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 The single dose (French) protocol

17-20mm 14 mm 36 h.

DAY 1 2 3 4 5 6 7 8 FSH/HMG 75 UI GnRH Antagonist 3 mg HCG 10000 UI

GnRH Antagonists Protocols Multiple doses (Lubeck) daily protocol

17-20mm 36 h.

DAY 1 2 3 4 5 6 7 FSH/HMG 75 UI GnRH Antagonist 0.25 mg HCG 10000 UI

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

Cochrane study; Al-Inany, 2001

• 5 RCTs • 1796 women randomized -1211 antagonist -585 agonist

Cochrane study; Al-Inany, 2006

• 27 RCTs • 3865 women randomized -2292 antagonist -1573 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 -0.02 (95% CI -0.03 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)

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. Kolibianakis EM, 2006

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 mg N = 34

Stimulation duration Total dose of rec-FSH E 2 at day hCG No of oocytes retrieved No of mature oocytes Pregnancy rate Severe OHSS Cancellation of over-response 12.9

1921  325 2077  754 13.4  6.1

8.3  4.2

35.2% 1 (3%) 0% (Avril et al 2002)

Previous cycle Long agonist N = 34

3254  652 18.2  5.9

15.5  5.5

8 (23%) 38%

IVI : 1/7/2002 – 30/6/2003 1473 cycles / 1092 transfers

50 40 30 20 10 0

45,6 43,6 34,6 31,5 28,4 28,6

PREG/trans PREG/cycle Agonist

n = 705 / 535 n = 768 / 555

Implanta Antagonist p = NS

PCO p <0.01

Dr. José Navarro 70 60 50 40 30 20 10 0

64,9 35,1

Gesta/Transfer

52,9 22,8 41,1 22,3

Gesta/cycle Agonist n = 70/57 n = 57/37 Implanta Antagonist

2004

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

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

•70 pts in Agonist arm •59 pts in Antagonist arm

30 20 10 0 60 50 40 34,6 58,5 34 57,6 GnRH Agonist GnRH Antagonist

p>0.05 for both IR and PR

IR PR

1. No premature LH surge 2. Shorter duration in Antagonist arm 3. No difference in consumed gonadotropins 4. Similar OHSS incidence Bahceci et al, 2005

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

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

4219.8 pg/ml

in 24 h to

2613.7 pg/ml

(36.7%; P < 0.001). An average of 24.9 ± and decreased 8.8 oocytes were obtained at retrieval and an average of 19.1 ± Fertilization occurred in 13.9 ± 8.0 were metaphase II (79.2%). 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 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 Jiann-Loung Hwang, 2004

Premature luteinization

Serum Progesterone elevation (> 1.0-1.5 ng/mL) at the end of the follicular phase, before hCG administration *

5-35 % of cycles with a GnRH agonist

(Edelstein et al, 1990, Silverberg et al, 1991)

*

20-38% of cycles with a GnRH antagonist

( Ubaldi et al, 1996. Bosch et al, 2003)

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 M M NICOLA DOLDI, 2006

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

of stimulation were observed in the antagonist when compared with the agonist group. levels on days 1, 5 and 8 • E2 was approximately versus

twice as high

in the antagonist when compared with the agonist group on day 5 of stimulation (432 • • 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

Georg Griesinger, 2006

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

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 GnRHa + GnRH antagonis vs. OCP+ GnRHa+hCG

Lawrence Engmann, 2006

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