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?
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
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)
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
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
Is LH necessary
during ovarian stimulation?
Endogenous LH: Yes
Exogenous LH: ???
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?
A) SINGLE FOLLICLE SELECTION
B) MULTIPLE FOLLICLE SELECTION
FSH WINDOW
OVARY
GnRH
E2
Inhibin
LH
FSH
(basal)
Negative
feedback
(-)
Messinis, 2006
Hum. Reprod. Update 12, 557-571
MULTIPLE FOLLICULAR DEVELOPMENT
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
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
Is LH suppressed in all
treatment cycles?
NO
It depends on the treatment protocol
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
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)
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
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
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)
<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
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)
To maintain adequate
amounts of LH,
• apply milder ovarian stimulation
protocols!
• use lower doses of the GnRH
agonist!
• supplement with exogenous LH!
Supplementation with
exogenous LH
To whom?
• Non-selected patients
• Poor responders
• Hypogonadotrophic hypogonadism
Supplementation with
exogenous LH
To whom?
• Non-selected patients
• Poor responders
• Hypogonadotrophic hypogonadism
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)
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)
Kolibianakis et al., Hum Reprod Update. 2007, 13, 445-52
Favours FSH Favours FSH+LH
FSH vs FSH+rLH
Live birth rate
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
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
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
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
Supplementation with
exogenous LH
To whom?
• Non-selected patients
• Poor responders
• Hypogonadotrophic hypogonadism
• 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)
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
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
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
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
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
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
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
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
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
Supplementation with
exogenous LH
To whom?
• Non-selected patients
• Poor responders
• Hypogonadotrophic hypogonadism
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-
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
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
CONCLUSIONS (1)
Additional LH is possibly
not needed
• In the majority of IVF/ICSI unselected
cycles with multiple follicular
development
Additional LH is possibly
needed (still debatable)
• In poor responders
• In older women
CONCLUSIONS (2)
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)
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