Head of Department of Obs/Gynae University of Thessaly ... · Head of Department of Obs/Gynae...
Transcript of Head of Department of Obs/Gynae University of Thessaly ... · Head of Department of Obs/Gynae...
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Head of Department of Obs/Gynae
University of Thessaly, Larissa, Greece
Professor IOANNIS E. MESSINIS
MD, PhD (Aberdeen, UK), FRCOG (UK)
Disclosure of interest:
Nothing to disclose
LH IN THE STIMULATION PROTOCOL.
Is it necessary? To whom? Would
adding LH increase OHSS risk?
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Is LH necessary?
From a physiological point of view:
• LH contributes to follicle maturation
– by stimulating steroids production
– by sustaining the growth of the selected
dominant follicle
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A
T
Chole-
sterole
cAMP
A T
E1
E2 LH
FSH FSH
Induction of
FSHR aromatase
5α-reductase 5α-reduced A
Theca
cell Granulosa
cell
(-)
R
R R
TWO-CELL TWO-GONADOTROPHIN THEORY
(Early follicular phase)
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CLASS 5 CLASS 6 CLASS 8
Intercycle rise
of FSH
Follicles
10-12 mm
CYCLIC
RECRUITMENT
SELECTION
DOMINANCE
18 mm
GROWTH OF THE DOMINANT
FOLLICLE
Messinis et al., 2010
Ann. N.Y. Acad. Sci.
1205, 5-11
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A
T
Chole-
sterole
cAMP
A T
E1
E2 LH
FSH FSH
Induction of
FSHR aromatase
5α-reductase 5α-reduced A
Theca
cell Granulosa
cell
(-)
R
R R
TWO-CELL TWO-GONADOTROPHIN THEORY
(Mid- to late follicular phase)
LH
R
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Is LH necessary
during ovarian stimulation?
Endogenous LH: Yes
Exogenous LH: ???
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Exogenous LH: To whom?
• Are there any subgroups of infertile
women who might get an extra
benefit from the use of LH at any
stage of ovarian stimulation?
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A) SINGLE FOLLICLE SELECTION
B) MULTIPLE FOLLICLE SELECTION
FSH WINDOW
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OVARY
GnRH
E2
Inhibin
LH
FSH
(basal)
Negative
feedback
(-)
Messinis, 2006
Hum. Reprod. Update 12, 557-571
MULTIPLE FOLLICULAR DEVELOPMENT
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Cycle days 2 3 4 5 6 7 8 9 10
Control
rFSH/uFSH
uFSH
rFSH (Gonal-f)
Messinis et al.,
1998
Hum. Reprod.
13, 2415-20
20
10
0 7
0 10000
1000
100
FSH
IU/l
LH
IU/l
E2
pmol/l
OVARIAN STIMULATION
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100
80
60
40
20
0 3000 6000 9000 12000 15000
LH
IU/l
Estradiol (pmol/l)
r=-0.44
P<0.05
0
LH SUPPRESSION DURING
OVARIAN HYPERSTIMULATION
Messinis et al., 1986; Clin. Endocrinol. 25, 393-400
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Is LH suppressed in all
treatment cycles?
NO
It depends on the treatment protocol
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7
6
5
4
3
2
1 0
2000
1500
1000
500
0
LH
IU/l
E2
pg/ml
6 7 8 9 10 11 -2 -1 HCG
Up to day 7 (n=115)
Up to day of HCG (n=115)
LH IS NOT SUPPRESSED
Cedrin-Durnerin et al., 2000, Hum. Reprod. 15, 1009-1014
8
6
4
2
0
2000
1000
0
Decapeptyl
GnRH ag. short protocol
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7
3
6
5
4
2
1
0
Screen 1 6 7 8 9 10 11 HCG ET final
OPU after ET
HMG days
n=228 278 302 291 291 225 161 103 298 253 235 222 55
Felberbaum et al., 2000; Hum. Reprod. 15, 1015-1020
MEDIAN
VALUE
8
6
4
2
0
LH
IU/l
FSH PLUS A GnRH ANTAGONIST
(cetrorelix)
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6 8
4 2
10
6
2
1000
800
200
3
2 1
0 24 48
E2
pg/ml
FSH
mIU/ml
LH
mIU/ml
P4
ng/ml
HOURS
E2 patches Ganirelix
LH IS SUPPRESSED BY E2
(but not....... by the antagonist)
Messinis et al., 2010
Fertil. Steril.
