European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 137–140
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Dual suppression with oral contraceptive pills in GnRH antagonist cycles for patients with polycystic ovary syndrome undergoing intracytoplasmic sperm injection ¨ zmen a,*, Y.E. S¸u¨ku¨r b, M.M. Seval a, C. Ates¸ c, C.S. Atabekog˘lu a, M. So¨nmezer a, B. O B. Berker a a
Department of Obstetrics and Gynaecology, Ankara University School of Medicine, Ankara, Turkey Department of Obstetrics and Gynaecology, Kec¸io¨ren Training and Research Hospital, Ankara, Turkey c Department of Biostatistics, Ankara University School of Medicine, Ankara, Turkey b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 June 2014 Received in revised form 23 August 2014 Accepted 22 October 2014
Objective: To evaluate the effects of a gonadotropin-releasing hormone (GnRH) antagonist protocol, with or without oral contraceptive pill (OCP) pretreatment, in patients with polycystic ovary syndrome (PCOS) undergoing intracytoplasmic sperm injection (ICSI). Study design: In this retrospective cohort study, 410 infertile patients with PCOS were assessed in their first ICSI cycles between January 2006 and June 2013. In Group A (n = 208), patients underwent a long luteal GnRH agonist protocol, and in Groups B (n = 143) and C (n = 59), patients underwent a GnRH antagonist protocol. The patients in Group C also received OCPs containing 30 mg of ethinyl oestradiol and 3 mg of drospirenone prior to treatment. The main outcome measures were pregnancy and ovarian hyperstimulation syndrome (OHSS) rates. Results: Demographic features, body mass index, duration of infertility, serum baseline hormone levels, cycle outcomes, multiple pregnancy rates, miscarriage rates, OHSS rates, total number of Grade A embryos and total number of transferred embryos were comparable between the groups. Clinical pregnancy rates were 27.4%, 26.6% and 23.7% in Groups A, B and C, respectively (p = 0.853). Conclusions: OCP pretreatment was found to have no beneficial or adverse effects in patients with PCOS undergoing a GnRH antagonist protocol for ICSI, but can be used for cycle scheduling. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: GnRH agonist GnRH antagonist ICSI Oral contraceptive PCOS
Introduction Debate continues regarding the optimal controlled ovarian stimulation (COS) protocol in patients with polycystic ovary syndrome (PCOS) due to problems encountered in in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. Heterogeneous follicular maturation, lower fertilization and pregnancy rates, and a high risk of cycle cancellation in order to avoid ovarian hyperstimulation syndrome (OHSS) are the main problems in such cases [1]. Recently, downregulation with gonadotropinreleasing hormone (GnRH) antagonists has been widely recommended in patients with PCOS due to advantages including short stimulation duration, lower gonadotropin consumption and almost zero incidence of severe OHSS [2–4]. However, GnRH
* Corresponding author. Tel.: +90 3125956405; fax: +90 3123203553. ¨ zmen). E-mail address: [email protected] (B. O http://dx.doi.org/10.1016/j.ejogrb.2014.10.033 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
antagonist protocols are less flexible than long luteal GnRH agonist protocols, so use of GnRH antagonists can be problematic in terms of cycle initiation and scheduling, especially in patients with oligomenorrhoea [2]. Use of oral contraceptive pills (OCPs) in the preceding cycle can be used for cycle scheduling in patients receiving a GnRH antagonist protocol, as this avoids increases in both follicle-stimulating hormone (FSH) and luteinizing hormone (LH), along with improved synchronization and homogeneity of follicular recruitment in the late luteal phase by oestradiol or progesterone components [2,5,6]. However, the use of OCPs in GnRH antagonist cycles can lead to negative consequences such as longer stimulation duration and increased gonadotropin consumption [2]. In a recent metaanalysis, OCP pretreatment in GnRH antagonist cycles of normoresponders was found to be associated with a significant reduction in livebirth rates [7]. Although the reason is unclear, the progesterone component may have had a negative impact on endometrial receptivity in the subsequent cycle, and/or low
138
B. O¨zmen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 137–140
endogenous LH levels may have impaired oocyte competence when COS was performed with recombinant human FSH in GnRH antagonist cycles [7]. In a recent randomized controlled trial (RCT), OCP pretreatment in GnRH antagonist cycles was reported to have no beneficial effects compared with long luteal GnRH agonist cycles in patients with PCOS [8]. The aim of this study was to assess the possible effects of OCP treatment before GnRH antagonist cycles on COS and cycle outcomes in patients with PCOS undergoing ICSI.
