Gonadotrophin-releasing hormone antagonists for assisted reproductive technology in women with poor ovarian response. Subgroup analysis of Cochrane systematic review and meta- analysis Youssef MAFM, Hesham G Al-Inany, Mohamed Aboulghar, Frank Broekmans, Monique Sterrenburg, Janine Smit, Ahmed M Abou-Setta Cairo University

? What is the problem ? ≈ 9-24% of IVF/ICSI patients respond poorly to ovarian stimulation !!! Poor ovarian responders

Natural Populations

ART Populations

Is there a treatment for poor ovarian responders ?

Different treatment options 1. 1.Various Pituitary down regulation protocols& 2.High dose or mild dose of Gn.

Pituitary downregulation protocols Short GnRH agonist 2. 2.Long GnRH agonist 3. 3.GnRH antagonist 4. 4.Natural cycle

Long GnRH agonist Long GnRH agonist is the standard protocol used for poor responders, however, this protocol has many drawbacks: 1.Prolonged duration of ovarian stimulation, 2.Multiple injections, 3.More patient’s distress 4.Increased the cost without improving IVF outcome kasr al ainy school of Medicine Cairo University

GnRH antagonist protocol Last decade, GnRH antagonist has been emerged as an alternative to GnRH agonist protocols in IVF/ICSI cycles. GnRH antagonists competitively desensitize pituitary GnRH receptors immediate & reversible suppression of gonadotropin secretion kasr al ainy school of Medicine Cairo University

GnRH antagonist protocol Due to these pharmacokinetic characteristics it was anticipated that, GnRH antagonists are an optimal alternative to long GnRH agonist because their use occurs after the commencement of gonadotropin stimulation, thus theoretically:- 1.Minimizing their impact on early follicular recruitment 2.Reduces suppression of endogenous gonadotrophins. kasr al ainy school of Medicine Cairo University

GnRH antagonist protocol GnRH antagonist might have many advantages over GnRH agonist such as:- 1.Fewer injections, 2.Shorter duration of stimulation, 3.Less incidence of OHSS. kasr al ainy school of Medicine Cairo University

GnRH antagonist protocol So it has been promised to be more patient friendly than long GnRH agonist in general, however, there is a great controversy about its impact on pregnancy outcomes in poor responders kasr al ainy school of Medicine Cairo University

Aim of the review The aim of this subgroup analysis of the recently published Cochrane review was to compare GnRH antagonist desensitization protocol with the standard long GnRH agonist in women with poor ovarian response undergoing IVF/ICSI treatment cycles kasr al ainy school of Medicine Cairo University

Inclusion criteria Type of studies: RCT Participants: Infertile couples with poor ovarian response undergoing IVF/ICSI Intervention: Long GnRH agonist protocol versus GnRH antagonist protocol for pituitary downregulation kasr al ainy school of Medicine Cairo University

Outcomes Primary outcome: Ongoing pregnancy rate Secondary outcomes: 1.Clinical pregnancy rate 2.Duration of ovarian stimulation & amount of Gonadotropin used, 3.Number of retrieved oocytes 4.Cycle cancellation rate kasr al ainy school of Medicine Cairo University

Literature search Menstrual Disorders & Subfertility Group's Specialised Register of controlled trials The Cochrane Central Register of Controlled Trials (CENTRAL) MEDLINE (1966 to Jan 2011) EMBASE (1980 to Jan 2011) National Research Register Web-based trials databases such as Current Controlled Trials References check. We also contacted drug companies for any published, unpublished or ongoing studies not identified with our search strategy No language restriction kasr al ainy school of Medicine Cairo University

Results

Flow diagram of study selection kasr al ainy school of Medicine Cairo University Publications excluded, (n= 19) RCTs included in meta-analysis (n=6) RCTs withdrawn (n=0) RCTs with usable information (n=6) 1.Inza Cheung Marci Tazegul Kim Sbarcia 2009 Potentially relevant publications identified and screened for retrieval (n= 25)

Ongoing pregnancy rate

Clinical pregnancy rate

No. retrieved oocytes

Cancellation rate

Duration of stimulation

Amount of Gonadotropins

Studies characteristics The overall methodological quality of the trials was: Good 2. 2.Published as a full manuscript in peer-reviewed journals The studies were generally small and not well powered for all the clinical relevant outcomes In five of six randomized trials, concealment of allocation was not clearly described 5. 5.In three studies there was no blinding and in two studies it was unclearly reported 6. 6.An intention to treat analysis was stated to have been carried out in only one study

Results Consistencies were found among the studies in outcomes such as OPR, CPR & cancellation rate There were Inconsistencies between studies in outcomes such as number of oocytes, duration of stimulation and amount of Gn used.

Summary of results The present meta-analysis indeed suggests that GnRH antagonist in poor responders result in: ≈ Comparable pregnancy rates ≈ Comparable number of retrieved follicles ≈ Comparable cancellation rate 4. 4.Shorter duration of stimulation 5. 5.Less amount of Gn kasr al ainy school of Medicine Cairo University

Take home message In view of its equivalence, GnRH antagonist is an alternative for long GnRH agonist in poor responder patients undergoing ovarian stimulation and IVF/ICSI cycles kasr al ainy school of Medicine Cairo University

Results Although the inconsistency of studies ‘results in a meta-analysis reduces the confidence of recommendations about treatment, it is an expected due to clinical and methodological diversity between studies such as inclusion criteria for participation and study quality but it cannot be regarded as a major cause of the differences in the results of the studies included in this subgroup analysis