Gonadotrophin-releasing hormone antagonists
for assisted reproductive technology in women
with poor ovarian response. Subgroup analysis
of Cochrane systematic review and metaanalysis
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 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
responders
kasr al ainy school of Medicine
Cairo University
pregnancy
outcomes
in
poor
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
Potentially relevant publications identified and
screened for retrieval (n= 25)
Publications excluded, (n= 19)
RCTs included in meta-analysis (n=6)
RCTs withdrawn (n=0)
RCTs with usable information (n=6)
1.
2.
3.
4.
5.
6.
Inza 2004
Cheung 2005
Marci 2005
Tazegul 2008
Kim 2009
Sbarcia 2009
kasr al ainy school of Medicine
Cairo University
Ongoing pregnancy rate
GnRH antagonist
Study or Subgroup
Long GnRH agonist
Odds Ratio
Events
Total
Events
Cheung 2005
3
33
3
33 23.7%
Marci 2005
4
30
0
30
Tazegul 2008
8
48
10
Total (95% CI)
Total events
111
15
Heterogeneity: Chi² = 2.79, df = 2 (P = 0.25); I² = 28%
Test for overall effect: Z = 0.40 (P = 0.69)
Odds Ratio
Total Weight M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
1.00 [0.19, 5.36]
3.7% 10.36 [0.53, 201.45]
48 72.5%
0.76 [0.27, 2.13]
111 100.0%
1.17 [0.53, 2.58]
13
0.01 0.1
1
10
100
Long GnRH agonist GnRH antagonist
Clinical pregnancy rate
GnRH antagonist
Study or Subgroup
Long GnRH agonist
Odds Ratio
Events
Total
Events
Cheung 2005
5
33
3
33
3.6%
1.79 [0.39, 8.17]
Inza 2004
7
23
9
22
9.2%
0.63 [0.18, 2.16]
Kim 2009
15
54
7
28
9.5%
1.15 [0.41, 3.27]
5
30
2
30
2.4%
2.80 [0.50, 15.73]
Sbarcia 2009
25
285
48
285
62.8%
0.47 [0.28, 0.79]
Tazegul 2008
10
48
11
48
12.5%
0.89 [0.34, 2.33]
446 100.0%
0.71 [0.49, 1.02]
Marci 2005
Total (95% CI)
Total events
473
67
Heterogeneity: Chi² = 7.26, df = 5 (P = 0.20); I² = 31%
Test for overall effect: Z = 1.86 (P = 0.06)
Total Weight
Odds Ratio
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
80
0.01 0.1
1
10
100
Long GnRH agonist GnRH antagonist
No. retrieved oocytes
GnRH antagonist
Study or Subgroup Mean
Cheung 2005
Long GnRH agonist
SD Total Mean
5.89 3.02
Mean Difference
SD Total Weight IV, Fixed, 95% CI
33
5.6
4.17
33
4.8
2
54
4.7
2.1
28 10.9% 0.10 [-0.84, 1.04]
Marci 2005
5.6
1.6
30
4.3
2.2
30 10.2%
Sbarcia 2009
3.7
2.5
285
4.3
2.4
285 59.9% -0.60 [-1.00, -0.20]
5.44 1.29
48
5.47
2.45
48 15.8% -0.03 [-0.81, 0.75]
Total (95% CI)
450
Heterogeneity: Chi² = 13.78, df = 4 (P = 0.008); I² = 71%
Test for overall effect: Z = 1.33 (P = 0.18)
IV, Fixed, 95% CI
3.1% 0.29 [-1.47, 2.05]
Kim 2009
Tazegul 2008
Mean Difference
1.30 [0.33, 2.27]
424 100.0% -0.21 [-0.52, 0.10]
-1 -0.5 0 0.5 1
Long GnRH agonist GnRH antagonist
Cancellation rate
GnRH antagonist
Study or Subgroup
Long GnRH agonist
Odds Ratio
Events
Total
Events
Cheung 2005
2
33
1
33
10.0%
2.06 [0.18, 23.94]
Kim 2009
2
15
1
7
12.6%
0.92 [0.07, 12.28]
Marci 2005
1
5
2
2
26.6%
0.07 [0.00, 2.33]
Sbarcia 2009
4
25
7
48
42.8%
1.12 [0.29, 4.25]
Tazegul 2008
2
10
1
11
8.1%
2.50 [0.19, 32.80]
101 100.0%
1.02 [0.41, 2.51]
Total (95% CI)
Total events
88
11
Heterogeneity: Chi² = 3.07, df = 4 (P = 0.55); I² = 0%
Test for overall effect: Z = 0.04 (P = 0.97)
Total Weight
Odds Ratio
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
12
0.01 0.1
1
10
100
Long GnRH agonist GnRH antagonist
Duration of stimulation
GnRH antagonist
Study or Subgroup
Mean Difference
SD Total Mean
SD
10.5
2.7
33
11.5
2.4
33
Kim 2009
10
1.4
54
11.6
1.7
28 10.9% -1.60 [-2.33, -0.87]
Marci 2005
9.8
0.8
30
14.6
1.2
30 21.9% -4.80 [-5.32, -4.28]
Sbarcia 2009
11.3
1.8
285
12
2.1
285 56.6% -0.70 [-1.02, -0.38]
Tazegul 2008
10.6
1.63
48
12.03
2.86
Cheung 2005
Total (95% CI)
Mean
Long GnRH agonist
450
Heterogeneity: Chi² = 177.28, df = 4 (P < 0.00001); I² = 98%
Test for overall effect: Z = 14.26 (P < 0.00001)
Total Weight
48
Mean Difference
IV, Fixed, 95% CI
IV, Fixed, 95% CI
3.8% -1.00 [-2.23, 0.23]
6.7% -1.43 [-2.36, -0.50]
424 100.0% -1.76 [-2.00, -1.52]
-4
-2
0
2
4
Long GnRH agonist GnRH antagonist
Amount of Gonadotropins
GnRH antagonist
Long GnRH agonist
Study or Subgroup
Mean
SD Total
Mean
SD Total Weight
Cheung 2005
3,150
813
33
3,445
730
33 14.5%
-295.00 [-667.79, 77.79]
Kim 2009
2,963.9 433.1
54
3,390.2 443.2
28 50.1%
-426.30 [-627.03, -225.57]
Marci 2005
18,487.5 1,612.5
30
27,225 2,550
30
Sbarcia 2009
2,686 1,994
285
3,018 1,989
Tazegul 2008
2,467.7 342.4
Total (95% CI)
48 3,872.683 1,257.1
450
Heterogeneity: Chi² = 243.42, df = 4 (P < 0.00001); I² = 98%
Test for overall effect: Z = 9.36 (P < 0.00001)
Mean Difference
IV, Fixed, 95% CI
Mean Difference
IV, Fixed, 95% CI
1.7% -8737.50 [-9817.12, -7657.88]
285 18.9%
-332.00 [-658.98, -5.02]
48 14.8% -1404.98 [-1773.57, -1036.40]
424 100.0%
-678.54 [-820.55, -536.53]
-1000 -500
0
500 1000
Long GnRH agonist GnRH antagonist
Studies characteristics
The 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 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
stimulation and IVF/ICSI cycles
kasr al ainy school of Medicine
Cairo University
ovarian
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