Materials and methods Patients with PCOS treated at a university-based infertility clinic between January 2006 and June 2013 were recruited in this retrospective cohort study. The study was approved by the Institutional Review Board of Ankara University School of Medicine. PCOS was diagnosed according to the 2006 criteria of the Androgen Excess Society (hirsutism/hyperandrogenaemia and oligo-anovulation/polycystic ovaries and exclusion of other androgen excess or related disorders) [9]. In total, 683 patients with PCOS who underwent ICSI/embryo transfer (ET) cycles during the study period were selected from the hospital database. After application of inclusion and exclusion criteria, the data for 410 patients with PCOS were found to be eligible for this study. The inclusion criteria were female, age < 35 years and baseline FSH level < 12 IU/l. The exclusion criteria were body mass index (BMI) > 30 kg/m2, secondary infertility, presence of any untreated thyroid dysfunction/hyperprolactinaemia and uterine abnormality. For eligible participants, all data regarding COS and clinical outcomes were extracted from the database, and the patients were divided into three groups according to downregulation protocol and OCP pretreatment. The patients in Group A (n = 208) underwent standardized luteal downregulation with a GnRH agonist [leuprolide acetate 1 mg SC (Lucrin); Abbott, Istanbul, Turkey] commenced on the 21st day of the preceding menstrual cycle. The dose of leuprolide acetate was halved on commencement of menstrual bleeding, and continued at the same dose until injection of human chorionic gonadotropin (hCG). The patients in Groups B (n = 143) and C (n = 59) underwent downregulation with a GnRH antagonist [ganirelix 0.25 mg SC (Orgalutran); MSD, The Netherlands], started on Day 6 of ovarian stimulation. The patients in Group C received OCPs [30 mg ethinyl oestradiol + 3 mg drospirenone (Yasmin); Schering, Istanbul, Turkey] prior to the GnRH antagonist protocol. In all groups, COS was performed with rFSH (either Gonal-F, Serono, Bari, Italy or Puregon, MSD, The Netherlands) initiated on Day 3 of induced or spontaneous menstrual bleeding in Groups B and C. The initial gonadotropin dose ranged between 150 and 300 IU depending on BMI, age and ovarian response to COS. The gonadotropin dose was adjusted according to monitoring data regarding follicular development and serum oestradiol, progesterone and LH levels. Triggering was implemented when at least three
follicles > 17 mm diameter were present using a single dose of 10,000 IU of hCG (Pregnyl; Organon, Istanbul, Turkey). After 36 h, transvaginal-ultrasound-guided oocyte collection was performed. Fertilization was achieved with ICSI in all couples, and ET was performed 3 days after oocyte collection. A maximum of three embryos were transferred under ultrasound guidance. All women received 90 mg/day vaginal micronized progesterone (Crinone 8% gel; Serono, Istanbul, Turkey) for luteal phase support from the day of oocyte collection until the pregnancy test performed 12 days after ET, and women with a positive pregnancy test continued to take luteal phase support until 10 weeks of gestation. Pregnancy and clinical pregnancy were defined, respectively, by measuring serum b-hCG levels 2 weeks after ET and as the presence of a fetus with a heart beat at 6 weeks of gestation. The implantation rate was calculated separately for each woman as the number of gestational sacs divided by the number of transferred embryos multiplied by 100. Severe OHSS was diagnosed when the hematocrit level exceeded 45%, and any symptoms of abdominal discomfort, oliguria and/or respiratory difficulty were reported together with moderate ascites and/or thrombocytosis. The primary outcome measures were implantation and clinical pregnancy rates. The secondary outcome measures were multiple pregnancy, miscarriage and severe OHSS rates. Statistical analyses Statistical Package for the Social Sciences (SPSS) Version 15.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. Shapiro–Wilk test was used to test the distribution of normality. According to the results, non-parametric tests were preferred. Continuous variables were compared using Kruskal–Wallis test. Categorical variables were compared using Chi-squared test or Fisher’s exact test where appropriate. p < 0.05 was considered to indicate significance. When a significant difference was identified, a post-hoc analysis was performed between all group pairs to define the source of significance.
Results The groups were comparable in terms of baseline and demographic parameters including age, BMI, duration of infertility, adjuvant male factor infertility and serum baseline hormone levels (Table 1). The cycle outcomes of all three groups are shown in Table 2. The groups were found to be comparable in terms of the numbers of retrieved and MII oocytes, numbers of generated Grade A and transferred embryos, stimulation duration and endometrial thickness on the day of oocyte collection (Table 2). The outcome measures of the study are shown in Table 3. The implantation rates of Groups A, B, and C were 15%, 20%, and 22%, respectively (p = 0.853). The clinical pregnancy rates were 27.4%, 26.6% and 23.7%, respectively (p = 0.853). Similar multiple
Table 1 Demographic characteristics of the study groups.
Age (years) Body mass index (kg/m2) Duration of infertility (years) Adjuvant male factor, n (%) Baseline FSH (IU/ml) Baseline LH (IU/ml) Baseline oestradiol (IU/ml) Free testosterone (pg/ml)
Group A (n = 208)
Group B (n = 143)
Group C (n = 59)
p-Value
28.9 4.9 24.2 3.9 2.4 1.7 62 (29%) 6.3 1.9 6.4 3.9 53 42 2.4 0.9
28.0 5.1 23.6 3.9 2.1 1.1 40 (28%) 6.0 2.1 6.5 4 49 41 2.6 0.8
27.6 4.3 24.7 4.0 2.2 1.4 17 (29%) 6.4 1.5 6.1 3.8 62 62 2.5 0.7
0.099 0.156 0.313 0.791 0.363 0.756 0.988 0.094
FSH: follicle-stimulating hormone; LH: luteinizing hormone. Data shown as mean standard deviation unless otherwise indicated.
