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)

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