94, 1554-6
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1 6 8 10
Stimulation day
1 6 8 10
Stimulation day
LH IU/L FSH IU/L
FSH PLUS A GnRH AGONIST (LONG)
Ganirelix
Buserelin (LONG)
Borm & Mannaerts, 2000
Hum. Reprod. 15, 1490-1498
8
6
4
2
0
20
15
10
5
0
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HOW MUCH LH?
LH thresholds studied
• 3.0 mIU/ml (Esposito et al., 2001)
• 1.2 mIU/ml (O’Dea et al., 2008)
• 1.0 mIU/ml (Cabrera et al/. 2005)
• 0.7 mIU/ml (Balasch et al., 2001)
• 0.5 mIU/ml (Westergaard et al., 2000)
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<0.5 IU/L
(n=20)
Normal LH
(n=41)
E2 on HCG (pg/ml) 1778±1762 2923±2213 NS
E2/mm of FD (pg/ml) 7.2±3.6 10.4±4.3 0.03
No. of oocytes 185 536
Fertilization rate (%) 75.7 84.2 <0.02
Supernumerary
embryos/patient 5.1±4.4 7.8±5.4 0.05
OVARIAN STIMULATION
(Midfollicular LH)
P
Fleming, 1998
Hum. Reprod. 13, 1788-92
Long GnRH ag
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LH VALUES IN IVF CYCLES
• Better outcome if day 8 LH0.5 IU/l in rFSH/ganirelix cycles (Kolibianakis et al., 2004)
• Higher rate of early pregnancy loss (Westergaard et al., 2000) if day 8 LH<0.5 IU/l
• Lower live birth rate if LH0.5 IU/l (Propst et al., 2011)
• Serum LH (rFSH/triptorelin) cannot predict ovarian response and outcome (Penarrubia et al., 2003)
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To maintain adequate
amounts of LH,
• apply milder ovarian stimulation
protocols!
• use lower doses of the GnRH
agonist!
• supplement with exogenous LH!
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Supplementation with
exogenous LH
To whom?
• Non-selected patients
• Poor responders
• Hypogonadotrophic hypogonadism
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Supplementation with
exogenous LH
To whom?
• Non-selected patients
• Poor responders
• Hypogonadotrophic hypogonadism
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r-FSH r-FSH + rLH P-value
All patients 28.7% 27.2% 0.699
(n=261) (n=265)
Patients 35 y 27.6% 29.6% 0.699
(n=210) (n=216)
Patients >35 y 33.3% 16.3% 0.065
(n=51) (n=49)
rFSH vs rFSH+rLH (MID-FOLLICULAR rLH SUPPLEMENTATION)
NyboeAndersen et al., 2008
Hum. Reprod. 23, 427-34
GnRH-ag long (IVF/ICSI)
(ongoing live gestation
10-12 weeks)
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244 WOMEN IN TWO GROUPS:
Group I (n=122): GnRH-ag/rFSH
Group II (n=122): GnRH-ag/rFSH+rLH
- More oocytes, higher implantation rate
in Group II than in Group I
- No differences in clinical results
Franco et al., 2009
Reprod. Biol. Endocrinol. 7, 58
rFSH vs rFSH+rLH (from the beginning of treatment)
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Kolibianakis et al., Hum Reprod Update. 2007, 13, 445-52
Favours FSH Favours FSH+LH
FSH vs FSH+rLH
Live birth rate
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IVF
ICSI
Al-Inany et al., 2009; Gynecol Endocrinol 25, 372-8
Ongoing pregnancy / live birth rate
Favours HP-HMG Favours FSH
HP-HMG vs rFSH
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28 trials, 7339 couples:
Odds ratio 0.97, 95% CI 0.87 to 1.08
Van Wely et al., 2011
Cochrane Database Syst. Rev. Feb 16;(2):CD005354.