B. O¨zmen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 137–140 Table 2 Cycle characteristics of the study groups. Group B (n = 143)
Group A (n = 208) Stimulation duration (days) No. of retrieved oocytes No. of MII oocytes No. of Grade A embryos No. of transferred embryos Total dose of gonadotropins (IU) Endometrial thickness on day of oocyte collection (mm)
Group C (n = 59)
p-Value
9.9 2.4
9.6 1.9
9.9 2.4
0.495
15.0 6.2
14.2 5.5
14.6 5.5
0.719
11.7 6.4 3.9 1.7
10.5 6.1 4.1 1.9
12.3 7.6 4.3 2.1
0.122 0.205
2.1 0.9
2.0 0.9
1.9 0.8
0.142
2180 992
2244 918
1952 796
0.050
10 2
10.4 1.9
0.358
9.7 1.8
Data shown as mean standard deviation.
Table 3 Comparison of outcome measures.
Fertilization rate, % Implantation rate, % Clinical pregnancy rate, n (%) Multiple pregnancy rate, n (%) Miscarriage rate, n (%) Severe OHSS rate, n (%)
Group A (n = 208)
Group B (n = 143)
Group C (n = 59)
p-Value
72 15 57 14 4 12
69 20 38 5 2 2
71 22 14 2 1 1
0.735 0.853 0.853 0.353 1.00 0.071
(27.4) (6.7) (1.9) (5.8)
(26.6) (3.5) (1.4) (1.4)
(23.7) (3.4) (1.7) (1.7)
OHSS: ovarian hyperstimulation syndrome.
pregnancy and miscarriage rates were observed in all three groups (Table 3). The rates of severe OHSS in Groups A, B and C were 5.8%, 1.4% and 1.7%, respectively (p = 0.071) (Table 3). Comments This retrospective cohort study was conducted to assess the effects of OCP pretreatment in patients with PCOS undergoing ICSI cycles with GnRH antagonist downregulation. OCP pretreatment was not found to affect the rates of implantation, clinical pregnancy, multiple pregnancy, miscarriage and severe OHSS in these patients. Stimulation duration and final gonadotropin consumption were comparable between patients receiving the GnRH antagonist protocol and patients receiving the long luteal GnRH agonist protocol without OCP pretreatment. GnRH antagonist downregulation is widely used, and is a vital option in patients with PCOS, as problems such as loss of endogenous feedback, multifollicular development, OHSS and cycle scheduling have been encountered frequently with GnRH agonist downregulation in IVF/ICSI cycles [2]. On the contrary, the GnRH antagonist protocol competitively inhibits pituitary GnRH receptors and rapidly inhibits secretion of gonadotropins and steroid hormones, thus preventing a premature increase in LH or luteinization, follicle maturation arrest and asynchronous oocyte maturation [2,10]. Nevertheless, comparisons between GnRH agonist and antagonist protocols in patients with PCOS have revealed controversial results. Hosseini et al. reported higher clinical pregnancy rates and lower OHSS rates in antagonist cycles in patients with PCOS [11]. Similar results were reported in other studies, especially in patients with high risk of OHSS [12,13]. On the contrary, a meta-analysis of 4 RCTs reported similar rates of pregnancy and OHSS, and similar numbers of retrieved oocytes among patients with PCOS following GnRH antagonist and agonist protocols [3]. More recently, a meta-analysis of seven RCTs
139
revealed similar rates of clinical pregnancy and miscarriage, total gonadotropin consumption, number of retrieved oocytes and serum oestradiol levels on the day of hCG injection [14]. However, as expected, the rate of OHSS was significantly lower in patients following the GnRH antagonist protocol [14]. Therefore, the authors concluded that the GnRH antagonist protocol appears to be safer in patients with PCOS, although the mechanism behind the low risk of severe OHSS remains unclear, and OHSS-related factors such as gonadotropin consumption, serum oestradiol levels and number of retrieved oocytes were similar among patients following GnRH agonist and antagonist protocols [14]. Clinically, the major disadvantages of GnRH antagonist cycles in comparison with GnRH agonist cycles are scheduling and initiation of treatment. In antagonist downregulated cycles, the initiation of rFSH is commonly performed on Day 2 of the natural cycle [15]. OCPs can be used in scheduling and prediction of the day of oocyte collection in antagonist cycles. OCPs may also ensure follicular homogeneity and lead to an increase in the number of retrieved mature oocytes. A possible explanation for increased follicular homogeneity is suppressed release of endogenous gonadotropins due to low FSH concentrations after use of OCPs. Huirne et al. reported more oocyte recruitment, MII oocytes and good-quality embryos after OCP pretreatment [16]. Nonetheless, these advantages did not lead to higher clinical pregnancy rates in the present study. In a randomized study, Garcia-Velasco et al. compared a GnRH antagonist protocol plus OCP suppression in the preceding cycle with a long luteal GnRH agonist protocol in 228 women with regular cycles [17]. They found comparable rates of clinical, ongoing and multiple pregnancies, and similar OHSS rates. However, the low power of the study and lack of OCP use in women following the GnRH agonist protocol made it difficult to reach a clear conclusion [17]. In a recent RCT, Tehraninejad et al. compared GnRH antagonist and agonist protocols after OCP treatment in patients with PCOS, with 95 patients randomized into two treatment arms [18]. In this study, all enrolled cases were pretreated with OCPs containing 30 mg ethinyl oestradiol plus 0.3 mg levonorgestrel. The authors reported similar rates of fertilization and clinical pregnancy, with reduced risk of OHSS in the GnRH antagonist arm [18]. In a different RCT, Haydardedeoglu et al. reported the