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					Ovulation Induction in The New

  hMG vs recombinant FSH

       Hesham Al-Inany, MD

•Multifollicular development with
gonadotropin administration is still
an integral component for ovarian
stimulation in IVF / ICSI cycles
       hMG                Recombinant FSH

•hMG extracted from the   Batch to batch consistency
urine of menopausal       Free from urinary proteins
women has been used       Can be produced in limitless
successfully for many     quantities
years for ovarian
  Recombinant FSH VS Urinary FSH ( before 1996 )
Pregnancy rate/started cycle ( GnRHa long protocol )

Study               Treatment      Control                OR               Weight        OR
                       n/N          n/N              (95% CI Fixed)         %       (95% CI Fixed)

Alvino                8/28          6/29                                     3.5    1.53(0.45,5.17)
Hedon                 20/57         9/33                                     6.1    1.44(0.56,3.69)
O’Dea                 12/56         13/58                                    8.3    0.94(0.39,2.29)
Out                  179/585       107/396                                  73.0    1.19(0.90,1.58)
RHFSG                 12/60         10/63                                    6.4    1.32(0.53,3.34)

Total (95% CI)       231/787       145/579                                 100.0    1.20(0.94,1.54)

Test for heterogeneity chi-square = 0.57        df = 5       p = 0.97
Test for overall effect z = 1.49 p 0.14

                                           -1   -2       1      5     10
                                      Favours                    Favours
                                        u GN                     rec FSH
Recombinant Insulin & Factor

•Significant medical benefits in
clinical practice have never been
convincingly demonstrated for
biotech substitutes
                Zwart-van Rijkom et al,2002
Concerns Price 3 X

  In 1995                € 5.0 million

     volume increased by <100%

  In 2000                € 26.8million

               Zwart-van Rijkom et al,2002
 Why recFSH was welcomed

•The concept that LH is redundant
and the wish for a more purified
product drove the conversion from
hMG to recFSH.
      Good drug OR Super drug

•Claimed higher efficacy and bioactivity
for recombinant FSH
                Out et al, 1995
                Coelingh Bennink et al, 1997
           LH supplementation: is it

•Lisi et al., 2001           Schats et al,2000
•Filicori et al, 2001
                             Balasch et al, 2001
•Westergaard et al., 2001
•Tesarik and Mendoza, 2002   Daya 2002
•Commenges-Ducos et al,      Balasch et al, 2003
     Role of Meta-analysis

•The most widely cited meta-
analysis to compare recFSH vs
urinary gonadotrophins has focused
only on uFSH-P, uFSH-HP
                    Daya& Gunby,1999

•To compare recombinant FSH to hMG
regarding their clinical efficacy.

•Should be based upon most up to
date evidence

•RCTs are considered the gold

•Power calculation is essential

•Meta-analysis of:

•Truly randomized controlled trials
•IVF/ICSI cycles
       Search Strategy

•Cochrane MDSG Specialized
•Hand searching
Primary outcome

 •Live Birth Rate
    Per Woman
  (Cochrane handbook, version 8)

•The results were combined for
meta-analysis with RevMan software
(using the Mantel-Haenszel

•Results were pooled using a fixed-
effects model only after confirming
that heterogeneity was not present
•Eight truly RCTs were included in
this meta-analysis
•     Janssen 1998
•     Gordon 2001
•     Ng 2001
•     Strehler 2001
•     Westergaard 2001
•     Diedrich 2002
•     Kilani 2003
•     Balasch 2003
               Excluded Trials
•Balasch et al, 1996      (rFSH vs combined
rFSH & hMG)

•Kornilov et al, 1999 (unclear data)
•Serhal et al, 2000 (Quasirandomized trial)
•Mahmoud et al, 2001 (rFSH vs combined
rFSH & hMG)

•Meo et al, 2002 ( retrospective study)
•Commenges-Ducos et al, 2002 (rFSH
vs combined rFSH & hMG)

•Eskandar et al, 2004 ( not RCT)

•The sample size of 2105 women is
needed to test whether hMG is
equivalent or even superior to
recombinant FSH in an IVF/ET
The included trials enrolled 2031
 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
Live Birth / Ongoing Pregnancy rate

          O.R.: 1.21 (95% CI 0.95-1.54)
Clinical pregnancy rate / woman

        O.R.: 1.20 (95% CI 0.99-1.46)
Significant result with Long

      O.R.: 1.26 (95% CI 1.00-1.60)

              How To Explain

•GnRH agonist down-regulation may
result in profound suppression of LH
concentration, impairing adequate
oestradiol synthesis
                    Fleming et al, 2000
•LH was shown to improve the
implantation rate
           Gordon et al, 2001
           Ganirelix dose-finding study ,1998
           Schoolcraft et al, 1999

•Identifying which women will require
additional LH is costly and unreliable
           Diedrich et al, 2002
          LH is needed

•The low endogenous LH
concentrations achieved with GnRH
agonists may amplify the differences
in treatment outcomes seen with the
use of hMG and recombinant FSH
Miscarriage Rate

O.R.: 1.3 (95% CI 0.76-2.25)
Multiple pregnancy rate

    O.R.: 1.35 (95% CI 0.97-1.89)

O.R.: 1.79 (95% CI 0.74-4.33)
             Economic View
 Product     Egypt    TURKEY     Bahrain
hMG 75 IU    45 EP    16.6 USD   9.070 BD
recFSH 75                        20.190 BD
             145 EP   33.9 USD
recFSH 150
             200 EP   56.7 USD   36.340 BD
recFSH 50
             81 Ep    25.4 USD   14.400 BD
recFSH 100
             140 EP   43.3 USD   28.800 BD
     Good drug OR Super drug!!!

•Claimed higher efficacy and bioactivity of the
recombinant FSH
                         Out et al, 1995

•Then reduction in amount of recombinant FSH
is expected
Significant reduction in Amount of
        Gonadotrophin (IU)

     O.R.: -317.8 (95% CI -346.58 - -289.12)
         Further Support

•Filicori et al, 2003   IUI cases

•Lloyd et al, 2003      highly
purified hMG
            How to explain

• LH activity supplementation enhances
  FSH activity and optimizes FSH
  ovulation induction in women
  undergoing COH for ART procedures
•hMG enjoy a safety proven by 30 years
of post marketing use, which is the real
gold standard for the safety of a
pharmaceutical product.
       Take Home message

•The use of hMG is the most cost
effective option for ovulation
induction in ART programs
•Decision makers should
establish their choice of one
drug over the other based on
the most up-to-date available
Thank You

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