PKOS’unda GnRH anolog vs. antagonist Dr.Engin Oral İ.Ü. Cerrahpaşa Tıp Fakültesi Kadın Hastalıkları ve Doğum Anabilim Dalı Reprodüktif Endokrinoloji Bilim Dalı Tüp Bebek Ünitesi

Agonist GnRH reseptörlerinde down regülasyon ve desensitizasyon

Antagonist Hipofizer Gn reseptörlerinde kompetitif blokaj

Antagonist (Beklenen Avantajlar) Flare-up etki yok Hemen etki (FSH ve LH) Süpresyon etkisi doz bağımlı Östrojen eksikliği semptomları yok Daha kısa tedavi süresi Daha az gonadotropin kullanımı Deri altı uygulama Antagonist siklüslerinde ovulasyon tetiklemesi için agonistler kullanılabilir Daha az OHSS Daha az maliyet

GnRH ANTAGONİST İki İlaç İki protokol Ganirelix Multiple doz Antagon, Orgalutron (Organon) Lübeck Cetrorelix Cetrotide (Serono) Tek doz French

GnRH Antagonists Protocols FSH/HMG 75 UI HCG UI GnRH Antagonist 3 mg The single dose (French) protocol MENSTRUATION 17-20mm 36 h. DAY mm

FSH/HMG 75 UI HCG UI GnRH Antagonist 0.25 mg MENSTRUATION 17-20mm 36 h. DAY Multiple doses (Lubeck) daily protocol GnRH Antagonists Protocols

Why is the clinical acceptance of gonadotropinreleasing hormone antagonist cotreatment during ovarian hyperstimulation for in vitro fertilization so slow? Bart C. J. M. Fauser, and Paul Devroey,2005

Agonist vs Antagonist Trials 5 RCTs 1796 women randomized antagonist -585 agonist Cochrane study; Al-Inany, 2001 Cochrane study; Al-Inany, RCTs 3865 women randomized antagonist agonist

Description of Studies Twenty-seven RCTs were identified twenty trials involved an unspecifed population of infertile couples seven trials were performed in specific infertile populations. –'poor responders' (Inza 2004;Cheung 2005; Marci 2005), –'polycystic ovary syndrome‘ (Kim 2004;Bahceci 2005), – 'mild male factor' or 'unexplained infertility'(Zikopoulos 2005) and 'tubal factor' (Causio 2004).

Analysis done on the number of women randomised, not all on participants Individual trials –Significant less FSH/HMG –Significant shorter duration of stimulation – No statistically significant pregnancy rate

Pregnancy per Women –Clinical pregnancy rate significantly lower in the antagonist group. (OR 0.84, 95% CI 0.72 to 0.97 ) in favor of the long GnRHa protocol. –Absolute treatment effect (ATE) 4.7% –Number needed to treat to benefit (NNTB) 21 –Ongoing pregnancy/ live birth rate significantly lower in the antagonist group. (P= 0.03; OR 0.82, 95% CI 0.69 to 0.98)

Incidence of Severe OHSS –Statistically significant reduction in incidence of severe OHSS with antagonist protocol. The relative risk ratio was (P = 0.01; RR 0.61, 95% CI 0.42 to 0.89). –Interventions to prevent OHSS (e.g. coasting, cycle cancellation) were administered more frequently in the agonist group (P = 0.03; OR 0.44, 95% CI 0.21 to 0.93). Risk difference was estimated to be (95% CI to 0.00).

Spontaneous miscarriage rate –No statistically significant difference between the two protocols regarding the incidence of multiple pregnancy and miscarriage rates –Similar between the two groups [(P = 0.31; OR 0.84, 95% CI 0.59 to 1.19) and (P = 0.83; OR 0.95, 95% CI 0.61 to 1.49)

Kolibianakis EM, 2006 GnRHa vs. Antagonist A systematic review and meta analysis The rate of live birth rate was 2.7% higher with agonists, but the difference included zero.