outcomes of patients with PCOS who were treated with OCPs plus a GnRH agonist protocol and OCPs plus a GnRH antagonist protocol [8]. They randomized 300 patients with PCOS into two treatment arms, and all cases were pretreated with OCPs containing 30 mg ethinyl estradiol plus 3 mg drospirenone. The authors reported similar rates of ongoing pregnancy in the two arms, and the rates of OHSS and multiple pregnancy were not significantly different [8]. To the authors’ knowledge, this is the first study to compare three different stimulation protocols (i.e. GnRH antagonist protocol with and without OCP pretreatment and long luteal GnRH agonist protocol) in ICSI/ET cycles of patients with PCOS. In parallel with the literature, this found similar rates of implantation, clinical pregnancy and multiple pregnancy in the three groups. The OHSS rate was higher in patients with GnRH agonist downregulation compared with cases with GnRH antagonist downregulation, but the difference did not reach statistical significance. However, this study found similar OHSS rates among patients with PCOS treated with GnRH antagonist and GnRH antagonist plus OCP pretreatment. Therefore, it can be concluded that OCP treatment before GnRH antagonist cycles does not provide additional protection against OHSS. The GnRH antagonist protocol, with or without OCP pretreatment, has no advantages over the GnRH agonist protocol in terms of stimulation duration, number of retrieved oocytes and total gonadotropin consumption, but has a positive effect on cycle scheduling.
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In conclusion, this study did not find an unequivocal beneficial effect of OCP pretreatment of patients with PCOS undergoing a GnRH antagonist protocol for ICSI. Therefore, OCP pretreatment or suppression should not be recommended routinely for cycle scheduling in GnRH antagonist downregulation. However, as patients with PCOS often have oligomenorrhoea, OCP pretreatment may be useful in initiation and cycle scheduling with no negative effects on stimulation or cycle outcomes. Nonetheless, larger RCTs are needed to determine the effect of OCP pretreatment in patients with PCOS undergoing a GnRH antagonist protocol for ICSI.
[6]
[7]
[8]
[9]
Conflict of interest statement None declared.
[10]
Condensation
[11]
Oral contraceptive pill pretreatment was found to have no beneficial or adverse effects in patients with polycystic ovarian syndrome undergoing a GnRH antagonist protocol for ICSI, but can be used for cycle scheduling.
[12]
[13]
References [14] [1] Hart R. PCOS and infertility. Panminerva Med 2008;50:305–14. [2] Tarlatzis BC, Fauser BC, Kolibianakis EM, Diedrich K, Devroey P, Brussels GnRH Antagonist Consensus Workshop Group. GnRH antagonists in ovarian stimulation for IVF. Hum Reprod Update 2006;12:333–40. [3] Griesinger G, Diedrich K, Tarlatzis BC, Kolibianakis EM. GnRH-antagonists in ovarian stimulation for IVF in patients with poor response to gonadotrophins, polycystic ovary syndrome, and risk of ovarian hyperstimulation: a metaanalysis. Reprod Biomed Online 2006;13:628–38. [4] Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin releasing hormone antagonists for assisted conception: a Cochrane review. Reprod Biomed Online 2007;14:640–9. [5] Barmat LI, Chantilis SJ, Hurst BS, Dickey RP. A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women
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pretreated with oral contraceptives before in vitro fertilization. Fertil Steril 2005;83:321–30. Guivarc’h-Leveque A, Arvis P, Bouchet JL, et al. Efficacite de la programmation des cycles FIV en antagonists par les estrogenes. Gynecol Obstet Fertil 2010;38:18–22. Griesinger G, Kolibianakis EM, Venetis C, Diedrich K, Tarlatzis B. Oral contraceptive pretreatment significantly reduces ongoing pregnancy likelihood in gonadotropin-releasing hormone antagonist cycles: an updated meta-analysis. Fertil Steril 2010;94:2382–4. Haydardedeog˘lu B, Bulgan Kılıc¸dag˘ E, Parlakgu¨mu¨s¸ AH, Zeynelog˘lu HB. IVF/ICSI outcomes of the OCP plus GnRH agonist protocol versus the OCP plus GnRH antagonist fixed protocol in women with PCOS: a randomized trial. Arch Gynecol Obstet 2012;286:763–9. Azziz R, Carmina E, Dewaily D, Diamanti-Kandarakis E, Escobar-Morreale HF, Hutterweit W. Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006;91:4237–45. Klingmuller D, Schepke M, Enzweiler C, Bidlingmaier F. Hormonal responses to the new potent GnRH antagonist Cetrorelix. Acta Endocrinol (Copenh) 1993;128:15–8. Hosseini MA, Aleyasin A, Saeedi H, Mahdavi A. Comparison of gonadotropin releasing hormone agonists and antagonists in assisted reproduction cycles of polycystic ovarian syndrome patients. J Obstet Gynaecol Res 2010;36:605–10. Aboulghar MA, Mansour RT, Amin YM, Al-Inany HG, Aboulghar MM, Serour GI. A prospective randomized study comparing coasting with GnRH antagonist administration in patients at risk for severe OHSS. Reprod Biomed Online 2007;15:271–9. Ragni G, Vegetti W, Riccaboni A, Engl B, Brigante C, Crosignani PG. Comparison of GnRH agonists and antagonists in assisted reproduction cycles of patients at high risk of ovarian hyperstimulation syndrome. Hum Reprod 2005;20: 2421–5. Xiao J, Chen S, Zhang C, Chang S. Effectiveness of GnRH antagonist in the treatment of patients with polycystic ovary syndrome undergoing IVF: a systematic review and meta analysis. Gynecol Endocrinol 2013;29:187–91. Huirne JA, Lambalk CB. Gonadotropin releasing hormone receptor antagonists. Lancet 2001;358:1793–803. Huirne JA, van Loenen AC, Donnez J, et al. Effect of an oral contraceptive pill on follicular development in IVF/ICSI patients receiving a GnRH antagonist: a randomized study. Reprod Biomed Online 2006;13:235–45. Garcia-Velasco JA, Bermejo A, Ruiz A, Martinez-Salazar J, Requena A, Pellicer A. Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol vs the long protocol: a randomized, controlled trial. Fertil Steril 2011;96: 590–3. Tehraninejad ES, Nasiri R, Rashidi B, Haghollahi F, Ataie M. Comparison of GnRH antagonist with long GnRH agonist protocol after OCP pretreatment in PCOS patients. Arch Gynecol Obstet 2010;282:319–25.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Dual suppression with oral contraceptive pills in GnRH antagonist cycles for patients with polycystic ovary syndrome undergoing intracytoplasmic sperm injection ¨ zmen a,*, Y.E. S¸u¨ku¨r b, M.M. Seval a, C. Ates¸ c, C.S. Atabekog˘lu a, M. So¨nmezer a, B. O B. Berker a a
Department of Obstetrics and Gynaecology, Ankara University School of Medicine, Ankara, Turkey Department of Obstetrics and Gynaecology, Kec¸io¨ren Training and Research Hospital, Ankara, Turkey c Department of Biostatistics, Ankara University School of Medicine, Ankara, Turkey b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 June 2014 Received in revised form 23 August 2014 Accepted 22 October 2014
Objective: To evaluate the effects of a gonadotropin-releasing hormone (GnRH) antagonist protocol, with or without oral contraceptive pill (OCP) pretreatment, in patients with polycystic ovary syndrome (PCOS) undergoing intracytoplasmic sperm injection (ICSI). Study design: In this retrospective cohort study, 410 infertile patients with PCOS were assessed in their first ICSI cycles between January 2006 and June 2013. In Group A (n = 208), patients underwent a long luteal GnRH agonist protocol, and in Groups B (n = 143) and C (n = 59), patients underwent a GnRH antagonist protocol. The patients in Group C also received OCPs containing 30 mg of ethinyl oestradiol and 3 mg of drospirenone prior to treatment. The main outcome measures were pregnancy and ovarian hyperstimulation syndrome (OHSS) rates. Results: Demographic features, body mass index, duration of infertility, serum baseline hormone levels, cycle outcomes, multiple pregnancy rates, miscarriage rates, OHSS rates, total number of Grade A embryos and total number of transferred embryos were comparable between the groups. Clinical pregnancy rates were 27.4%, 26.6% and 23.7% in Groups A, B and C, respectively (p = 0.853). Conclusions: OCP pretreatment was found to have no beneficial or adverse effects in patients with PCOS undergoing a GnRH antagonist protocol for ICSI, but can be used for cycle scheduling. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: GnRH agonist GnRH antagonist ICSI Oral contraceptive PCOS
Introduction Debate continues regarding the optimal controlled ovarian stimulation (COS) protocol in patients with polycystic ovary syndrome (PCOS) due to problems encountered in in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. Heterogeneous follicular maturation, lower fertilization and pregnancy rates, and a high risk of cycle cancellation in order to avoid ovarian hyperstimulation syndrome (OHSS) are the main problems in such cases [1]. Recently, downregulation with gonadotropinreleasing hormone (GnRH) antagonists has been widely recommended in patients with PCOS due to advantages including short stimulation duration, lower gonadotropin consumption and almost zero incidence of severe OHSS [2–4]. However, GnRH
* Corresponding author. Tel.: +90 3125956405; fax: +90 3123203553. ¨ zmen). E-mail address: [email protected] (B. O http://dx.doi.org/10.1016/j.ejogrb.2014.10.033 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
antagonist protocols are less flexible than long luteal GnRH agonist protocols, so use of GnRH antagonists can be problematic in terms of cycle initiation and scheduling, especially in patients with oligomenorrhoea [2]. Use of oral contraceptive pills (OCPs) in the preceding cycle can be used for cycle scheduling in patients receiving a GnRH antagonist protocol, as this avoids increases in both follicle-stimulating hormone (FSH) and luteinizing hormone (LH), along with improved synchronization and homogeneity of follicular recruitment in the late luteal phase by oestradiol or progesterone components [2,5,6]. However, the use of OCPs in GnRH antagonist cycles can lead to negative consequences such as longer stimulation duration and increased gonadotropin consumption [2]. In a recent metaanalysis, OCP pretreatment in GnRH antagonist cycles of normoresponders was found to be associated with a significant reduction in livebirth rates [7]. Although the reason is unclear, the progesterone component may have had a negative impact on endometrial receptivity in the subsequent cycle, and/or low
138
B. O¨zmen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 137–140
endogenous LH levels may have impaired oocyte competence when COS was performed with recombinant human FSH in GnRH antagonist cycles [7]. In a recent randomized controlled trial (RCT), OCP pretreatment in GnRH antagonist cycles was reported to have no beneficial effects compared with long luteal GnRH agonist cycles in patients with PCOS [8]. The aim of this study was to assess the possible effects of OCP treatment before GnRH antagonist cycles on COS and cycle outcomes in patients with PCOS undergoing ICSI.
