Transcript Diapositiva 1

RECOMBINANT VS. URINARY
FSH IN IUI
J. Serna MD PhD
QUESTIONS



Is it necessary multiple follicle
development for IUI?
IUI vs. TI?
Best medication?
QUESTIONS

Is it necessary multiple follicle
development for IUI?
– Balance risk/benefits
– Difficult to draw clear conclusions from
studies in subfertile couples
PRs IN IUI
Etiology
Non Stimulated
Clomiphene
hMG
Male Factor
4.6
5.9
11.2
Unexplained
6.0
17.3
21.6
Endometriosis
-
-
10.4
Anovulation
-
18.2
15.6
Cervical
-
-
12.1
PR:
Natural cycle: 4.6%
CC:
11.8%
Gonadotropins 17.7%
IUI: Ovarian Stimulation
Drug
Martinez 90
Arici 94
Cohlen 98
Nulsen 93
CC
Diagnosis
P
Male
NC
MFD
3/30
5/35
Unexplained
NC
MFD
1/20
6/23
<.05
Male
NC
MFD
1/26
1/26
NS
Male
NC
MFD
13/153
21/153
NS
Unexplained
NC
MFD
1/41
11/57
<.05
Male
NC
MFD
1/41
7/54
<.05
CC
Gonadotropins
Pregnancy Rate
Gonadotropins
NS
OR
0.78
OR
2
Male factor: CC do not  PR, but gonadotropins does
Unexplained: CC and gonadotropinas  PR vs. NC
Duran HE Hum Reprod Update 2002
IUI-D: Ovarian Stimulation
Ovarian Stimulation Natural Cycle
Number of
cycles
1009
420
Number of
pregnancies
205 (20.3)
48 (11.4)
Cumulative PR
77.1 ± 3.3
51.0 ± 3.5
Remohí 1996
IUI-D: Ovarian Stimulation
PR/Cycle
PR/Patient
Natural cycle
13%
32%
CC
10%
18%
Gonadotropins
21%
53%
Lashen 1999
QUESTIONS



Is it necessary multiple follicle
development for IUI?
IUI vs. TI?
Best medication?
Metaanalysis: MFD + TI
vs. MFD + IUI
OR 2.37 FSH + IUI
PR/cycle > double vs. NC
and > 5 times FSH + IUI vs. NC
Hughes E, Hum Reprod 1997; 12(9): 865-72


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In most cases it is better MFD vs.
natural cycle
Gonadotropins are better than CC in
most non-PCO patients
TI yields worst results than IUI
QUESTIONS



Is it necessary multiple follicle
development for IUI?
IUI vs. TI?
Best medication?
Drugs for ovarian stimulation
- Clomiphene citrate
- Gonadotropins
- hMG
- FSH ( uFSH vs rFSH)
Gonadotropins


Menotropin
Urofollitropin
– Almost no LH

rFSH
– Highest purity
– Batch to batch consistency
– Potentially allergenic urinary proteins
Urinary Highly Purified Human FSH (uhpFSH)
 Active FSH Immunoselection (anti-FSH Ab)
 Metrodin® HP:
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95 % purity
LH activity 0,1 UI/mg
FSH activity 9000 UI/mg
< 5 % other proteins
Less batch to batch variability
 Better control intersubject variability
Lunenfeld B. Reprod Biomed Online 2002; 4 supp 1: 11-17
Prionic risk
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Evidence of urinary prion excretion in asymptomatics animals and humans
Not able to develop the disease after CNS injection
Shaked GM. J Biol Chem 2001; 276: 31479-82
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Theoretical risks:
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Urinary products: infected donors
Recombinant products: hamster cells, bovine serum
Reichl H. Hum Reprod 2002; 17: 2501-8
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Debate:

Absence of data do not exclude the risk of CJD transmission.
Matorras R. Hum Reprod 2002; 7: 1675
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Main problem: price, activity
Crosignani PG. Hum Reprod 2002; 7: 1676.
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There is no demonstrated infective reason to interrupt urinary products, nor
absolute security with recombinant counterparts.
Balen A. Hum Reprod 2002; 7: 167-9
Constantly Looking for Quality and Consistincy
rFSH
PMSG
Porcine
FSH
1930
hCG
Pituitary
FSH
1950
hMG
uFSH
Purity
Specific activity
Consistency
1980
1995
Lunenfeld B. Reprod Biomed Online 2002; 4 supp 1: 11-17
2004
Safety
Efficacy
Efficiency
Side Effects
Immunereactions Creutzfeld-Jacob
rLH rFSH- Modified Gn
rHCG fbm
Side Effects
AIM