rFSH vs URINARY
(HMG, P-FSH, HP-FSH)
LIVE BIRTH RATE (IVF/ICSI)
NO DIFFERENCE
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Dose 0
(n=16)
Dose 50
(n=20)
Dose 100
(n=16)
Dose 150
(n=15)
Treatment
Days........... 10.3±1.4 9.3±1.4 9.9±1.3 10.4±1.1
Total dose
FSH............ 1538±209 1385±232 1475±195 1562±163
Oocytes
retreived.... 9.3±6.3 8.5±4.4 9.2±4.2 11.3±5.7
Cl. Preg./
cycle.......... 25% 27% 38% 31%
Live birth
rate............. 25% 27% 25% 31%
Thuesen et al. 2012
Hum. Reprod. 27, 3074-84
Prospective RCT
HCG in IU from day 1
ADDITION OF HCG TO rFSH
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18
16
14
12
10
8
6
4
2
0 12-14 mm 14-17 mm >17 mm
No of follicles
Mean diameter
2.6 2.4
6.2 5.5
16.5 14.7
rFSH+rLH
HP-hMG+uFSH
Oocyte
donors
Requena et al., 2014; Reprod. Biol. Endocrinol. 12, 10
OVARIAN STIMULATION
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Supplementation with
exogenous LH
To whom?
• Non-selected patients
• Poor responders
• Hypogonadotrophic hypogonadism
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• Meta-analysis of 3 RCTs:
Higher pregnancy rate in favour of co-
administering rLH
OR 1.85 (95% CI 1.10-3.11)
Mochtar et al., Cochrane Database Syst Rev 2007
rLH IN POOR RESPONDERS
(Pooled pregnancy estimates)
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r-FSH
(n=68)
r-FSH + rLH
(n=63) ITT Population
Analysis
Implantation rate 11.3 18.1 0.049
Live birth/started cycle 7.4 19.0 0.047
Live birth rate/ET 9.3 21.4 NS
P-value
PP Population
Analysis
Implantation rate 10.0 17.4 NS
Live birth/started cycle 7.7 17.5 NS
Live birth rate/ET 9.6 19.6 NS
MID-FOLLICULAR rLH
SUPPLEMENTATION (35-39 y)
ICSI results Matorras et al., 2009
RBMOnline 19, 879-887 GnRH-ag long
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35 y (n=172 vs 161) 36-39 y (n=142 vs 150)
IR
CPR
PLR
OPR/ET
OPR(ITT)
1.00 1.50 0.50 1.00 2.00 0.00
rFSH vs rFSH+rLH
GnRH-antag. Bosch et al., 2011
Fertil. Steril. 95, 1031-6
RCT
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rFSH vs rFSH+rLH
Meta-analysis
Women 35 years Hill et al., 2012
Fertil. Steril. 97, 1108-14
Favors rFSH Favors rLH + rFSH
Clinical pregnancy rate
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Early LH
(from day 1)
(n=264)
Late LH
(from day 7)
(n=266)
Total FSH dose (IU) 4090±934 4223±1086
Total LH dose (IU) 2163±285 1042±348
Retrieved oocytes 3.7±2.1 3.5±2.4
Preg. Rate/ET (%) 17.6 19.9
Ong./delivered (%) 12.6 14.9
SUPPLEMENTATION OF
recFSH WITH recLH
Revelli et al., 2012
JARG 29, 869-75
Poor responders
Prospective RCT
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rFSH
(n=128)
rFSH+rLH
(n=125)
FSH 12.8±3.9 12.1±3.4 NS
LH 1.6±1.2 3.0±1.2 0.00
E2 5135±3179 6524±3802 0.01
P
FSH 2.0±1.7 1.8±0.7 NS
LH 0.5±0.5 0.6±1.0 NS
E2 2941±1809 2879±1875 NS
Day
of
HCG
Day
of
ET
rLH SUPPLEMENTATION
(from day 6 of stimulation)
RCT (women ≥35 y)
GnRH ant. (IVF/ICSI)
Mean±SD
Konig et al., 2013
Hum. Reprod. 28, 2804-12
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rFSH
(n=128)
rFSH+rLH
(n=125)
Total oocytes 10.9±6.4 10.2±6.1
Cl. Preg. (ITT) 29.7% 28.0%
Ong. Preg. (ITT) 21.9% 20.0%
