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GnRH analog regimens in poor respondersresponders
A. La MarcaA. La Marca
Institute of Obstetrics and Gynecology
University of Modena and Reggio Emilia
ItalyItaly
No universally accepted definition of poor response
<3-5 developed follicles<3-5 developed follicles
<3-5 retrieved oocytes
Peak E2Peak E2
Day 3 FSH
40>40 years
Inhibin B
AMH
Daily or total Gonadotropin dose
Days of stimulation
Previous cycle cancellation
Proposed protocols for poor responders
Increased FSH doses
Addition of LH
Adjunctive therapies
Alternative GnRH agonist protocolg p
GnRH antagonistGnRH antagonist
Natural cycleNatural cycle
The use of GnRH agonist in ART
Reduction of cancellation rates due to LH surges by use of
20%Main positive
effectsto LH surges by use of
GnRH agonists10% Decresed cancellations
I d t
0%
Increased no. oocytes
Increased PR
Better sched lingno GnRH agonist long protocol Better scheduling
Main negative
Impaired steroidogenesis
Reduced ovarian response to FSHg
effects Direct/indirect effect on oocyte quality (?)
Endometrial effect (?)
Cochrane review
Depot vs daily GnRH agonist protocols in ART
There is no difference in clinical pregnancy rate.
However the use of depot GnRH agonist increased the f fnumber of gonadotropin ampoules and the duration of
the ovarian stimulation as compared with the use of daily GnRH agonistdaily GnRH agonist
B d h fi di d il G RH i h ld b f dBased on these findings, daily GnRH agonist should be preferred to depot formulation in poor responders
Albuquerque et al., Hum Reprod 2003
GnRH agonists in poor responders
Long protocolg p
Low daily dose
Stop protocol
Flare Protocol
Standard doseStandard dose
Micro dose
Ultra shortUltra-short
The low daily dose: the rationale
10LH level [U/L]
4
6
8
0
4
2
Days
Reduction in GnRH agonist dose
What is the minimal GnRH agonist dose able to prevent a spontaneous LH surge?
Triptorelin dose (mcg)5 15 50 100
N 11 10 11 12
D f ti l ti 9 (7 12) 7 5 (7 11) * 10 (7 17) 10 5 (7 18) *Days of stimulation 9 (7-12) 7.5 (7-11) * 10 (7-17) 10.5 (7-18) *
LH on hCG day (IU/L) 2.5 (1-8) * 2.3 (1.3-5.6) * 1.8 (1.1-4.5) * 0.95 (0.4-2.7)LH on hCG day (IU/L) 2.5 (1 8) 2.3 (1.3 5.6) 1.8 (1.1 4.5) 0.95 (0.4 2.7)
P on hCG day (nM/L) 4.6 (0.9-6)* 3.1 (1.2-8.3) * 2.4 (0.9-8.6) 1.4 (0.5-3.5)
Spontaneous ovulation (n) 3 0 0 0
Janssens et al., Hum Reprod 1998
What is the minimal GnRH agonist dose able to prevent a spontaneous LH surge?
AUC LH (U h/L)
12
14
AUC . LH (U.h/L)
*
8
10
12
4
6
8
2
4 *
05 15 50 100
Janssens et al., Hum Reprod 1998
The low GnRH agonist daily dose
On the basis of this findings several authors tried to reduce GnRH agonist doseOn the basis of this findings several authors tried to reduce GnRH agonist dose during FSH administration in order to improve ovarian responsiveness.
