Optimizing the

Management of the

Poor Responder

Kaylen Silverberg, M.D.

Texas Fertility Center

Austin, Texas

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Agenda

Definitions

Pathophysiology

Ovarian Reserve Testing

Treatment Alternatives

Novel Approaches

Who Is the Poor

Responder?

Background

Poor Responder

5-18% of all ART patients

Diminished ovarian reserve

Advanced age, Ovarian surgery, Idiopathic

Definitions

# mature follicles, retrieved oocytes

Peak E2 levels

Day 3 FSH, E2 levels

Repetitive premature LH surges

Over 20 published definitions (and climbing…)

Poor Responder:

Pathophysiology

Declining oocyte quality

Oocyte chromosomal degeneration (dissociated chromatids) a

23.7% < 34 yo

52% 35-39 yo

95.8% >40 yo

Mitochondrial DNA deletions increase with patient age b

a Lim et al. Fertil Steril 1997;68:265 b Keefe et al. Fertil Steril 1995;6:577

Age Related Decline in

Fertility

0

10

20

30

40

50

60

<30 31-

33

34-

36

37-

39

40 41 42 43 44

Delivery/ET

Rosenwaks, et al.

%

Patient Age

Hormonal Tests of

Ovarian Reserve

Day 3 FSH Levels

Day 3 Estradiol Levels

Inhibin B Levels

AMH

Clomiphene Challenge Testing

Day 3 FSH Levels

FSH

Level

<15 15-20 20-25 > 30

Cxl. Rate

(%)

5% 10% 20% 40%

Toner et al. Fertil Steril 1991 (n=1478)

• Indirect measure of ovarian reserve

• Pregnancy/delivery rates fall as FSH rises

• Begins to rise 5-6 years before menopause onset

• Predictive value supported by many other investigators

• Elevated D3 FSH portends poor response, but many

poor responders have normal D3 FSH levels

Day 3 Estradiol Levels

Smotrich

1995

292 < 80 pg/mL 0.4% 37%

> 80 18.5% 14.8%

Licciardi 452 < 75 pg/mL 20

> 75 0

Author # Pts D3 E2 Cxl(%) Preg(%)

• Proposed mechanism involves negative hypothalamic

feedback on FSH, leading to false negative FSH levels

•Some studies suggest no incremental value over

Day 3 FSH alone

Basal FSH & E2 Variability

0

10

20

30

40

50

60

70

FSH Estradiol

CD 2

CD 3

CD 4

CD 5

Hansen et al Hum Reprod 1996;11:486

Predictors of Ovarian Reserve

Normal

Responders

(n=84)

Poor

Responders

(n=36)

P

D3 FSH 6.6 12.9 <0.001

D3 E2 167 270 .58

D3 Inhibin 118 70 <0.001

Antral Foll 11.6 4.2 <0.001

# oocytes 9.5 2.1 <0.001

Preg rate 31/77 3/30 .003

Laszlo et al. Fertil Steril 2002;77:328

Clomiphene Citrate Challenge

Testing (CCCT)

Basal (D3) FSH, E2

CC 100 mg cycle days 5-9

Day 10 FSH, E2

Abnormal: “Elevated” Day 3 or Day 10 FSH

Tanbo (1992):

< 12: 32% cxl rate, 10% preg rate

> 12: 85% cxl rate, 0% preg rate

Loumaye (1990):

< 26: 1% cxl rate, 28% preg rate

> 26: 25% cxl rate, 0% preg rate

Sonographic Evaluation of

Ovarian Reserve

Antral follicle counts

Ovarian volume

Doppler imaging techniques

Antral Follicle Counts 2-5 mm antral follicles

Typically measured on Day 2 or 3

Correlates with Day 3 FSH, amount of gonadotropin used, peak E2 level, # oocytes, and pregnancy rates a

Better predictor of ovarian response than patient age, D3 FSH level b, or inhibin B level c,d

Normal responders typically have > 10 antral follicles vs. < 5 for poor responders b,e

a Chang et al. Fertil Steril 1998;69:505 b Beckers, et al. Hum Reprod 2000;15:43 c Fauser Fertil Steril 2000;74:629 d Laszlo et al. Fertil Steril 2002;77:328 e Beckers, et al. Fertil Steril 2002;78:291

Ovarian Volume vs.

