The use of rec-LH to facilitate monofollicular development

1
The use of rec-LH to facilitate monofollicular
development
European r-hLH Research Group
Zeev Shoham, M.D
Department of OB/GYN Kaplan Medical Center,
Rehovot, Israel
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Multiple Gestation
From curiosity to epidemic
3
Multiple Gestation
Rate
Japan U.S/Europe Africa Monozygous O.I./ART
6.7/1000 11/1000 40/1000 3.5/1000 37
4
Complications
Maternal
Fetal
5
Complications
Premature birth
6
ECONOMIC IMPACT OF MULTIPLE PREGNANCIES
(1986-1991)
13,206 Pregnant women
Callahan et al, NEJM, 1994
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ECONOMIC IMPACT OF MULTIPLE PREGNANCIES (1991)
SINGLETON TWINS TRIPLETS

9,845 US 37,947 US 109,765 US
Callahan et al, NEJM, 1994
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(No Transcript)
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Complications
Embryo reduction
4-5
Miscarriage
Premature labor
75
Traumatic experience
10
Multiple pregnancy rate related to the number of
follicles gt 16 mm on hCG day
No. of
No. of
No. of
Clinical
No. of
Birth
No. of
Multiple
follicles on
cycles
clinical
pregnancy
birth
rate
twins
birth rate
day
hCG
pregnancy
rate ()
()
()
1
foll.
277
47
17.09
39
14.18
2
5.13
2
foll.
77
20
25.97
17
22.08
2
11.76
3
foll.
32
11
34.38
10
31.25
2
20.00
gt 3
foll.
19
5
26.32
4
21.05
2
50.00
Overall
405
83
20.60
70
17.37
8
11.4
11
FSH Administration Regimen
Chronic Low Dose (CLD) S. Franks et al. Step
Down (SD) B. Fauser et al. Sequential (SE)
J.N. Hugues et al.
150 IU
hCG
112.5 IU
75 IU
75 IU
Days
7
14
21
28
150 IU
112.5 IU
75 IU
hCG
Foll. gt 10 mm
½
150 IU
112.5 IU
hCG
75 IU
75 IU
6
12
Foll. gt 14 mm
12
lt5 mm
10 mm
20 mm
Recruitment
Dominance
FSH dependent
Acquiring LH receptors Stimulating E2 Lowering
FSH threshold
Highly responsive to FSH LH
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FSH Threshold Hypothesis Brown 1978
ovulation
Only those antral follicles which coincide with
the early follicular phase rise in FSH can enter
the final stages of follicular growth
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LH effect - dose dependent
Low -dose
High -dose
Enhance steroidogenesis
Progesterone synthesis Aromatase activity
suppression Inhibition of cell growth
Overes et al. Hum Reprod 1992 Yong et al. J Clin
Endocrinol Metab 1992
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FSH threshold theory and LH Ceiling theory
As each follicle has a threshold beyond which
it must be stimulated by FSH, it may also have a
ceiling within which it should be stimulated by
LH, unless further normal development be
terminated.
Brown NZ J Obstet Gynecol 1978 Hillier Hum Reprod
1994
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To obtain preliminary information on efficacy of
r-hLH during the late follicular phase in the
presence or absence of exogenous FSH. For
minimising the number of preovulatory
follicles. Rescuing stimulation cycles with
an excessive no. of follicles.
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United Kingdom S. Franks D. Baird S. Smith
Holland J. Schoemaker
Israel R. Homburg
Italy C. Flamigni
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Study design
To assess the efficacy of two doses of r-hLH
225
450
Given at the late follicular phase to FSH treated
PCOS patients
if
gt4 foll. 8-13 mm
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• 17 patients enrolled
• Placebo 5 patients
• r-hLH 225 IU/day 4 patients
• r-hLH 450 IU/day 8 patients

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PRIOR TO STUDY patients received FSH
stimulation. If met following criteria
gt 4 follicles with a diameter gt 8 mm and lt 13 mm
Endometrium thickness gt 8 mm
450 IU r-hLH 225 IU r-hLH (7 days
max) Placebo
randomization
FSH
When at least one follicle of gt 18 mm and lt 3
follicles of gt 11 mm gt hCG 5000 IU
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Serum LH levels in PCOS anovulatory patients is
variable
Serono - 180 WHO/II mean basal level - 7.41 IU/L
(SD 5.71)
Serono - 387 WHO/II mean level (hCG/d) - 7.73
IU/L (SD 8.37)
gt50
450 IU (r-hLH)
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Mean total number of follicles at baseline (gt8-13
mm) and on day of hCG (gt14 mm)
Placebo
225 IU r-hLH
450 IU r-hLH
18
14
14
9.75
8.88
10
No. of follicles
8-13
5.6
6
3.75
3.8
2.25
1.5
1.25
gt11
2
gt14
23
Mean serum E2 levels at baseline and on day of
hCG
Placebo
225 IU r-hLH
450 IU r-hLH
4000
Serum E2 level (pmol/L)
3000
2000
1000
Baseline
hCG day
24
Mean serum P4 levels at baseline and on day of
hCG
Placebo
225 IU r-hLH
450 IU r-hLH
8
Serum P4 level (nmol/L)
6
4
2
Baseline
hCG day
25
Mean serum LH levels at baseline and on day of
hCG
Placebo
225 IU r-hLH
450 IU r-hLH
8
Serum LH level (IU/L)
6
4
2
Baseline
hCG day
26

Double-blind, Placebo-controlled, Randomized,
Parallel-group
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United Kingdom S. Franks D. Baird
Israel R. Homburg Z. Shoham
Italy C. Flamigni H. Fusi
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Study design
10-13 mm
R-hFSH-187.5
R-hFSH-150
R-hFSH-112.5
R-hLH-225
Randomization
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• 20 patients started the Blinded Phase
• Gonal-F/Placebo 6 patients
• r-hLH/Placebo 6 patients
• Gonal-F/r-hLH 8 patients

Treatment continued until Follicle
reach 18 mm (hCG 10,000) 7 days of
treatment
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Mean total number of follicles at baseline (gt 10
mm) and on day of hCG (gt11 and gt14 mm)
End of treatment
6.0
Baseline gt10 mm
PN.S.
P0.01
4.17
P0.01
2.67
No. of follicles
gt11
2.0
1.83
2.0
gt11
2
1.5
1.5
gt14
0.5
gt11
gt14
gt14
R-hFSH/Placebo
R-hLH/Placebo
R-hFSH/r-hFSH
31
Mean serum E2 levels at baseline and on day of
hCG
3452
Baseline
3000
Serum E2 level (pmol/L)
2000
725
1000
116
R-hFSH/Placebo
R-hLH/Placebo
R-hFSH/r-hFSH
32
Conclusion
There might be some clinical role to r-hLH for
promoting mono-ovulation
Emergence of a dominant follicle . Absence of
follicular phase luteinisation.
Define a new target population
Currently tested population is very small
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Conclusion
Pending issues are Existence of complete
follicular regression, Unknown impact on
pregnancy rate
Refine LH administration Optimal dose
of LH ? 250, 700, 1500 IU ? Optimal
starting time ? 8 to 13 mm ? 14 mm ?
Should a minimal amount of FSH be kept ?
yes