There are many types of gonadotropins: some are recombinant , others are urinary derived. some contain LH like activity , others do not. which to use?? many research with conflicting results but the final word came from Cochrane mega- systematic review. This talk will illustrate this issue

1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬

2. GN: FINAL WORD
Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane
Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G
Al-Inany

3. 3
WHY DO WE NEED THIS TALK
 To update our knowledge and understanding
 To provide evidence for decision-makers
 To provide our patients with best care based on
Evidence

4. 4
BUT
EVIDENCE
IS NOT ALL THE SAME

5. IBSA
Satel
lite
Sym
posi
um
5
E
VI
D
E
N
C
E
THE EVIDENCE PYRAMID

6. IBSA
Satel
lite
Sym
posi
um
6
WHY SR ARE ON THE TOP
 Rigorous methodology
 Peer reviewed
 Relatively large sample size
 Ensures the highest quality evidence (based on
RCT)

7. IBSA
Satel
lite
Sym
posi
um
7
RCT ANATOMY
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group

8. 8
IVF/ICSI CYCLES
 Multifollicular development
is still an integral
component for ovarian
stimulation in IVF / ICSI
cycles (Keck et al, 2005)

9. 9
In The Market
VS
rec FSHHuman
derived Gn

10. 10
HOW TO KNOW
 large randomised trial is needed to estimate the
difference between human derived Gn and rFSH
(van Wely et al., 2003).

11. 11
SAMPLE SIZE CALCULATION FOR SUCH RCT
 For a study to have 80% power to detect a difference of 5% in
ongoing pregnancies (or live births), it will need to randomise
over 2400 women (Andersen et al, 2006)
 Which is unlikely to happen (huge fund and long duration)

12. 12
SO THE SOLUTION
 systematic review and meta-analysis of
randomised trials comparing the effectiveness of
hMG versus rFSH following a long down-regulation
protocol in IVF-ICSI cycles

13. HOWEVER,
 Several systematic reviews and one international
Health Technology Assessment report compared
rFSH with urinary gonadotrophins (hMG, FSH-P,
FSH-HP) Daya 1998; Larizgoitia 2000; Agrawal
2000; Daya 2002;Van Wely 2003;NCC-WCH
2004;Al-Inany 2003; Al-Inany 2008;Coomarisamy
2008).

14. EXOGENOUS GONADOTROPIN THERAPY
The goal:

15. EFFECTIVENESS
Meta-analysis :
Al-Inany et al, 2005

16. 16
hMG (363/ 1453) vs. rFSH (324/ 1484)
(P < 0.04; O.R = 1.20, 95% CI = 1.01 - 1.42)
Al-Inany et al., RBM Online, (2008)
Live birth rate

17. RECENTLY RELEASED

18. ONGOING PREGNANCY/ LIVE-BIRTH RATE

19. CONFLICTING RESULTS
 Two reviews compared rFSH to urinary FSH and
found higher pregnancy rates per cycle started for
rFSH (Daya 2002, updated from Daya 1998).
 Three reviews compared rFSH versus urinary
gonadotrophins (hMG, FSH-P, FSH-HP together)
and found no evidence of a difference between
these two groups (Larizgoitia 2000;Al-Inany
2003;NCC-WCH 2004).

20. MOREOVER
 Three reviews compared rFSH with hMG and and
reported evidence of a difference in live birth and
clinical pregnancy rate per cycle between rFSH and
hMG (Van Wely 2002;Al-Inany 2008;Coomarisamy
2008).

21. CONFOUNDING FACTORS
 Firstly, gonadotrophin-releasing hormone (GnRH)
agonists and GnRH antagonist are often used in
conjunction with gonadotrophins to facilitate cycle
control and achieve pituitary down-regulation in
ovarian stimulation during assisted reproductive
treatment cycles.

22. INFLUENCE OF PHARMACEUTICAL COMPANIES
 Secondly many trials have been performed by
pharmaceutical companies and the conflict of
interest may have introduced bias.

23. CRYO EMBRYOS
 Thirdly, it is now customary to freeze
supernumerary embryos and to transfer
frozen/thawed embryos if transfer of fresh embryos
has failed.

24. OBJECTIVES
 To compare the effectiveness of recombinant
gonadotrophin (rFSH) with the three main types of
urinary-derived gonadotrophins (i.e. hMG, FSH-P
and FSH-HP) for ovarian stimulation in women
undergoing IVF or ICSI treatment cycles.