Pregnancy Rates

0

5

10

15

20

25

30

35

40

45

50

< 3 cm 3-9 cm > 9 cm

Smallest Ovary

Total OvarianVolume

Syrop Fertil Steril 1995;64:1167

Poor Responder:

Treatment Alternatives High Dose Gonadotropin Clomiphene Citrate plus High Dose hMG Letrozole Reduction/Elimination of GnRH-A Addition of LH GnRH-antagonists Growth Hormone, GH-RH Estrogen/Progesterone pretreatment Recombinant Gonadotropins vs. combo protocols “Flare” protocols Micro-dose Lupron Flare DHEA

High Dose Gonadotropin

Therapy

Laufer

1982

Land

1996

Karande

1990

Hershlag

1996

Design R P R R

N 55 126 34 48

Old/New

hMG dose

150/225 Doubled 300/450 225/300-600

Change in E2

peak?

YES NO

Increase in #

oocytes

YES YES NO NO

Improved

Outcome?

NO NO NO NO

High Dose hMG Plus

Clomiphene Blankstein (1989)

N=18, CC100 + hMG(75-150)

Increased peak E2, improved follicular development

10/18 to retrieval (0/18 in prior cycle)

Pantos (1990)

N=271, CC 100 + hMG (150-225)

Data difficult to interpret as patients received different doses of hMG

No improvement in stimulation or pregnancy rate

Benadiva (1995)

N=93, previously failed gonadotropins alone

No improvement in cxl rate, peak E2, stimulation length

Increased implantation rate and live birth rate

Cycle cxl rates of 25-30% due to LH surge

Poor Responders: Letrozole

N=147, OCP/hMG150/FSH225

Antagonist at 14mm

Letrozole

(n=71)

Control

(n=76)

P

Oocytes 6.1 4.3 0.03

Peak E2 384 485 NS

PR/cycle (%) 22 15 NS

Garcia-Velasco et al. Fertil Steril 2005;84:82

Poor Responders: Letrozole

P,R;N=70, OCP/rFSH 450 ± Letrozole 5mg

Antagonist “flexible” dosing

Letrozole

(n=35)

Control

(n=35)

P

Total FSH 2980 3850 <0.05

Cycle Cxl 8.6 28.6 <0.05

PR/ET (%) 25.8 20 NS

Ozmen, et al RBM online. 2009;19:478-85

Adjunctive GnRH-agonists Advantages

Lower cancellation rates

Prevents LH surge

Higher peak E2 levels

Greater number of retrieved oocytes

Higher pregnancy rates

Disadvantages

Longer stimulations

Direct ovarian suppression

More exogenous gonadotropin required

“Stop” GnRH-a Protocol Administer luteal GnRH-a until onset of menses

High dose gonadotropin therapy

Faber:

12.5% cxl rate

Over half of the patients produced > 10 oocytes, and had 3 embryos for transfer

Clinical pregnancy rate 32.5% per transfer

Dirnfield:

No benefit

Wang:

13.5% cxl rate

Clinical pregnancy rate 20.5% per transfer

Faber, et al. Fertil Steril 1998;69:826

Dirnfield et al. Fertil Steril 1999;72:406

Wang et al. J Asst Reprod Genet 2002;19:1

LH Supplementation

P, R Controlled trial (n=84)

rFSH, rLH

Basal FSH ≥10, ≥40yo, 1st IVF cycle

No differences:

OPR, implantation rate

# days of gonadotropin, E2 level, #

follicles, # oocytes, # embryos/ET

Barrenetxea, et al. Fertil Steril 2008;89:546-53

GnRH Antagonists

Directly, quickly suppress pituitary FSH, LH production

Lessen duration of direct ovarian suppressive effect

Daily dose (0.25mg) vs single dose (3 mg) – equally effective a,b,c

Optimal size for antagonist initiation??

