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