Cl. Preg. (per Prot.) 33.6% 30.2%
Ong. Preg. (per Prot.) 24.8% 21.6%
Ong. Preg. including
frozen-thawed 27.4% 25.9%
rLH SUPPLEMENTATION
(from day 6 of stimulation)
Konig et al., 2013
Hum. Reprod. 28, 2804-12
RCT (women ≥35 y)
GnRH ant. (IVF/ICSI)
Mean±SD
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POOR RESPONDERS rFSH+rLH vs rFSH
No of oocytes 0.75 (95% CI 0.14-1.36) ITT (n=12 studies)
0.75 (95% CI 0.13-1.36) PP
Clinical Pregnancy 1.30 (95% CI 1.01-1.67) ITT (n=14 studies)
Ongoing pregnancy rate 1.36 (95% CI 1.04-1.79) ITT (n=11 studies)
Live birth rate NS
Lehert et al., 2014
Reprod. Biol. Endocrinol. 12, 17
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rFSH
rFSH+rLH
or HMG
- Nyboeandersen et al., 2008
(RCT) 3.8% 2.6%
- Al-Inany et al., 2008
(Meta-analysis) OR: 1.21 (95% CI 0.78-1.86)
- Coomarasamy et al., 2008
(Meta-analysis) OR: 1.39 (95% CI 0.72-2.69)
- Bosch et al., 2011
(RCT) ≤35y 5.3% 7.0%
35-39y 5.0% 3.0%
LH AND OHSS
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LH AND OHSS
• Low dose HCG supplementation to
FSH
– Less in the antagonists vs agonists OR:
0.30 (95% CI 0.09-0.96)
Meta-analysis
Kosmas et al., 2009
RBMOnline 19, 619-30
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Supplementation with
exogenous LH
To whom?
• Non-selected patients
• Poor responders
• Hypogonadotrophic hypogonadism
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75 IU
recFSH
5
10
15
20
FSH (IU/L)
Follicle
diameter (mm) E2 (pmol/L)
Follicle
FSH
E2
200
100
7 14 21
0 6 10 15 20 25 30 35 Days
Shoham et al., 1993
Fertil. Steril. 59, 738-42
HYPO-, HYPO-
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HYPOGONADOTROPHIC
HYPOGONADISM
(Usage of HMG or rFSH with rLH)
FSH LH E2
IU IU (pmol/l)
Couzinet et al., 1988 225 225 2753
(HMG) (HMG)
Kousta et al.,1996 150 225 780
El-Shawarby et al., 2004 50-75 75 3155
Based on a review by: Messinis, 2005
Hum. Reprod. 20, 2688-97
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CLINICAL RESULTS
(starting dose 150 IU/day)
50 patients were treated in 167 cycles:
- All women ovulated - 33 pregnant (66%)
- 39 pregnancies (9 multiples, 31%,
10 aborted, 26%)
- Patients who took home at least one baby
28 (56%)
Messinis et al., 1988
Fertil. Steril. 50, 31-35 ~4 cycles
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CONCLUSIONS (1)
Additional LH is possibly
not needed
• In the majority of IVF/ICSI unselected
cycles with multiple follicular
development
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Additional LH is possibly
needed (still debatable)
• In poor responders
• In older women
CONCLUSIONS (2)
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CONCLUSIONS (3)
Additional LH is needed
(absolutely necessary)
• In women with hypogonadotrophic
hypogonadism during ovulation
induction or ovarian stimulation for
IVF/ICSI (from the beginning of the
treatment)
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STILL EXPERIMENTAL
• The administration of rLH
– to substitute rFSH and sustain the
follicle growth in IVF cycles
– to attain a ‘ceiling effect’ in ovulation
induction facilitating mono-follicular
development