12-13 mm

14-15 mm or larger??

a,b Olivennes et al Hum Reprod 1998;13:2411, RBM Online 6;4:432, 2003 c Albano et al Fertil Steril 1997;67:917

Agonist vs Antagonist: Data

Cochrane review (2002) 1

5 studies

Lower delivery rates with antagonist 0.79 (CI 0.63-0.99)

5% absolute treatment effect, so for every 20 couples treated, there will

be one more pregnancy with agonist

Cochrane review (2006) 2

27 studies

Significantly lower pregnancy/delivery rates with antagonist (p<0.05)

1 Al-Inany et al, Hum Reprod. 2002;17:874 2 Al-Inany et al, Cochrane Database Syst Rev. 2006;19:3

Oral Contraceptive Pre-

Treatment Potential Advantages

Prevents rescue of corpus luteum from previous cycle

Blocks cyst development

Synchronized follicular cohort development

Allows better scheduling of cycles

Decreases gonadotropin requirements??

Lower cancellation rates

Greater number of retrieved oocytes

Higher pregnancy rates

Potential Disadvantages

Longer stimulations??

Residual ovarian suppression

Exacerbated ovarian suppression when combined with GnRH-a

More exogenous gonadotropin required???

Oral Contraceptive Pretreatment

No OCPs OCPs P

Baseline Cysts >

10 mm (%)

24 0 < 0.05

E2 < 50 pg/mL (%) 62 100 < 0.05

Peak E2 (pg/mL) 1688 (188) 2431 (501) < 0.05

# oocytes 9.9 (1.0) 11.8 (1.2) < 0.05

Fertilization (%) 55.7 69.1 < 0.05

Testosterone

(ng/mL)

41.9 (9.8) 25.1 (3.4) < 0.05

Gelety, TJ: ASRM abstract 010, 1997

Luteal Estrogen

Hill, et al. Fertil Steril 2009; 91:739-43

Outcome

Variable

E2 (n=57) No E2 (n=228) P Value

% embryos > 7c 46.4 (%) 40.6% .05

Implantation Rate

(%)

19.7 21.8 .57

Chemical Preg

(%)

45.6 44.3 .86

Clinical Preg (%) 38.6 36.4 .76

Preg Loss (%) 30.8 32.7 .85

Delivery (%) 28.1 22.4 .36

Recombinant FSH vs. Urinary

FSH: Clinical Efficacy

In randomized prospective statistically powered clinical studies, significantly more oocytes were retrieved and less medication required with r-FSH than with u-FSH. (Bergh 97; Frydman 98; Schats et al 2000)

Pregnancy rates significantly improved

FIVNAT 1999: data from 37,211 cycles

Clinical pregnancy rates achieved with r-FSH were statistically higher than those achieved with urinary FSH (Daya et al 1999)

Meta Analysis: 12 randomized controlled trials (2875 cases, Daya, 1999)

Short “Flare” GnRH

Protocol Potential benefits:

Initial stimulatory effect on FSH, LH

Shortened stimulation

Decreased gonadotropin requirements

Potential detriments:

Increased androgen production

Corpus luteum rescue

Diminished oocyte quality

Decreased pregnancy rates

Conflicting data in few, small studies

GnRH-A Flare Studies

No change in peak E2 levels

No change, to slight decrease in number of oocytes retrieved

Most studies show increase in follicular phase and early luteal LH and progesterone production

Increase in atretic oocytes

Larger studies show no increase in pregnancy rates

Katayama, et al. 1988

Brzyski et al. 1988

Dirnfeld et al. 1991

Micro Dose Lupron Flare:

Higher E2 levels, more mature oocytes, no spont. LH surges, 90% with improved outcome, 9% preg rate (n=34) 1

Higher E2 levels, more mature oocytes, fewer cxl cycles, no LH surges , 50% preg rate – used growth hormone as well (n=32) 2

Higher E2 levels, fewer cxl cycles, more patients to embryo transfer, 35% preg rate (n=34) 3

1 Scott RT, Navot D Fertil Steril 1994;61:880 2 Schoolcraft W, Schlenker T, et al Fertil Steril 1997;67:93 3 Surrey E, et al. Fertil Steril 1998;69:419

Materials and Methods

Prospective, sequential trial of LLL and ULDLF

protocols

n=53 (1997-1998)

IVF

LLL

LA 0.5 mg (OCP overlap or LH timing)