Materials and methods Patients with PCOS treated at a university-based infertility clinic between January 2006 and June 2013 were recruited in this retrospective cohort study. The study was approved by the Institutional Review Board of Ankara University School of Medicine. PCOS was diagnosed according to the 2006 criteria of the Androgen Excess Society (hirsutism/hyperandrogenaemia and oligo-anovulation/polycystic ovaries and exclusion of other androgen excess or related disorders) [9]. In total, 683 patients with PCOS who underwent ICSI/embryo transfer (ET) cycles during the study period were selected from the hospital database. After application of inclusion and exclusion criteria, the data for 410 patients with PCOS were found to be eligible for this study. The inclusion criteria were female, age < 35 years and baseline FSH level < 12 IU/l. The exclusion criteria were body mass index (BMI) > 30 kg/m2, secondary infertility, presence of any untreated thyroid dysfunction/hyperprolactinaemia and uterine abnormality. For eligible participants, all data regarding COS and clinical outcomes were extracted from the database, and the patients were divided into three groups according to downregulation protocol and OCP pretreatment. The patients in Group A (n = 208) underwent standardized luteal downregulation with a GnRH agonist [leuprolide acetate 1 mg SC (Lucrin); Abbott, Istanbul, Turkey] commenced on the 21st day of the preceding menstrual cycle. The dose of leuprolide acetate was halved on commencement of menstrual bleeding, and continued at the same dose until injection of human chorionic gonadotropin (hCG). The patients in Groups B (n = 143) and C (n = 59) underwent downregulation with a GnRH antagonist [ganirelix 0.25 mg SC (Orgalutran); MSD, The Netherlands], started on Day 6 of ovarian stimulation. The patients in Group C received OCPs [30 mg ethinyl oestradiol + 3 mg drospirenone (Yasmin); Schering, Istanbul, Turkey] prior to the GnRH antagonist protocol. In all groups, COS was performed with rFSH (either Gonal-F, Serono, Bari, Italy or Puregon, MSD, The Netherlands) initiated on Day 3 of induced or spontaneous menstrual bleeding in Groups B and C. The initial gonadotropin dose ranged between 150 and 300 IU depending on BMI, age and ovarian response to COS. The gonadotropin dose was adjusted according to monitoring data regarding follicular development and serum oestradiol, progesterone and LH levels. Triggering was implemented when at least three
follicles > 17 mm diameter were present using a single dose of 10,000 IU of hCG (Pregnyl; Organon, Istanbul, Turkey). After 36 h, transvaginal-ultrasound-guided oocyte collection was performed. Fertilization was achieved with ICSI in all couples, and ET was performed 3 days after oocyte collection. A maximum of three embryos were transferred under ultrasound guidance. All women received 90 mg/day vaginal micronized progesterone (Crinone 8% gel; Serono, Istanbul, Turkey) for luteal phase support from the day of oocyte collection until the pregnancy test performed 12 days after ET, and women with a positive pregnancy test continued to take luteal phase support until 10 weeks of gestation. Pregnancy and clinical pregnancy were defined, respectively, by measuring serum b-hCG levels 2 weeks after ET and as the presence of a fetus with a heart beat at 6 weeks of gestation. The implantation rate was calculated separately for each woman as the number of gestational sacs divided by the number of transferred embryos multiplied by 100. Severe OHSS was diagnosed when the hematocrit level exceeded 45%, and any symptoms of abdominal discomfort, oliguria and/or respiratory difficulty were reported together with moderate ascites and/or thrombocytosis. The primary outcome measures were implantation and clinical pregnancy rates. The secondary outcome measures were multiple pregnancy, miscarriage and severe OHSS rates. Statistical analyses Statistical Package for the Social Sciences (SPSS) Version 15.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. Shapiro–Wilk test was used to test the distribution of normality. According to the results, non-parametric tests were preferred. Continuous variables were compared using Kruskal–Wallis test. Categorical variables were compared using Chi-squared test or Fisher’s exact test where appropriate. p < 0.05 was considered to indicate significance. When a significant difference was identified, a post-hoc analysis was performed between all group pairs to define the source of significance.