hCG
GnRHa daily dose FSH stimulation
hCG
GnRH-a administration
Triptorelin 0.1 mg/d 0.05 mg/d (Feldberg, 1994)p g g ( g, )
Leuprolide 0.5mg/d 0.25 mg/d (Olivennes, 1996)
Leuprolide 1mg/d 0.5 mg/d (Kowalik, 1998)
The low GnRH agonist daily dose
Feldberg 1994 Olivennes 1996 Kowalik 1998
Study design Retro Pros Retro
Cancellation rate =
FSH ampolues =
E2 on hCG
No Oocytes =
No embryos nd
GnRH agonists in poor responders
Long protocol
Low daily dose
Stop protocolStop protocol
Flare Protocol
Standard dose
Micro dose
Ultra-short
The “stop protocol”
hCG
GnRHa daily dose FSH stimulation
GnRH-a administration
2 RCT N i d t2 RCT
7 Prospective trials with historical controls
No improved outcome
7 Prospective trials with historical controls
1 retrospective study
improved outcome
1 retrospective study
The “stop protocol”
Dirnfeld (1999) Garcia Velasco (2000)Dirnfeld (1999) Garcia Velasco (2000)
Design RCT (stop vs non stop) RCT (stop vs non stop)
Criteria for low response < 4 oocytes; FSH >9 < 3 oocytes
No. Cycles 40 vs 38 34 vs 36y
Retrieved oocytes/cycle 6.5 vs 7.7 8.7 vs 6.2 (p<0.05)
C ll ti t 5 22 5 % ( 0 05) 2 8 5 9 (NS)Cancellation rate 5 vs 22.5 % (p<0.05) 2.8 vs 5.9 (NS)
No.clinical pregnancy /ET 11.1 vs 10.3 % (NS) 14.3 vs 18.7 % (NS)
Outcome Decreased cancellation rate
Increase no. of oocytes
GnRH agonists in poor responders
Long Protocol
Low daily dose
Stop protocolStop protocol
Flare Protocol
Standard dose
Micro dose
Ultra-short
The flare – up protocol
hCG
FSH stimulation
GnRH-a administration
The flare regimens involve follicular phase initiation of GnRHThe flare regimens involve follicular phase initiation of GnRH agonist with minimal delay before commencing COH
This approach should:
eliminate excessive ovarian suppressioneliminate excessive ovarian suppression
give additional gonadotropin stimulus
The flare – up protocol
Absence of well deigned, large RCT on flare up protocol in poor responders vs standard protocols
Padilla (1996) Toth (1996) Karande (1997)
Design Prosp, no controls Retro Prosp
Criteria for low response No flare up to GnRH test FSH > 15 IU/L FSH > 7
No. Cycles 53 65 80
R t i d t / l d d 10Retrieved oocytes/cycle nd nd 10
Canellation rate 11.3 % nd 23.8 %
No.clinical pregnancy /ET 29 % 20.4 vs 11.7 % (p<0.05)
13.4 %
O t I d ll ti I d I fOutcome Increased cancellation rate
Increased pregnancy rate
Increase no. of oocytes
The flare – up protocol
Studies reporting negative results:
Craner D, 1999
Kondaveeti U 1996
Loumaye E1989
Ron El R 1990Ron El R, 1990
Gindoff P, 1990
Anserini P 1997Anserini P, 1997
Possible explanation of negative results
the increase in LH levels
Serum gonadotropins and steroids in flare up vs long protocol cycles
IU/L IU/L
20
25LHFSH
IU/L hCG
20
25LHFSH
IU/L hCG
15
20 FSH
15
20 FSH
5
10
5
10
0
5
-20 -10 0 10 200
5
-20 -10 0 10 20
Flare up + FSH
Long protocol + FSHFSH FSH
Filicori et al., 1996
Serum gonadotropins and steroids in flare up vs long protocol cycles
nmol/L nmol/L4 Flare up
Long
nmol/L
80
100 Flare upLong
nmol/L
* *3
60
80
1
240*
0
1
0
20
0P T
serum
0P TFollicular fluid
Filicori et al., 1996
GnRH agonists in poor responders
Long Protocol
Low daily dose
Stop protocol
Flare Protocol
Standard dose
Micro dose
Ultra-short
Micro dose flare-up protocols
hCG
FSH stimulation
GnRH-a administrationOC
Low GnRHa daily dose
Rationale
OC in the cycle before COH to avoid the corpus luteum rescue
low GnRh agonist dose to avoid the increase in LH
Micro dose flare-up protocols
The dose of GnRH analogs in micro dose protocols:The dose of GnRH analogs in micro dose protocols:
Scott and Navot (1994) Leuprolide 20 mcg /bid
Schoolcraft (1997) Leuprolide 40 mcg /bid
Surrey (1998) Leuprolide 40 mcg/bid
Leondrines (1999) Leuprolide 20 mcg/bid
Micro dose flare-up. Effects on gonadotropins and estradiol
180200
Estradiol (pg/ml)
*120140160180 Control
Micro dose *
6080
100120
*
0204060
1618
(IU/L) *0
1st 2nd 3rd
Scott et al., 1994 101214
Micro doseStandard
468
Surrey et al., 199802
delta LH delta FSH
Micro dose flare-up. Clinical outcome
Scott (1994) Schoolcraft (1997) Surrey (1998) Leondrines (1999)(1999)
Design Prosp, historical controls
Prosp, historical controls
Prosp, historical controls
Retro
Criteria for low response
Peak E2 < 500 pg/ml < 4 follicles < 4 oocytes < 4 oocytes
No. Cycles 34 32 34 71
Retrieved oocytes/cycle
5.1 vs 1.8 10.9 7.3 vs 6.4 % 13.3 vs 16.5oocytes/cycleCanellation rate
0 % 12.5 % 6.7 vs 53.3 % 22.5 vs 8.2%
N li i l 11 8 0 % 50 % 41 7 % 0% 47 60No.clinical pregnancy /ET
11.8 vs 0 % 50 % 41.7 % vs 0% 47 vs 60
