that the GnRH agonist group showed significantly higher endometrial thickness (11.2 2.4 mm vs 10.6 2.0 mm; p 0.05) and a higher pregnancy rate (31.3% vs 24.6%; p 0.05), suggestive of a higher endometrial receptivity, compared with the GnRH antagonist group. The presence of GnRH receptors on the endometrium was demonstrated previously and the GnRH gene expression was present through the whole menstrual cycle, in particular, increased during the secretory phase (Dong et al. 1998; Raga et al. 1998; Takeuchi et al. 1998). Endometrial GnRH expression may play a paracrine/autocrine role in the implantation. Furthermore, there are sufficient data which suggest that GnRH antagonist is an inhibitor of cell cycle by decreasing the synthesis of growth factors in the endometrium (Hernandez 2000). As a result, there is a possibility that GnRH antagonists may compromise the endometrial development. However, Sirayapiwat et al. (2007) recently showed that GnRH antagonist has no effect on the endometrium of regularly menstruating women, as assessed by endometrial thickness, histological dating and morphometric analysis, while serum E2 and LH levels were lowered by GnRH antagonist. The impact of obesity on endometrial receptivity was investigated in an oocyte donation model (Bellver et al. 2007). A total of 2.656 patients undergoing their first oocyte donation cycle were enrolled in this retrospective study. The recipients were stratified based on BMI as 20.0 kg/m2 (n 471), 20.0–24.9 kg/m2 (n 1613), 25.0–29.9 kg/m2 (n 450) and 30.0 kg/m2 (n 122). Implantation, pregnancy, miscarriage and ongoing pregnancy rates were comparable among all BMI subgroups, although there was a trend of inferior outcome with higher BMI subgroups. Ongoing pregnancy rates were significantly lower in the overweight and obese groups compared with the underweight and normal groups. These data imply that endometrial receptivity might be decreased in overweight and obese females. The main limitation of our study was that it was a retrospective one. But we thought that the sample size of our study was adequate and the design of the study (inclusion and exclusion criteria) increased the power of the study. In conclusion, we noted that the luteal-long GnRH agonist protocol produced higher implantation rates and higher clinicalongoing pregnancy rates in overweight and obese patients when compared with the flexible-multidose GnRH antagonist protocol. To clarify this result, further studies should be designed for overweight and obese patients.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Al-Inany H. 2002. GnRH agonist versus antagonist therapy. Human Reproduction 17:1413; author reply 1413–1414. Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J et al. 2011. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews (5):CD001750. Barash A, Weissman A, Manor M, Milman D, Ben-Arie A, Shoham Z. 1998. Prospective evaluation of endometrial thickness as a predictor of pituitary down-regulation after gonadotropin-releasing hormone analogue administration in an in vitro fertilisation program. Fertility and Sterility 69:496–499. Bellver J, Melo MA, Bosch E, Serra V, Remohi J, Pellicer A. 2007. Obesity and poor reproductive outcome: the potential role of the endometrium. Fertility and Sterility 88:446–451. Ben-Rafael Z. 2012. Agonist or antagonist: what is preferable for in vitro fertilisation? Gynecological Endocrinology 28(Suppl 1):18–21. Bukulmez O, Yarali H, Yucel A, Sari T, Gurgan T. 2000. Intracytoplasmic sperm injection versus in vitro fertilisation for patients with a tubal factor as their sole cause of infertility: a prospective, randomized trial. Fertility and Sterility 73:38–42. Cota AM, Oliveira JB, Petersen CG, Mauri AL, Massaro FC, Silva LF et al. 2012. GnRH agonist versus GnRH antagonist in assisted reproduction cycles: oocyte morphology. Reproductive Biology and Endocrinology 10:33. Dong KW, Marcelin K, Hsu MI, Chiang CM, Hoffman G, Roberts JL. 1998. Expression of gonadotropin-releasing hormone (GnRH) gene in human uterine endometrial tissue. Molecular Human Reproduction 4:893–898. Esinler I, Bozdag G, Yarali H. 2008. Impact of isolated obesity on ICSI outcome. Reproductive Biomedicine Online 17:583–587. Fedorcsak P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N et al. 2004. Impact of overweight and underweight on assisted reproduction treatment. Human Reproduction 19:2523–2528. Harlass FE, Plymate SR, Fariss BL, Belts RP. 1984. Weight loss is associated with correction of gonadotropin and sex steroid abnormalities in the obese anovulatory female. Fertility and Sterility 42:649–652. Hernandez ER. 2000. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists. Human Reproduction 15:1211–1216. Hollmann M, Runnebaum B, Gerhard I. 1996. Effects of weight loss on the hormonal profile in obese, infertile women. Human Reproduction 11:1884–1891. Kaya A, Atabekoglu CS, Kahraman K, Taskin S, Ozmen B, Berker B et al. 2012. Follicular fluid concentrations of IGF-I, IGF-II, IGFBP-3, VEGF, AMH, and inhibin-B in women undergoing controlled ovarian hyperstimulation using GnRH agonist or GnRH antagonist. European Journal of Obstetrics, Gynecology, and Reproductive Biology 164:167–171. Kim CH, Moon JW, Kang HJ, Ahn JW, Kim SH, Chae HD et al. 2012. Effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase compared with GnRH agonist long protocol in non-obese and obese patients with polycystic ovary syndrome undergoing IVF/ICSI. Clinical and Experimental Reproductive Medicine 39:22–27. Kumbak B, Akbas H, Sahin L, Karlikaya G, Karagozoglu H, Kahraman S. 2010. Ovarian stimulation in women with high and low body mass index: GnRH agonist versus GnRH antagonist. Reproductive Biomedicine Online 20:314–319. Lashen H, Ledger W, Bernal AL, Barlow D. 1999. Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilisation. Human Reproduction 14:712–715. Lewis CG, Warnes GM, Wang XJ, Matthews CD. 1990. Failure of body mass index or body weight to influence markedly the response to ovarian hyperstimulation in normal cycling women. Fertility and Sterility 53:1097–1099. Ludwig M, Felberbaum RE, Devroey P, Albano C, Riethmuller-Winzen H, Schuler A et al. 2000. Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonist Cetrorelix (Cetrotide) in controlled ovarian stimulation for assisted reproduction. Archives of Gynecology and Obstetrics 264:29–32. Marci R, Lisi F, Soave I, Lo Monte G, Patella A, Caserta D et al. 2012. Ovarian stimulation in women with high and normal body mass index: GnRH agonist versus GnRH antagonist. Gynecological Endocrinology 28:792–795.
Luteal-long GnRH agonist versus flexible-multidose GnRH antagonist protocols 5
J Obstet Gynaecol Downloaded from informahealthcare.com by Selcuk Universitesi on 12/23/14 For personal use only.
Moschos S, Chan JL, Mantzoros CS. 2002. Leptin and reproduction: a review. Fertility and Sterility 77:433–444. Orvieto R, Meltzer S, Rabinson J, Zohav E, Anteby EY, Nahum R. 2008. GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of endometrial receptivity. Fertility and Sterility 90:1294–1296. Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. 2003. Obesity and reproductive disorders in women. Human Reproduction Update 9:359–372. Raga F, Casan EM, Kruessel JS, Wen Y, Huang HY, Nezhat C et al. 1998. Quantitative gonadotropin-releasing hormone gene expression and immunohistochemical localisation in human endometrium throughout the menstrual cycle. Biology of Reproduction 59:661–669.
Schenker JG. 1993. Prevention and treatment of ovarian hyperstimulation. Human Reproduction 8:653–659. Sirayapiwat P, Suwajanakorn S, Triratanachat S, Niruthisard S. 2007. The effects of GnRH antagonist on the endometrium of normally menstruating women. Journal of Assisted Reproduction and Genetics 24:579–586. Takeuchi S, Futamura N, Minoura H, Toyoda N. 1998. Possible direct effect of gonadotropin releasing hormone on human endometrium and decidua. Life Sciences 62:1187–1194. Wass P, Waldenstrom U, Rossner S, Hellberg D. 1997. An android body fat distribution in females impairs the pregnancy rate of in-vitro fertilisation-embryo transfer. Human Reproduction 12:2057–2060.