Treatment Of The Hyperresponder The Goal Increase follicular phase FSH levels Decrease follicular phase LH levels Decrease insulin and androgen levels Minimize excessive E 2 elevation Increase proportion of mature sized follicles Minimize the risk of OHSS

A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome E.M.E.W.Heijnen, 2006

Rationale for antagonists in PCOS Ability to –Flexibly supress LH in the folicular phase –Avoid lengthy supression, as seen with agonists, in those at risk for low response Use GnRH agonists to trigger ovulation in those at risk for OHSS Potential use in minimal stimulation protocols

Can Antagonists Be the optimal choice for COH in PCOS Must –Be ‘‘non inferior’’ to accepted protocols –Not increase the risk of OHSS –Result in equal patient tolerance –Be acceptably convenient to perform for both patient and physician

Cetrorelix 3 mg in PCOs Cetrorelix 3 mgPrevious cycle N = 34Long agonist N = 34 Stimulation duration12.9 Total dose of rec-FSH1921  325 E 2 at day hCG2077   652 No of oocytes retrieved13.4   5.9 No of mature oocytes8.3   5.5 Pregnancy rate35.2% Severe OHSS1 (3%)8 (23%) Cancellation of over-response0%38% (Avril et al 2002)

IVI : 1/7/2002 – 30/6/ cycles / 1092 transfers n = 705 / 535n = 768 / 555 p = NS 45,643,6 28,4 34,6 28,6 31,5

PCO 64,935,1 52,922,8 41,122,3 n = 70/57n = 57/37 p <0.01 Dr. José Navarro 2004

Kolibianakis E, 2003 Reproductive outcome of polycystic ovarian syndrome patients treated with GnRH antagonists and Rec FSH for IVF/ICSI

A significantly lower ongoing pregnancy rate per oocyte retrieval and a higher occurence of OHSS was observed in the group of patients with BMI >29. Also in the BMI ≤29 group there is a tendency towards higher ongoing implantation rate and a lower miscarriage rate

The impact of using GnRH antagonist in COH for ART in women with PCOD: a randomized study Bahceci et al, pts in Agonist arm 59 pts in Antagonist arm 1.No premature LH surge 2.Shorter duration in Antagonist arm 3.No difference in consumed gonadotropins 4. Similar OHSS incidence p>0.05 for both IR and PR

Comparison of GnRH agonists and antagonists in assisted reproduction cycles of patients at high risk of ovarian hyperstimulation syndrome G.Ragni, 2005 historical controls 18 pregnancies (20.7 per initiated cycle; 31.6% per embryo transfer)

Triggering final oocyte maturation using different doses of human chorionic gonadotropin: a randomized pilot study in patients with polycystic ovary syndrome treated with gonadotropin-releasing hormone antagonists and recombinant follicle-stimulating hormone Eighty PCOS patients. Patients were randomized to receive 10,000 IU (28), 5000 IU (26), or 2500 IU (26) of hCG for triggering final oocyte maturation The median fertilization rates were 52.8%, 65.4%, and 55.6% after administration of 10,000 IU, 5000 IU and 2500 IU, respectively. The ongoing pregnancy rates per PCOS patient receiving hCG were 26.9% (7 of 26), 30.8% (8 of 26) and 34.8% (8 of 23), respectively A decrease in the dose of hCG used to trigger final oocyte maturation does not appear to affect adversely the probability of pregnancy in PCOS patients treated by IVF using GnRH antagonists and recombinant FSH Efstratios M. Kolibianakis, 2007

Ganirelix acetate causes a rapid reduction in estradiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome 87 patients treated with long luteal (LL) or microdose flare (MDF) with ovarian hyperresponse and 87 control patients without ovarian hyperresponse. In the treatment group, there was a significant, reproducible reduction in serum E2 levels. Mean E2 at the start of ganirelix treatment was pg/ml and decreased in 24 h to pg/ml (36.7%; P < 0.001). An average of 24.9 ± 8.8 oocytes were obtained at retrieval and an average of 19.1 ± 8.0 were metaphase II (79.2%). Fertilization occurred in 13.9 ± 8.1 embryos (72.8%). In this high risk group, two cases of severe OHSS (2.3%) occurred. The ongoing pregnancy rate was 51.8%. Compared with the control group, there were no statistically significant differences in the rate of oocyte recovery, oocyte maturity, 2PN rate, fertilization, cancellation, OHSS or pregnancy. GnRH-antagonist treatment of women pretreated with GnRH agonist rapidly reduced circulating serum E2 without adversely affecting oocyte maturation, fertilization rates or embryo quality and resulted in a high pregnancy rate in this subgroup of patients at risk of OHSS. Robert L.Gustofson, 2006