Outcome Increased no. Oocytes
Increased no. Oocytes
Decrease cancellation rate
Inceased cancellation rateOocytes
Increased PROocytes
Increased PRcancellation rate
Increased PRcancellation rate
Micro dose vs regular dose flare-up
No prospective studies, no RCTs
Microdose Regular dose
n 15 36n 15 36
No. oocyte retrieved = =
Mature oocytes = =
FR = =
No. embryos transferred = =
No FSH ampoules = =No. FSH ampoules = =
PR = =
Delivery rate = =Detti LD et al., Fertil Steril 2005
GnRH agonists in poor responders
Long Protocol
Low daily dose
Stop protocolStop protocol
Flare Protocol
Standard dose
Micro dose
Ultra-short
Ultra-short and other very short regimens
FSH i l i
hCG
GnRH a
FSH stimulation
GnRH-a
GnRHa dailyDay 3 Macnamee et al., 1989
GnRHa daily dose
hCG
FSH stimulation
GnRH-aD 7
GnRHa daily dose
Day 7
Hazout et al., 1993
Effect of GnRH agonist discontinuation on pituitary function
Standard flare up
Early GnRHa discontinuation
7LH (IU/L)
2000E2 (pg/ml)
Early GnRHa discontinuation
56
7
1500
2000
3
45
* 1000*
12 *
* * * 500
*
*
06 7 8 9 10 11 hcg
d
06 7 8 9 10 11 hcg
dday day
Cedrin-Durnerin I et al., 2000
Protocols based on GnRH agonist vs antagonist in poor responders
The GnRH antagonists have been soon indicated as candidate for the use in poor responders
GnRH antagonist in
Prevention of LH surge within a few hours
antagonist in poor
responder
advantages Absence of inhibition on early folliculogenesis
Few injections
GnRH agonist vs antagonist in poor responders: a metanalysis
Only 6 trials fullfilled the inclusion criteria !!
Antagonist vs AgonistAntagonist vs Agonist
Ganirelix (n=2) Standard long protocol (n=2)
Franco JG, 2006Cetrorelix (N=4) Flare up protocol (n=4)
GnRH agonist vs antagonist in poor responders: a metanalysis
Flare up GnRH ant
No. Oocytes =
No. Mature oocytes
= =
Cancellation rateCancellation rate = =
PR per cycle = =p y
PR per oocyte = =
PR per transfer = =
Franco JG, 2006
Pituitary down regulation for poor responders at the Reproductive Medicine Unit of University Hospital of Modena – Italy
Results 2001-2005Identification of poor respondersIdentification of poor responders
>38 yrs
>day3 FSHPrevious cancelled cycle for no response
Prospectively Retrospectively>day3 FSH
< AMH
< antral follicles count
y p
low number of oocytes at the previous cylce
< antral follicles count
Protocol used in the previous cycleCOH for poor responders
y
Phisician’s preference for a given protocol
Frequently prescribed down regulation protocol in
Low GnRHa daily dose
Flare up protocoldown regulation protocol in poor responders
Flare up protocol
GnRH antagonist protocol
Pituitary down regulation for poor responders at the Reproductive Medicine Unit of University Hospital of Modena – Italy
Low daily dose Flare up GnRH antagonist
No. of cycles 47 75 78
Age (yrs) 37±5 38±5 37±6
Days of stimulation 12.3±2 12.5±3 11.8±1.7y
No. of ampoules FSH/LH/HMG 48±16 40±10 38±13
N f t t 4 1±2 4 2±3 4 0±2No. of mature oocytes 4.1±2 4.2±3 4.0±2
Fertilization rate (%) 80 75 80
Clinical PR / transfer (%) 16 15 13
Interventions for poor responders to COH in IVF
A Cochrane Collaboration - 2007
“ …there is insufficient evidence to support the routine use of any particular intervention either for pituitary downregulation, ovarian simulation or adjuvant therapy in the management of poor responders to COH in IVF.
More robust data from good quality RCTs with relevant outcomes are needed.”
Conclusions
The more recent trend is for the reduction in dose and duration of GnRH agonists administration This reflects theduration of GnRH agonists administration. This reflects the fear that these medications may affect ovarian response and oocyte quality.a d oocyte qua ty
GnRH antagonists give results similar to those obtained with low dose-GnRH agonistswith low dose-GnRH agonists.
Conclusions
P i ll dPrevious cancelled cycle
Try to change the protocol for pituitary down regulationTry to change the protocol for pituitary down regulation
GnRH GnRHGnRH agonist
GnRH antagonist
Conclusions
Prospectively identifiedProspectively identified poor responder
Low GnRH agonist Standard Micro dose GnRHLow GnRH agonist daily dose
Standard flare-up
Micro dose flare-up
GnRH antagonist
We are prescribing not according to EBM but our own preferencep
ESHRE WORKSHOP
Ovarian reserve: new insights for clinical management
Modena, ItalyModena, Italy
April 18-19, 2008
Scientific organizers:
A.Volpe (IT)
N. Macklon (NL)
Scientific Secretary:
A L M (IT) S Gi li i (IT)A. La Marca (IT), S. Giulini (IT)
www.eshre.com