gonadotrophin-releasing hormone antagonists for assisted reproductive technology in women with poor...
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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. Various Pituitary down regulation protocols
&&2. High dose or mild dose of Gn.
Pituitary downregulation protocols
1. Short GnRH agonist
2. Long GnRH agonist
3. GnRH antagonist
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 MedicineCairo 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 MedicineCairo 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 MedicineCairo 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 MedicineCairo 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 MedicineCairo 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 MedicineCairo 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 MedicineCairo 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 MedicineCairo 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 MedicineCairo University
Results
Flow diagram of study selection
kasr al ainy school of MedicineCairo University
Publications excluded, (n= 19)
RCTs included in meta-analysis (n=6)
RCTs withdrawn (n=0)
RCTs with usable information (n=6)
1.Inza 20042.Cheung 20053.Marci 20054.Tazegul 2008 5.Kim 20096.Sbarcia 2009
Potentially relevant publications identified and screened for retrieval (n= 25)
Ongoing pregnancy rate
Study or Subgroup
Cheung 2005Marci 2005Tazegul 2008
Total (95% CI)
Total eventsHeterogeneity: Chi² = 2.79, df = 2 (P = 0.25); I² = 28%Test for overall effect: Z = 0.40 (P = 0.69)
Events
348
15
Total
333048
111
Events
30
10
13
Total
333048
111
Weight
23.7%3.7%
72.5%
100.0%
M-H, Fixed, 95% CI
1.00 [0.19, 5.36]10.36 [0.53, 201.45]
0.76 [0.27, 2.13]
1.17 [0.53, 2.58]
GnRH antagonist Long GnRH agonist Odds Ratio Odds RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Long GnRH agonist GnRH antagonist
Clinical pregnancy rate
Study or Subgroup
Cheung 2005Inza 2004Kim 2009Marci 2005Sbarcia 2009Tazegul 2008
Total (95% CI)
Total eventsHeterogeneity: Chi² = 7.26, df = 5 (P = 0.20); I² = 31%Test for overall effect: Z = 1.86 (P = 0.06)
Events
57
155
2510
67
Total
33235430
28548
473
Events
3972
4811
80
Total
33222830
28548
446
Weight
3.6%9.2%9.5%2.4%
62.8%12.5%
100.0%
M-H, Fixed, 95% CI
1.79 [0.39, 8.17]0.63 [0.18, 2.16]1.15 [0.41, 3.27]
2.80 [0.50, 15.73]0.47 [0.28, 0.79]0.89 [0.34, 2.33]
0.71 [0.49, 1.02]
GnRH antagonist Long GnRH agonist Odds Ratio Odds RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Long GnRH agonist GnRH antagonist
No. retrieved oocytes
Study or Subgroup
Cheung 2005Kim 2009Marci 2005Sbarcia 2009Tazegul 2008
Total (95% CI)
Heterogeneity: Chi² = 13.78, df = 4 (P = 0.008); I² = 71%Test for overall effect: Z = 1.33 (P = 0.18)
Mean
5.894.85.63.7
5.44
SD
3.022
1.62.5
1.29
Total
335430
28548
450
Mean
5.64.74.34.3
5.47
SD
4.172.12.22.4
2.45
Total
332830
28548
424
Weight
3.1%10.9%10.2%59.9%15.8%
100.0%
IV, Fixed, 95% CI
0.29 [-1.47, 2.05]0.10 [-0.84, 1.04]1.30 [0.33, 2.27]
-0.60 [-1.00, -0.20]-0.03 [-0.81, 0.75]
-0.21 [-0.52, 0.10]
GnRH antagonist Long GnRH agonist Mean Difference Mean DifferenceIV, Fixed, 95% CI
-1 -0.5 0 0.5 1Long GnRH agonist GnRH antagonist
Cancellation rate
Study or Subgroup
Cheung 2005Kim 2009Marci 2005Sbarcia 2009Tazegul 2008
Total (95% CI)
Total eventsHeterogeneity: Chi² = 3.07, df = 4 (P = 0.55); I² = 0%Test for overall effect: Z = 0.04 (P = 0.97)
Events
22142
11
Total
33155
2510
88
Events
11271
12
Total
3372
4811
101
Weight
10.0%12.6%26.6%42.8%8.1%
100.0%
M-H, Fixed, 95% CI
2.06 [0.18, 23.94]0.92 [0.07, 12.28]0.07 [0.00, 2.33]1.12 [0.29, 4.25]
2.50 [0.19, 32.80]
1.02 [0.41, 2.51]
GnRH antagonist Long GnRH agonist Odds Ratio Odds RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Long GnRH agonist GnRH antagonist
Duration of stimulation
Study or Subgroup
Cheung 2005Kim 2009Marci 2005Sbarcia 2009Tazegul 2008
Total (95% CI)
Heterogeneity: Chi² = 177.28, df = 4 (P < 0.00001); I² = 98%Test for overall effect: Z = 14.26 (P < 0.00001)
Mean
10.5109.8
11.310.6
SD
2.71.40.81.8
1.63
Total
335430
28548
450
Mean
11.511.614.6
1212.03
SD
2.41.71.22.1
2.86
Total
332830
28548
424
Weight
3.8%10.9%21.9%56.6%6.7%
100.0%
IV, Fixed, 95% CI
-1.00 [-2.23, 0.23]-1.60 [-2.33, -0.87]-4.80 [-5.32, -4.28]-0.70 [-1.02, -0.38]-1.43 [-2.36, -0.50]
-1.76 [-2.00, -1.52]
GnRH antagonist Long GnRH agonist Mean Difference Mean DifferenceIV, Fixed, 95% CI
-4 -2 0 2 4Long GnRH agonist GnRH antagonist
Amount of Gonadotropins
Study or Subgroup
Cheung 2005Kim 2009Marci 2005Sbarcia 2009Tazegul 2008
Total (95% CI)
Heterogeneity: Chi² = 243.42, df = 4 (P < 0.00001); I² = 98%Test for overall effect: Z = 9.36 (P < 0.00001)
Mean
3,1502,963.9
18,487.52,686
2,467.7
SD
813433.1
1,612.51,994342.4
Total
335430
28548
450
Mean
3,4453,390.227,2253,018
3,872.683
SD
730443.22,5501,989
1,257.1
Total
332830
28548
424
Weight
14.5%50.1%1.7%
18.9%14.8%
100.0%
IV, Fixed, 95% CI
-295.00 [-667.79, 77.79]-426.30 [-627.03, -225.57]
-8737.50 [-9817.12, -7657.88]-332.00 [-658.98, -5.02]
-1404.98 [-1773.57, -1036.40]
-678.54 [-820.55, -536.53]
GnRH antagonist Long GnRH agonist Mean Difference Mean DifferenceIV, Fixed, 95% CI
-1000 -500 0 500 1000Long GnRH agonist GnRH antagonist
Studies characteristicsThe overall methodological quality of the trials was:-
1. Good
2. Published as a full manuscript in peer-reviewed journals.
3. The studies were generally small and not well powered for all the clinical
relevant outcomes.
4. In five of six randomized trials, concealment of allocation was not clearly
described
5. In three studies there was no blinding and in two studies it was unclearly
reported
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:-
1. ≈ Comparable pregnancy rates
2. ≈ Comparable number of retrieved follicles
3. ≈ Comparable cancellation rate
4. Shorter duration of stimulation
5. Less amount of Gn
kasr al ainy school of MedicineCairo 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 MedicineCairo 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