Ovarian stimulation by concomitant administration of cetrorelix acetate and HMG following Diane-35 pre-treatment for patients with polycystic ovary syndrome: a prospective randomized study Jiann-Loung Hwang, 2004 pretreated with three cycles of Diane-35, followed by 0.25mg of cetrorelix on cycle day 3. From day 4, cetrorelix and gonadotrophin were administered concomitantly until the day of HCG injection

Premature luteinization * 20-38% of cycles with a GnRH antagonist ( Ubaldi et al, Bosch et al, 2003) * 5-35 % of cycles with a GnRH agonist (Edelstein et al, 1990, Silverberg et al, 1991) Serum Progesterone elevation (> ng/mL) at the end of the follicular phase, before hCG administration

Premature luteinization and in vitro fertilization outcome in gonadotropin/gonadotropin-releasing hormone antagonist cycles in women with polycystic ovary syndrome Shimon Segal, 2008

Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization–embryo transfer NICOLA DOLDI, 2006 M M

Initiation of GnRH antagonist on Day 1 of stimulation as compared to the long agonist protocol in PCOS patients. A randomized controlled trial: effect on hormonal levels and follicular development Trifon G.Lainas, 2007

The primary outcome was E2 level on Day 5 of stimulation, while secondary outcomes were follicular development, LH during ovarian stimulation and progesterone levels Significantly more follicles on days 5, 7 and 8 of stimulation, significantly higher estradiol (E2) levels on days 1, 3, 5, 7 and 8 and significantly higher progesterone levels on days 1, 5 and 8 of stimulation were observed in the antagonist when compared with the agonist group. E2 was approximately twice as high in the antagonist when compared with the agonist group on day 5 of stimulation (432 versus 204 pg ml21, P < 0.001). These differences were accompanied by significantly lower LH levels on days 3 and 5 and significantly higher LH levels on days 1, 7 and 8 of stimulation in the antagonist when compared with the agonist group.

Clinical outcome from comparative studies on gonadotrophin-releasing hormone antagonist (GnRH- ant) versus gonadotrophin-releasing hormone agonist (GnRHa) protocol in PCOS patients Georg Griesinger, 2006

GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis G.Griesinger, 2005 P<0.03 favors hCG P:0.05 favors lower risk after hCG

GnRH agonist for triggering final oocyte maturation in patients at risk of ovarian hyperstimulation syndrome: still a controversy S. Kol, 2008

Triggering with human chorionic gonadotropin or a gonadotropin-releasing hormone agonist in gonadotropin- releasing hormone antagonist-treated oocyte donor cycles: findings of a large retrospective cohort study A total of 1171 egg donors performing 2077 stimulation cycles. The proportion of mature oocytes was comparable, whereas the difference in the fertilization rate reached statistical significance (65% vs. 69%). No significant differences were observed in the implantation rate or clinical and ongoing pregnancy rates per ET. The incidence of moderate/severe OHSS was 1.26% (13/1031; 95% confidence interval [CI], 0.74–2.15) and 0% (0/1046; 95% CI, 0.00–0.37) in the rhCG and GnRH agonist groups, respectively Recipient outcome was not significantly different when using oocytes from GnRH antagonist–treated donor cycles triggered with hCG or GnRH agonist. However, GnRH agonist triggering was associated with a lower incidence of moderate/severe OHSS in egg donors Daniel Bodri, 2008

GnRH agonist to induce oocyte maturation during IVF in patients at high risk of OHSS Lawrence Engmann, 2006 GnRHa + GnRH antagonis vs. OCP+ GnRHa+hCG

The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high- risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study Sixty-six patients under 40 years of age with polycystic ovarian syndrome, polycystic ovarian morphology, or previous high response undergoing IVF Patients were randomized to an ovarian stimulation protocol consisting of either GnRH agonist trigger after cotreatment with GnRH antagonist (study group) or hCG trigger after dual pituitary suppression with a GnRH agonist (control group). None of the patients in the study group developed any form of OHSS compared with 31% (10/32) of the patients in the control group. There were no significant differences in the implantation (22/61 [36.0%] vs. 20/64 [31.0%]), clinical pregnancy (17/30 [56.7%] vs. 15/29 [51.7%]), and ongoing pregnancy rates (16/30 [53.3%] vs. 14/29 [48.3%]) between the study and control groups, respectively. The use of a protocol consisting of GnRH agonist trigger after GnRH antagonist cotreatment combined with adequate luteal phase and early pregnancy E2 and P supplementation reduces the risk of OHSS in high-risk patients undergoing IVF without affecting implantation rate Lawrence Engmann, 2008