To compare the results of ovulation
induction in couples undergoing IUI
with uhpFSH vs. rFSH
Recombinant vs. Urinary Follicle-Stimulating
Hormone in Couples Undergoing Intrauterine
Insemination: A Randomized Study
Isaza V, Requena A, García-Velasco J, Martínez-Salazar J,
Remohí J, Pellicer A, Simón C.
IVI MADRID
Journal of Reproductive Medicine, 2002
Material and Methods
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Prospective Randomized
June 1999 to May 2000
108 women
224 cycles
Inclusion criteria
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Infertility more than 1 year
18 and 38 y.o.
At least one normal patent tube
MSC > 5 Mill/mL after swim-up
No previous OI, TI or IUI
No PCOs
Institutional review board approval + IC
Pretreatment work-up
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HSG and/or laparoscopy
TVU scan
D3 Serum FSH, LH, E2, PRL and TSH
D22 Progesterone
Semen analysis WHO + MSC
Diagnostic groups
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Endometriosis
Ovulatory Dysfunction
Male Factor
Unexplained infertility
Distribution of etiologies
Unexplained infertility
Male Factor
35%
6%
Endometriosis
39%
20%
Ovulatory dysfunction
Stimulation Protocol
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TVUS on 1st to 3rd cycle day
Ovulation induction started on D3 with
– rFSH 100 IU
– uFSH 150 IU
Randomly assigned by even/odd file record
number
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Patients with several cycles received
the same medication
100 UI
150 UI
rFSH
uFSH
5000 UI
hCG
rFSH
uFSH
1
MENS
2
3
4
5
TVS
6
TVS
IA
Stimulation Protocol
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TVUS Ovarian monitoring started on
D5
No dose adjustment
5,000 IU hCG with a 18 mm leading
follicle + E2
+12 & +36 h IUIs
Cancellations
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No ovarian response
5 or more follicles
Luteal phase support
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400 mg bid micronized vaginal progesterone
Serum hCG 12 days after 2nd IUI
Clinical pregnancy defined as HB 22-25 days after
the positive result
Outcomes measures
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Main
– Total number of follicles > 12 mm

Secondary
–
–
–
–
–
–
–
Follicles >17mm and 12-16
Number of cycles with 2- 4 follicles >17mm
Duration of gonadotropin treatment
Total FSH dose
Serum E2 on hCG
Ration E2/follicle > 17mm
E2/units of FSH
RESULTS
Characteristics
Age (yr)
rFSH (n =118
uFSH (n =106
cycles, 55 couples) cycles, 53 couples) P
NS
33.1 ± 0.3
32.4 ± 0.2
BMI (Kg/m2)
22.3 ± 2.6
23.7 ± 2.3
NS
Duration of infertility (mo)
40.5 ± 3.56
36.4 ± 1.9
NS
Male Factor
22 (40%)
23 (43.4%)
NS
Ovulatory dysfunction
11 (20%)
10 (18.9%)
NS
Endometriosis
3 (5.5%)
3 (5.7%)
NS
19 (34.5%)
17 (23.1%)
NS
FSH (mIU/mL)
6.2 ± 0.3
6.0 ± 0.2
NS
LH (mIU/mL)
6.2 ± 0.5
6.2 ± 0.4
NS
E2 (pg/mL)
42.3 ± 2.9
52.0 ± 4.4
NS
Infertility diagnosis
Unexplained infertility
Hormone levels on day 3
RESULTS
rFSH group
IUI cycle
118 Cycles
(55 couples
uFSH group
Cumulative
pregnancy
rate (%)
106 cycles
(53 couples)
Cumulative
pregnancy
rate (%)
1st
11/55
20.0
11/53
20.7
2nd
8/39
36.4
7/37
35.7
3rd
4/18
50.6
3/11
53.2
4th
2/6
67.1
1/5
62.6
P > 0.05 in each group
RESULTS
rFSH (n = 118
cycles)
uFSH (n = 106
cycles)
No. of days of
stimulation
7.4 ± 0.1
8.1 ± 0.02
<.005
FSH dose (IU)
799.1 ± 20.7
1293.0 ± 148.0
<.001
Total no. of follicles (>12
mm)
2.9 ± 0.1
3.7 ± 0.1
<.001
No. of follicles > 17mm
2.2 ± 0.1
2.0 ± 0.1
NS
No. of follicles 12-16 mm
0.7 ± 0.1
1.7 ± 0.1
<.001
679.6 ± 52.4
813.0 ± 54.1
0.9 ± 0.02
0.6 ± 0.01
<.001
308.9 ± 15.1
406.5 ± 24.1
<.001
Parameter
E2 at hCG (pg/mL)
E2/IU of FSH
E2/follicle > 17 mm
P
NS
RESULTS
DAYS OF STIMULATION
FSH dose (IU)
8,2
1400
8
1200
1000
7,8
800
7,6
600
7,4
400
7,2
200
7
0
rFSH
rFSH
uFSH
Total no. of follicles (>12 mm)
4
3,5
3
2,5
2
1,5
1
0,5
0
uFSH
No. of follicles > 17mm
2,2
2,15
2,1
2,05
2
1,95
1,9
rFSH
uFSH
rFSH
uFSH
RESULTS
No. of follicles 12-16 mm
2
E2 at hCG (pg/mL)
850
800
1,5
750
1
700
0,5
650
0
600
rFSH
uFHS
rFSH
E2/IU of FSH
E2/follicle > 17 mm
1
500
0,8
400
0,6
300
0,4
200
0,2
100
0
uFSH
0
rFSH
uFSH
rFSH
uFSH
RESULTS
Outcome
rFSH (n = 118
cycles, 55 couples)
uFSH (n = 106
cycles, 53
couples)
P
PR/cycle (%)
25/118 (21.2%)
22/106 (20.8%)
NS
PR/couple (%)
25/55 45.5%
22/53 (41.5%)
NS
Cumulative PR 4 cycles (%)
66.7%
65.8%
NS
Miscarriage rate (%)
2/25 (8.0%)
3/22 (26.3%)
NS
Multiple PR (%)
5/23 (21.7%)
5/19 (26.3%)
NS
Cancellation rate (%)
2/118 (1.7%)
2/106 (1.9%)
NS
CONCLUSION

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Shorter duration of stimulation
Less total FSH doses
Less total number of follicles
More follicles >17 mm
Less follicles 12-16

Better optimization of the results
CONCLUSION

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Similar Pregnancy Rates, Miscarriage
Rates
There was a trend towards a less Multiple
Rate