0.25 mg with FSH initiation

hCG 10,000 IU; 2 follicles > 18 mm

Silverberg & Vaughn, ASRM, 1998

Materials & Methods

ULDLF

21 days OCPs

3 days later, LA 40 µg BID

2 days later, FSH 225-300 IU BID

hCG 10,000 IU; 2 follicles >18 mm

TVA 36 h post hCG

D3 embryo transfer

Progesterone in oil 25 mg IM; D2 start

Silverberg & Vaughn, ASRM, 1998

Materials & Methods

4 analyses

separate (n=112 cycles)

completed both LLL & ULDLF (n=48)

failed LLL/ completed ULDLF (n=35)

failed ULDLF/ completed LLL (n=2)

Statistical Analysis

t test

paired t test

Silverberg & Vaughn, ASRM, 1998

Overall Results

53 poor responders

59 LLL cycles

53 ULDLF cycles

Cycle Cancellation Rates

LLL 22/59 (37.3%)

ULDLF 6/53 (11.3%) (p<0.05)

No spontaneous LH surges

Silverberg & Vaughn, ASRM, 1998

Overall Results

0

5

10

15

20

25

30

35

40

45

Clin Preg Delivery* Cxl Rate*

LLL

ULDLF

22/59

6/53

18/42

9/30 13/42

3/30

%

* p < 0.05 Silverberg & Vaughn, ASRM, 1998

Results: Direct Comparisons

LLL ULDLF P # cycles 24 24

# with ET 21 21

Stim (days) 11.0 (1.5) 10.8 (2.2) 0.8

Gonadotropin (IU) 4953 (1447) 6183 (1769) 0.01

E2 peak (pg/mL) 1160 (507) 1390 (803) 0.2

# oocytes retrieved 6.1 (2.5) 6.7 (3.7) 0.5

# oocytes fertilized 4.0 (2.0) 4.6 (2.6) 0.4

# embryos trans 3.5 (1.5) 3.6 (1.3) 0.8

Silverberg & Vaughn, ASRM, 1998

Results: Direct

Comparisons

0

10

20

30

40

50

60

Clin Preg* Delivery* Losses*

LLL

ULDLF

11/21

9/21

2/21

%

* p < 0.001

3/5

2/11

5/21

Silverberg & Vaughn, ASRM, 1998

ULDLF Results: Previous

LLL Failures

0

10

20

30

40

50

60

TVA (%) Clin Preg (%) Delivery (%)

%

21/35

12/35

8/35

Silverberg & Vaughn, ASRM, 1998

Summary

Poor responders do poorly

Comparing LLL and ULDLF:

No differences in stimulation parameters

No differences in # embryos transferred

Yet significantly higher Preg/Deliv rates

Evaluating LLL Failures

60% TVA, 23% Delivered

Poor responders who fail LLL have excellent outcome with ULDLF

Poor responders who complete LLL have higher delivery rate with ULDLF

ULDLF represents a better option for poor responders than does the LLL protocol

Modified Micro-Dose Flare vs.

GnRH Antagonist

Flare (n=24) Antagonist (n=24) P

Day 3 FSH 9 10 NS

Cxl rate (%) 21 25 NS

# ampules 59 68 NS

Peak E2 1196 868 < 0.05

# oocytes 5.5 4.5 < 0.05

Fert (%) 81 72 NS

Preg/ET (%) 21.0 16.6 NS

Akman et al. Hum Reprod 2001;16:868

Poor Responders:

Agonist vs Antagonist

Conflicting Data:

P,R n=534; higher OPR with microdose

flare vs. Antagonist/Letrozole 1

P,R; higher OPR with antagonist 2

Meta analysis of 6 trials

No differences in cycle cxl, # oocytes,

pregnancy rate 3

1 Schoolcraft et al. Fertil Steril. 2007 2 Lainas et al. Hum Reprod. 2008 3 Franco et al. Reprod Biomed Online. 2006;13:618

Growth Hormone

IGF-1 augments response of rat granulosa cells to FSH in vitro

GH increases IGF-1 production

GH appears to sensitize ovary to exogenous gonadotropins

Unanswered Questions:

Optimal Dosage?

Are physiologic doses adequate?

Only effective in GH deficient individuals?

Adashi E, et al. Endocrin Rev 1985;6:400

Adjunctive Growth Hormone

Homburg

1990

Ibrahim 1991 Owen 1991 Shaker

1992

Levron

1993

Design P,R, Plac P P,R, Plac P R

N 16 10 13 10 7

Stim hMG LLL/hMG Long foll

GnRH/hMG

LLL/hMG FSH/hMG

Exog .