Results The groups were comparable in terms of baseline and demographic parameters including age, BMI, duration of infertility, adjuvant male factor infertility and serum baseline hormone levels (Table 1). The cycle outcomes of all three groups are shown in Table 2. The groups were found to be comparable in terms of the numbers of retrieved and MII oocytes, numbers of generated Grade A and transferred embryos, stimulation duration and endometrial thickness on the day of oocyte collection (Table 2). The outcome measures of the study are shown in Table 3. The implantation rates of Groups A, B, and C were 15%, 20%, and 22%, respectively (p = 0.853). The clinical pregnancy rates were 27.4%, 26.6% and 23.7%, respectively (p = 0.853). Similar multiple
Table 1 Demographic characteristics of the study groups.
Age (years) Body mass index (kg/m2) Duration of infertility (years) Adjuvant male factor, n (%) Baseline FSH (IU/ml) Baseline LH (IU/ml) Baseline oestradiol (IU/ml) Free testosterone (pg/ml)
Group A (n = 208)
Group B (n = 143)
Group C (n = 59)
p-Value
28.9 4.9 24.2 3.9 2.4 1.7 62 (29%) 6.3 1.9 6.4 3.9 53 42 2.4 0.9
28.0 5.1 23.6 3.9 2.1 1.1 40 (28%) 6.0 2.1 6.5 4 49 41 2.6 0.8
27.6 4.3 24.7 4.0 2.2 1.4 17 (29%) 6.4 1.5 6.1 3.8 62 62 2.5 0.7
0.099 0.156 0.313 0.791 0.363 0.756 0.988 0.094
FSH: follicle-stimulating hormone; LH: luteinizing hormone. Data shown as mean standard deviation unless otherwise indicated.
B. O¨zmen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 137–140 Table 2 Cycle characteristics of the study groups. Group B (n = 143)
Group A (n = 208) Stimulation duration (days) No. of retrieved oocytes No. of MII oocytes No. of Grade A embryos No. of transferred embryos Total dose of gonadotropins (IU) Endometrial thickness on day of oocyte collection (mm)
Group C (n = 59)
p-Value
9.9 2.4
9.6 1.9
9.9 2.4
0.495
15.0 6.2
14.2 5.5
14.6 5.5
0.719
11.7 6.4 3.9 1.7
10.5 6.1 4.1 1.9
12.3 7.6 4.3 2.1
0.122 0.205
2.1 0.9
2.0 0.9
1.9 0.8
0.142
2180 992
2244 918
1952 796
0.050
10 2
10.4 1.9
0.358
9.7 1.8
Data shown as mean standard deviation.
Table 3 Comparison of outcome measures.
Fertilization rate, % Implantation rate, % Clinical pregnancy rate, n (%) Multiple pregnancy rate, n (%) Miscarriage rate, n (%) Severe OHSS rate, n (%)
Group A (n = 208)
Group B (n = 143)
Group C (n = 59)
p-Value
72 15 57 14 4 12
69 20 38 5 2 2
71 22 14 2 1 1
0.735 0.853 0.853 0.353 1.00 0.071
(27.4) (6.7) (1.9) (5.8)
(26.6) (3.5) (1.4) (1.4)
(23.7) (3.4) (1.7) (1.7)
OHSS: ovarian hyperstimulation syndrome.