25. 25
HP-FSH
HP-hMG
hMG
recFSH
It fills in a gap in evidence as recombinant FSH was
compared to hMG and to HP-hMG but no one compared hMG
to HP-hMG

26. TYPES OF STUDIES
 Randomised controlled trials only.
 Quasi-randomised controlled trials, in which
allocation was, for example, by alternation or
reference to case record number or to dates of
birth, were excluded.
 Crossover trials were excluded since the design is
not appropriate in this context (Vail 2003)

27. TYPES OF PARTICIPANTS
 Normogonadotrophic (defined as having normal
serum concentration of FSH and LH) women
undergoing fresh and/or frozen-thawed IVF or ICSI
treatment cycles

28. PRIMARY OUTCOMES
 Effectiveness:
live birth per woman or, if not reported, pregnancy
ongoing beyond 20 weeks per woman
 Adverse:
Rate of severe OHSS per woman

29. SECONDARY OUTCOMES
 Effectiveness:
frozen-thawed embryo transfers
 Clinical pregnancy rate
Adverse:
Multiple pregnancy rate
Miscarriage rate per woman

30. 42 RCTS
 including 8 abstracts form congress proceedings)
met all selection criteria and were included in the
review.
 The total number of participants was 9606

31. RESULTS
 There was no evidence of a difference in live
birth or pregnancy ongoing beyond 20 weeks (28
trials, N=7339; OR 0.97, 95% CI 0.87 - 1.08) for
rFSH versus urinary gonadotrophins.
 Meaning 25% live birth rate (22-26% in different
centers)

32. SUBGROUP ANALYSIS: HMG VS RFSH
 There were significantly less live births after rFSH
as compared to hMG (11 trials, N=3197; OR 0.84,
95% CI 0.72 - 0.99).
 This means that for a live birth rate of 25%, use of
rFSH instead would be expected to result in a live
birth rate between 19% and 25%.

33. ACCORDING TO DOWNREGULATION
 There was no evidence of a difference in live birth
between rFSH and urinary gonadotrophins for any
of the downregulation protocols
 (antagonist protocol, N=280; OR 0.88, 95% CI 0.53
- 1.45),
 (long GnRHa protocol, N=6437; OR 0.98, 95% CI
0.87 - 1.10),
 (short GnRHa protocol, N=402; OR 0.84, 95% CI
0.54 - 1.31),
 (no downregulation, N=220; OR 1.17, 95% CI 0.62 -
2.20)

34. SEVERE OHSS
 There was no evidence of a difference in the
primary safety outcome OHSS
 (32 trials, N=7740; OR 1.18, 95% CI 0.86 - 1.61).
 Typical rate of 2% OHSS

35. 35
HOW TO INTERPRET THE FIGURES!
 A benefit from recombinant FSH would be
displayed graphically to the left of the centre-line.
 A benefit from hMG would be displayed graphically
to the right of the centre-line

36. LIVE BIRTH RATE

37. OHSS

38. DOWN REGULATION PROTOCOL

39. FRESH/FROZEN CYCLES

40. INFLUENCE OF PHARMACEUTICAL COMPANIES

41. MULTIPLE PREGNANCY

42. MISCARRIAGE

43. CONCLUSION
Gonadotrophins
are
Gonadotrophins
are
Gonadotrophins

44. ECONOMIC ANALYSIS
 IVF/ICSI cycle, there are probabilities
- Pregnancy
- No pregnancy
- Abortion
- Repeat trial (usually up to 3 cycles)
- Stop trial

45. EXAMPLE : HMG, 1ST CYCLE
Start Cycle
10,000
Ovum Pickup
No OHSS
Ovum Pickup
OHSS
9810
190
Fertilization
& Transfer
No Oocytes
373+7=380
9437+183=9620
Clinical
Pregnancy
-ve βHCG
2982
6638
Ongoing
Pregnancy
Miscarriage
405
2577
3246
3392
Continue
Stop
Goal!
Therefore, for a cohort of 10,000 individuals the expected,
mathematically exact, outcome at the end of the 1st cycle is
380+405+3392 = 4177 patients who will restart the cycle, and
2577 who achieved ongoing pregnancy, and 3246 who gave
up on IVF from the first trial

46. MARKOV EV ANALYSIS: RFSH
rFSH: By the end of the 3rd cycle, the individual’s probability of ending at re-starting
the cycle is 6.6%, in ongoing pregnancy is 35.9%, and in discontinuing IVF is 57.5
%
% Start Cycle
% Pregnancy
% Stop IVF
0
0.2
0.4
0.6
0.8
1
1.2
1 2 3 stop
Cycle
Probability

47. MARKOV EV ANALYSIS: HMG
% Start Cycle
% Pregnancy
% Stop IVF
0
0.2
0.4
0.6
0.8
1
1.2
1 2 3 stop
Cycle
Probability
hMG: By the end of the 3rd cycle, the individual’s probability of ending at re-starting
the cycle is 6%, in ongoing pregnancy is 40.8%, and in discontinuing IVF is 53.2 %

48. HOW TO MAKE DECISION ABOUT DRUG

49. THANK YOU
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com