Gonad.

# Ooc

Peak

E2

No improvement in pregnancy rates

Growth Hormone: Larger Studies

Midluteal LA/hMG; P,R, placebo controlled (n=42); GH 12 IU/d days 1, 3, 5, 7 of hMG1

No differences: hMG dose, E2, #oocytes, #embryos, IGF-1 levels, preg rates

LLLA/hMG; P, R, placebo controlled (n=40)2

No differences: hMG dose, #oocytes

Microdose flare; Retro (n=32) 2

Higher E2, More oocytes, Fewer cxl; 50% OPR; patients previously canceled

1 Younis et al. Fertil Steril 1992;58:575-80 2 Bergh et al. Fertil Steril 1994;62:113-20 3Schoolcraft, et al. Fertil Steril 1997;67:93-7

GH: Cochrane Collaboration

9 studies (n=401)

Only 6 on poor responders (n=302)

Slight increase in LBR with GH

Conclusion: “Before recommending GH in

IVF, further research is necessary…GH

should only be considered in the context of

a clinical trial”…

Harper, et al. Published online 7/8/09; up to date as of 5/27/03

GH-Releasing Factor

P, R, placebo controlled; (n=196)

LLL, FSH

GRF 500µg BID (n=96) vs placebo (n=100) until hCG admin

Significant increases in:

GH and IGF-1 levels

No effect on:

Follicles >16mm, FSH dose, preg rate

Howles, et al. Hum Reprod 1999;14:1939-43

DHEA

Unknown mechanism

IGF mediated (increases IGF-1)

Suppressive effect on apoptosis

Synergy with gonadotropins

Possible reduction in aneuploidy

Effect peaks after 4-5 months of use

Several small retrospective studies show improvements in:

CXL rate, Oocyte #, Preg rate, time to pregnancy1

Improvement in oocyte production in poor responders2

Reduction in SAb incidence (retrospective, n=73, p<0.05)3

1Gleicher N. Repro Biol Endocrin 2011

2Barad D, Gleicher N. Fertil Steril 2005

3Gleicher N, et al. Repro Biol Endocrin 2009

DHEA

P, R trial, n=33 (51 cycles) a

75 mg/d DHEA

Delivery 23% vs. 4% (controls, p<0.05)

“We would like to present how insufficient the current evidence of acceptable quality is to warrant a conclusion that DHEA supplementation is an effective treatment for women with diminished ovarian reserve. More studies needed…” b

a Wiser, et al. Hum Reprod.2010;25:2496 b Yakin and Urman Hum Reprod Online, May 18,2011

Low Dose Aspirin

Retro (n=1250)

Study patients:

Higher AFC, longer stim, more

gonadotropin

Higher E2

Lower fert rate

NO DIFFERENCES in IR, OPR, SAB,

LBR Frattarelli J, et al. Fertil Steril 2008;89:1113-7

Assisted Hatching Schoolcraft (1994): Significantly improved

pregnancy rates in poor responders (64% vs. 19%)

Stein (1995): Significant improvement in pregnancy rates in women > 38 yo with 3 previous IVF failures (24% vs. 7%)

Tucker (1996): Significant improvement in clinical pregnancy rates, but no difference in delivery rates.

Meldrum, Silverberg (1998): Significant improvement in clinical pregnancy rates in women > 40 yo but no improvement in delivery rates.

Hellebaut (1996), Lanzendorf (1998): No differences in prospective, randomized trials

Donor

Oocytes

Conclusions

Day 3 FSH levels, AMH, antral follicle counts appear to be the best screening tests to identify poor responders

The Clomiphene Citrate Challenge represents a good dynamic screening test

Conclusions Probably Effective:

Micro dose flare

Possibly Effective

GnRH Antagonists

Recombinant FSH

CC/hMG

Letrozole

“Stop” GnRH protocol

Assisted Hatching

Growth Hormone

Conclusions

Probably Ineffective

High dose gonadotropins

Pulsatile gonadotropins

Adding LH

Flare protocols

GH-RH

Baby Aspirin

Inconclusive

DHEA

Definitely Effective:

Donor Oocytes!