pregnancy and miscarriage rates were observed in all three groups (Table 3). The rates of severe OHSS in Groups A, B and C were 5.8%, 1.4% and 1.7%, respectively (p = 0.071) (Table 3). Comments This retrospective cohort study was conducted to assess the effects of OCP pretreatment in patients with PCOS undergoing ICSI cycles with GnRH antagonist downregulation. OCP pretreatment was not found to affect the rates of implantation, clinical pregnancy, multiple pregnancy, miscarriage and severe OHSS in these patients. Stimulation duration and final gonadotropin consumption were comparable between patients receiving the GnRH antagonist protocol and patients receiving the long luteal GnRH agonist protocol without OCP pretreatment. GnRH antagonist downregulation is widely used, and is a vital option in patients with PCOS, as problems such as loss of endogenous feedback, multifollicular development, OHSS and cycle scheduling have been encountered frequently with GnRH agonist downregulation in IVF/ICSI cycles [2]. On the contrary, the GnRH antagonist protocol competitively inhibits pituitary GnRH receptors and rapidly inhibits secretion of gonadotropins and steroid hormones, thus preventing a premature increase in LH or luteinization, follicle maturation arrest and asynchronous oocyte maturation [2,10]. Nevertheless, comparisons between GnRH agonist and antagonist protocols in patients with PCOS have revealed controversial results. Hosseini et al. reported higher clinical pregnancy rates and lower OHSS rates in antagonist cycles in patients with PCOS [11]. Similar results were reported in other studies, especially in patients with high risk of OHSS [12,13]. On the contrary, a meta-analysis of 4 RCTs reported similar rates of pregnancy and OHSS, and similar numbers of retrieved oocytes among patients with PCOS following GnRH antagonist and agonist protocols [3]. More recently, a meta-analysis of seven RCTs
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revealed similar rates of clinical pregnancy and miscarriage, total gonadotropin consumption, number of retrieved oocytes and serum oestradiol levels on the day of hCG injection [14]. However, as expected, the rate of OHSS was significantly lower in patients following the GnRH antagonist protocol [14]. Therefore, the authors concluded that the GnRH antagonist protocol appears to be safer in patients with PCOS, although the mechanism behind the low risk of severe OHSS remains unclear, and OHSS-related factors such as gonadotropin consumption, serum oestradiol levels and number of retrieved oocytes were similar among patients following GnRH agonist and antagonist protocols [14]. Clinically, the major disadvantages of GnRH antagonist cycles in comparison with GnRH agonist cycles are scheduling and initiation of treatment. In antagonist downregulated cycles, the initiation of rFSH is commonly performed on Day 2 of the natural cycle [15]. OCPs can be used in scheduling and prediction of the day of oocyte collection in antagonist cycles. OCPs may also ensure follicular homogeneity and lead to an increase in the number of retrieved mature oocytes. A possible explanation for increased follicular homogeneity is suppressed release of endogenous gonadotropins due to low FSH concentrations after use of OCPs. Huirne et al. reported more oocyte recruitment, MII oocytes and good-quality embryos after OCP pretreatment [16]. Nonetheless, these advantages did not lead to higher clinical pregnancy rates in the present study. In a randomized study, Garcia-Velasco et al. compared a GnRH antagonist protocol plus OCP suppression in the preceding cycle with a long luteal GnRH agonist protocol in 228 women with regular cycles [17]. They found comparable rates of clinical, ongoing and multiple pregnancies, and similar OHSS rates. However, the low power of the study and lack of OCP use in women following the GnRH agonist protocol made it difficult to reach a clear conclusion [17]. In a recent RCT, Tehraninejad et al. compared GnRH antagonist and agonist protocols after OCP treatment in patients with PCOS, with 95 patients randomized into two treatment arms [18]. In this study, all enrolled cases were pretreated with OCPs containing 30 mg ethinyl oestradiol plus 0.3 mg levonorgestrel. The authors reported similar rates of fertilization and clinical pregnancy, with reduced risk of OHSS in the GnRH antagonist arm [18]. In a different RCT, Haydardedeoglu et al. reported the outcomes of patients with PCOS who were treated with OCPs plus a GnRH agonist protocol and OCPs plus a GnRH antagonist protocol [8]. They randomized 300 patients with PCOS into two treatment arms, and all cases were pretreated with OCPs containing 30 mg ethinyl estradiol plus 3 mg drospirenone. The authors reported similar rates of ongoing pregnancy in the two arms, and the rates of OHSS and multiple pregnancy were not significantly different [8]. To the authors’ knowledge, this is the first study to compare three different stimulation protocols (i.e. GnRH antagonist protocol with and without OCP pretreatment and long luteal GnRH agonist protocol) in ICSI/ET cycles of patients with PCOS. In parallel with the literature, this found similar rates of implantation, clinical pregnancy and multiple pregnancy in the three groups. The OHSS rate was higher in patients with GnRH agonist downregulation compared with cases with GnRH antagonist downregulation, but the difference did not reach statistical significance. However, this study found similar OHSS rates among patients with PCOS treated with GnRH antagonist and GnRH antagonist plus OCP pretreatment. Therefore, it can be concluded that OCP treatment before GnRH antagonist cycles does not provide additional protection against OHSS. The GnRH antagonist protocol, with or without OCP pretreatment, has no advantages over the GnRH agonist protocol in terms of stimulation duration, number of retrieved oocytes and total gonadotropin consumption, but has a positive effect on cycle scheduling.
B. O¨zmen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 137–140
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In conclusion, this study did not find an unequivocal beneficial effect of OCP pretreatment of patients with PCOS undergoing a GnRH antagonist protocol for ICSI. Therefore, OCP pretreatment or suppression should not be recommended routinely for cycle scheduling in GnRH antagonist downregulation. However, as patients with PCOS often have oligomenorrhoea, OCP pretreatment may be useful in initiation and cycle scheduling with no negative effects on stimulation or cycle outcomes. Nonetheless, larger RCTs are needed to determine the effect of OCP pretreatment in patients with PCOS undergoing a GnRH antagonist protocol for ICSI.
[6]
[7]
[8]
[9]
Conflict of interest statement None declared.
[10]
Condensation
[11]
Oral contraceptive pill pretreatment was found to have no beneficial or adverse effects in patients with polycystic ovarian syndrome undergoing a GnRH antagonist protocol for ICSI, but can be used for cycle scheduling.
[12]
[13]
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